Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C@H:7]([CH2:20][OH:21])[CH2:6]1)[CH2:2][CH2:3][CH3:4].F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.CC(C)([O-])C.[K+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:51].Cl.Cl>CN(C)C=O.CC(C)=O>[ClH:51].[ClH:51].[CH2:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[C@H:7]([CH2:20][O:21][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](CO)C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1

Procedure:
The piperidine base was prepared as described above from (±)-trans-1-butyl-3-hydroxymethyl-4-(4-dimethylaminophenyl)piperidine and 4-fluorobenzotrifluoride in dimethyl formamide with potassium tert-butoxide. The dihydrochloride was precipitated from an acetone solution by addition of 2.2 equivalents of conc. hydrochloric acid. The filtrate was evaporated at reduced pressure and the residue redispensed in acetone giving in all about 90% of the dihydrochloride. M.p. 211°-215° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)(C)C.S(=O)(O)[O-].[Na+].[NH2:20][C:21]1[CH:22]=[C:23]([C:34]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:45]([NH2:56])[CH:44]=2)([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])[CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.C(O)C>[F:36][C:35]([F:37])([F:38])[C:34]([C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:20][C:21]=2[CH:22]=1)([C:43]1[CH:48]=[CH:47][C:46]2[N:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([C:6]#[CH:5])[CH:8]=3)=[N:56][C:45]=2[CH:44]=1)[C:39]([F:40])([F:41])[F:42]
Reactant: Nc1cc(C(c2ccc(Nc3ccccc3)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Reactant: C[Si](C)(C)C#Cc1cccc(C=O)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#Cc1cccc(-c2nc3cc(C(c4ccc5c(c4)nc(-c4cccc(C#C)c4)n5-c4ccccc4)(C(F)(F)F)C(F)(F)F)ccc3n2-c2ccccc2)c1

Procedure:
The exact procedure described above (high dilution and dropwise addition) was repeated for 26.0 g of the aldehyde (VI), 110 g of sodium bisulfite, and 30.0 g of the tetramine (V) in a total volume of 4.5 L of 1:5 water-ethanol. At the end, the powdery end product (VIII) was fractionated by Soxhlet extraction into an ether-insoluble portion (high oligomers) and an ether-soluble portion (20.0 g, 46.9%). The latter material, when tested on the Kofler hot bench at 250° C., showed a gel time of about 3 minutes.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:14][CH2:19][CH2:18][O:17][CH3:16]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N)c(Cl)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.00 g, 25 mmol) in anhydrous dimethylformamide (40 mL) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (4.03 g, 20 mmol), stirred for 30 minutes, then treated with 2-bromoethyl methyl ether (3.48 g, 25 mmol). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (250 mL). The aqueous suspension was filtered, and the solid was washed with water, air dried, collected, and recrystallized from ether/hexane to afford 2.75 g (53%) of the title compound; mp 121.0°-122.5° C.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16](=[O:21])[C@@H:17]([CH3:20])[CH2:18][OH:19].O>CN(C)C=O>[CH3:14][O:15][C:16](=[O:21])[C@@H:17]([CH3:20])[CH2:18][O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Imidazole (13.3 g, 196 mmol) and tert-butyldimethylsilyl chloride (14.2 g, 94.1 mmol) were added to a solution of (S)-3-hydroxy-2-methylpropionic acid methyl ester (11.0 g, 93.1 mmol) in dimethylformamide (100 mL), and the mixture was stirred at room temperature for four hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was then dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 24 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)OC(C)(C)C)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate H) (9.5 g, 29.3 mmol) and K2CO3 (2.5 eq, 10.31 g, 73.3 mmol) in a round bottom flask is treated with dry DMF. tert-Butyl bromoacetate (1.02 eq, 4.2 ml, 30 mmol) is added dropwise via syringe under argon. The reaction suspension is stirred at RT for 1 hour. The reaction mixture is diluted with distilled water and extracted with EtOAc (3×). The separated organic layer is dried over MgSO4, filtered and the solvent is concentrated in vacuo. The title compound is obtained as a brown viscous oil, crystallizing on standing.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[CH3:7]>>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNC1
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCC2)cc1

