Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C@@H:6]([NH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=1)[CH2:7][CH2:8][CH3:9])[CH3:2].C1C[O:23][CH2:22]C1>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C@@H:6]([N:10]1[C:11]2=[N:12][C:13]([CH3:18])=[CH:14][CH:15]=[C:16]2[NH:17][C:22]1=[O:23])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)Nc1nc(C)ccc1N
Reactant: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of (S)-3-(3-amino-6-methyl-pyridin-2-ylamino)-hexanoic acid ethyl ester (350 mg, 1.32 mmol) in THF (10 mL) was added N,N′-carbonyldiimidazole (CDI) (321 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 247 mg (64%) of the title compound as a light brown oily residue. LCMS, M++1, m/z: 292.59.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 mL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). δH (DMSO-d6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J 1.1 Hz), 0.00 (6H, d, J 1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:39]/[C:40](/[CH3:47])=[CH:41]\[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:40]([CH3:47])[NH:39][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25]1)=[O:16]
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(Cl)c1Cl
Yield: 30.7 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl ethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 87°-89° C. (sintering). Yield 30.7%. IR(Nujol)cm-1 : 3335, 1695, 1680. NMR(CDCl3) δ: 1.15(3H, t,J=7,--CH2CH3), 3.25(6H,s, ##STR18## 4.16(1H,s,>N--CH<), 5.41(1H,s,C(4) --H), 5.96(1H,s,NH).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+]=[N-])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.O>CCOCC>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][NH2:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN)nn23)CC1

Procedure:
A solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.200 mmol) and Ph3P (0.063 g, 0.240 mmol) in 9:1 THF/H2O (5 mL) stirred at rt for 1 h and at 45° C. for 4 h. Then, diluted with Et2O (25 mL) and extracted with 0.5M HCl (2×5 mL). The combine aqueous layers neutralized with sat Na2CO3 and extracted with CH2Cl2 (2×20 mL). The combine CH2Cl2 layers dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as viscous pale yellow oil which was used in the subsequent step without purification. To a stirred solution of 2-allylbenzoic acid (0.065 g, 0.400 mmol) in CH2Cl2 (5 mL) containing cat. DMF was added 2M oxalyl chloride/DCM (0.400 ml, 0.801 mmol) at rt. After 1 h, concentrated and the resulting residue was re-dissolved in CH2Cl2 (3 mL) and added to a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and DIEA (0.105 ml, 0.600 mmol) in CH2Cl2 (2 mL) at rt. After 2 h the reaction was quenched with a drop of MeOH, concentrated and purified prep-HPLC to afford (S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.059 g, 0.096 mmol, 47.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.2, 7.7 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.30 (m, 3H), 6.46-6.53 (m, 1H), 6.49 (s, 1H), 5.98-6.06 (m, 1H), 5.83-5.98 (m, 2H), 5.39 (dd, J=1.6, 17.2 Hz, 1H), 5.14 (d, J=9.8 Hz, 1H), 5.06 (qd, J=1.5, 10.1 Hz, 1H), 5.01 (qd, J=1.7, 17.2 Hz, 1H), 4.84 (d, J=5.4 Hz, 2H), 4.15-4.28 (m, 2H), 3.97 (d, J=4.6 Hz, 2H), 3.64 (d, J=6.3 Hz, 2H), 2.61 (s, 3H), 1.98 (d, J=13.2 Hz, 1H), 1.84-1.94 (m, 2H), 1.70 (d, J=9.3 Hz, 1H), 1.31 (s, 3H), 1.21-1.26 (m, 12H). LCMS (M+H)=618.5.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][C@H:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][O:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 120 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (238.2 mg, 0.8157 mmol) and tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge, 203.9 mg, 0.7600 mmol) was added EtOH (3.0 mL), followed by DIPEA (539.5 mg, 4.174 mmol). The mixture was stirred at 120° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (227.1 mg, 69%). LCMS calc. for C18H24F3N4O5 (M+H)+: m/z=433.2. found 433.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH2:22][CH3:23])[N:15]=2)[CH:3]=1.CO.[NH3:26]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:26])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH2:22][CH3:23])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Solvent: CO
Product: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 40 °C
Yield: 100 %

Procedure:
A mixture of ethyl 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (147 mg, 439 μmol) in ammonia in methanol (7 N, 6.27 mL, 43.9 mmol) was heated to 40° C. for 16 h. The mixture was concentrated in vacuo to give 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (134 mg, 438 μmol, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (s, 1H), 9.16 (s, 1H), 8.82 (s, 1H), 8.18 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 2.69 (t, J=7.3 Hz, 2H), 2.29 (s, 3H), 1.76 (m, 1H), 0.95 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 305.9 [M+H].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([OH:31])[CH:25]=2.[C:32]([C@@H:36]1[CH2:41][CH2:40][C@H:39](O)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33].C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:32]([C@H:36]1[CH2:41][CH2:40][C@H:39]([O:31][C:26]2[CH:25]=[C:24]3[C:29]([CH:30]=[C:21]([CH3:20])[N:22]=[CH:23]3)=[CH:28][CH:27]=2)[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1cc2ccc(O)cc2cn1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2cn1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (5.14 g, 19.6 mmol) was added to a solution of 3-Methyl-isoquinolin-7-ol (2.08 g, 13.1 mmol) and cis-4-tert-butylcyclohexanol (3.06 g, 19.6 mmol) in Toluene (60 mL, 600 mmol). The mixture was stirred for 15 minutes then Diisopropyl azodicarboxylate (3.86 mL, 19.6 mmol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under vacuum. The crude product was dissolved in methylene chloride, adsorbed onto silica gel and purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound in 52% yield. ESI-MS (M+H+): 298.46.
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(O)(=O)C.S(Cl)([Cl:33])(=O)=O>C(Cl)Cl>[Cl:33][C:19]1[CH:18]=[C:17]([O:16][C:15]([F:24])([F:25])[F:14])[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
0.05 part by weight of diphenyl sulfide is added to a solution of 8.9 parts by weight of 4-trifluoromethoxyphenol in 30 parts by weight of glacial acetic acid, and 6.8 parts by weight of sulfuryl chloride are then added dropwise, without cooling. The mixture is subsequently stirred at room temperature for 3 hours, the solvent is stripped off and the residue is taken up in 50 parts by weight of methylene chloride. This solution is twice washed with 50 parts by weight of saturated bicarbonate solution, and is dried and concentrated. Distillation of the residue under reduced pressure gives 9.8 parts by weight (92% of theory) of 2-chloro-4-trifluoromethoxyphenol of boiling point 70° C./13 mbar.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:37])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:36])=[O:35])[CH:5]=[CH:6][CH:7]=1.[N:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C@@H:17]([NH:16][C:11]1[O:12][C:13]([CH3:14])([CH3:15])[C:8]([CH3:37])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:42]3[CH:43]=[N:38][CH:39]=[N:40][CH:41]=3)[CH:3]=2)[S:9](=[O:36])(=[O:35])[N:10]=1)[CH2:18][CH2:19][OH:20]
Reactant: OB(O)c1cncnc1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 34.5 %

Procedure:
Under inert gas, 45 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine, 11 mg of pyrimidine-5-boronic acid and 96 mg of cesium carbonate were dissolved in a mixture of 1 ml of dioxane and 0.4 ml of water. After purging with argon for 10 minutes, 6 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried using a diatomaceous earth cartridge (Varian Chem Elut®) and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 1.5 ml of methanol, 0.18 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 2.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (12.6 mg) with a molecular weight of 498.6 g/mol (C25H27N4O4S); MS (ESI): m/e=499 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22]O>S(=O)(=O)(O)O>[CH3:22][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 36 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 97/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1052.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC1>C(OCC)C>[CH:10]([NH:23][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCBr
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1

Procedure:
19.5 g of ethyl 4-bromobutyrate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 12 days. The resultant crystal paste is diluted with diethyl ether, filtered at the pump and the filtrate concentrated by evaporation. The residue (after evaporation) is distilled in vacuo. The first run which distils over at 100° to 110° (0.02 mm Hg) is excess benzhydrylamine. The main distillate obtained is 21.1 g (71% of theory) of ethyl 4-benzylhydrylaminobutyrate [B.P. 150° to 155° (0.02 mm Hg)].
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[N:25]=[C:26]2[N:31]([C:32](=[O:42])[C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:30][CH2:29][O:28][C:27]2([CH3:44])[CH3:43])=[O:23])(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+].O>CN(C=O)C>[N:45]([CH2:6][C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[N:25]=[C:26]2[N:31]([C:32](=[O:42])[C:33]=1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:30][CH2:29][O:28][C:27]2([CH3:43])[CH3:44])=[O:23])=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1COS(C)(=O)=O)c(OCc1ccccc1)c2=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(OCc1ccccc1)c2=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
To a solution of intermediate 194, (R)-(1-(2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methyl methanesulfonate (0.150 g, 0.239 mmol) in DMF (10 mL) was added sodium azide (0.019 g, 0.287 mmol). The resulting mixture was stirred at 50° C. for 6 h. Water (50 mL) was then added and the organic material was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.125 g, 91% yield). LCMS (M+H)+ m/z 576.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>C(OCC)C>[Br:22][CH:23]([CH3:27])[C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: CC(Br)C(=O)Cl
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Solvent: CCOCC
Product: CC(Br)C(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in 2-bromopropionyl chloride (8.5 g, 5 ml, 0.05 mol) by heating for 30 minutes on a 100°-110° C. oil bath. The reaction mixture was cooled, 20 ml of ethyl ether were added, and the resultant solution was extracted with aqueous potassium carbonate, dried and then crystallized. The product was obtained as a solid white substance (1 g, 34%), m.p. 112°-115° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.77; H, 4.15; N, 6.69; Br, 19.25. The product has the formula: ##STR1608##
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[CH3:12][C:13]([CH3:15])=[O:14]>C1COCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:13]([OH:14])([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1nccs1
Temperature: -20 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
2-Bromothiazole (12.00 g, 73.2 mmol) was taken up in THF (150 mL) and cooled to −20° C. Isopropylmagnesium chloride (2.0 M in THF, 38.4 mL, 77 mmol) was added dropwise. After stirring for 1 h (−10° C. to 0° C.), the reaction was cooled to back −20° C., and acetone (5.10 g, 88 mmol) was added dropwise. The reaction was stirred for 30 min at −20° C. then warmed to room temperature. After 2 h at room temperature, the reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography (0-50% ethyl acetate in hexanes) to afford 8.97 g (86%) of 2-(1,3-thiazol-2-yl)propan-2-ol as a pale yellow low-melting solid. MS ESI: [M+H]+ m/z 144.0.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][NH:27][CH:28]=O)=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=2)[N:4]=1)[CH3:2].C[Si](C)(C)O[Si](C)(C)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:48]>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[S:48][CH:28]=[N:27][N:26]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC=O)ccn34)c12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5nncs5)ccn34)c12
Temperature: 110 °C
Yield: 4.2 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-formylhydrazinecarbonyl)imidazo[1,2-a]pyridine-3-carboxamide (36 mg, 0.073 mmol) in toluene/dioxane (1 mL/1 mL) was added hexamethyldisiloxane (71 mg, 0.44 mmol) and P2S5 (81 mg, 0.36 mmol). The reaction mixture was sealed and heated in a microwave reactor to 110° C. for 3 hours. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the final product (1.5 mg). MS (ES+APCI) m/z=495 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:29])[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:16][CH3:17])[CH2:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:29])[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C@H:15]([NH3+:18])[CH2:16][CH3:17])[CH2:10][C:9]2([CH3:28])[CH3:27])=[CH:6][CH:7]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]([NH3+])C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Product: [Cl-]

Procedure:
tert-Butyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-1-oxobutan-2-ylcarbamate (200 mg, 0.46 mmol) and 4 N Hydrochloric acid in dioxane (8 mL) was stirred at rt for 2 hrs. The reaction mixture was then concentrated and dried under high vacuum to yield the product, which was used in next step without further purification.