Procedure:
A solution of 500 ml. of 50% aqueous pyrrolidine is treated in portions with 30.0 g. of 4-acetylbenzenesulfonyl chloride and the solution is stirred at room temperature for 1 hour. The resulting mixture is cooled to 0°-5° C. and the precipitated 1-(4-acetylbenzenesulfonyl)pyrrolidine is collected by filtration, washed with water and dried; m.p. 138°-139° C. after crystallizations from aqueous methanol and from 2-propanol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[CH2:40](O)[CH2:41][CH2:42][OH:43].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:43]1[C:2]2([CH2:7][CH2:6][CH:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]5[NH:32][C:31](=[O:33])[O:30][N:29]=5)=[CH:20][CH:21]=4)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]4[N:37]=[CH:38][N:39]=[C:9]34)[CH2:4][CH2:3]2)[O:1][CH2:40][CH2:41][CH2:42]1
Reactant: OCCCO
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCCO3)c2ncnn12
Yield: 39.2 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.20 g), propane-1,3-diol (0.058 g), 4-methylbenzenesulfonic acid (0.0072 g) and toluene (20 mL) was heated under reflux for 3 hr using a Dean-Stark trap. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.087 g, 39%).
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.Cl.[NH:49]1[CH2:54][CH2:53][CH:52]([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:65]=[C:56]1[C:55]([CH:52]2[CH2:53][CH2:54][N:49]([C:1]([O:2][C@H:3]([CH2:18][C:19]3[CH:27]=[C:26]([CH3:28])[C:25]4[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[N:24]=4)[CH:20]=3)[C:4](=[O:17])[N:5]3[CH2:10][CH2:9][CH:8]([N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]4)[CH2:7][CH2:6]3)=[O:37])[CH2:50][CH2:51]2)=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[NH:57]1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (89.5 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (0.16 mL, 0.90 mmol), and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 102 mg (60%) as a colorless film. Mass spec.: 755.53 (MH)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].O>B(F)(F)F.CCOCC>[C:1]([C:16]1[C:17]([OH:19])=[CH:18][C:9]([OH:8])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(O)cc1O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(C(C)=O)c(O)cc1O
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Acetic anhydride (3.06 g, 30.0 mmol) was added to methyl 2,4-dihydroxybenzoate (5.04 g, 30.0 mmol) in boron trifluoride diethyl etherate (7.6 ml) and the mixture was stirred and held at reflux for 3 hours and then allowed to cool to room temperature. Water (80 ml) was added and the mixture stirred at room temperature for 30 minutes. The resulting yellow solid was removed by filtration and sucked as dry as possible under vacuum. The solid was dissolved in dichloromethane and was washed with water, the organic layer was separated and the solvent removed in vacuo to afford methyl 5-acetyl-2,4-dihydroxybenzoate as a bright yellow solid (2.62 g, 42%) which was used without further purification. 1H NMR (DMSO-d6) 12.58 (1H, s), 11.22 (1H, s), 8.33 (1H, s), 6.45 (1H, s), 3.90 (3H, s), 2.62 (3H, s). MS: [M+H]+ 211.
Reaction SMILES: O1CC[C@@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@@H:36]([N:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@H](CN(C(=O)O)[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (116 mg, 0.251 mmol) was suspended in 8 mL anhydrous CH2Cl2 and gently heated until an homogenous solution was formed. After the reaction was cooled to room temperature, a 2.0 M solution of HCl in Et2O (0.126 mL, 0.251 mmol) was added in one portion. The reaction mixture was diluted with 25 mL Et2O, and the product precipitated from solution. The reaction was stirred for an additional 30 minutes before the solid was filtered and dried to obtain (R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride as a light yellow solid (99 mg, 70%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=7.7 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.42-7.49 (m, 3H), 6.97-7.08 (m, 2H), 5.08 (dd, J=6.1, 4.6 Hz, 1H), 4.52-4.54 (m, 2H), 3.66-3.78 (m, 3H), 3.58-3.60 (m, 1H), 3.48 (t, J=10.7 Hz, 1H), 3.23 (t, J=11.5 Hz, 1H), 3.00 (t, J=6.3 Hz, 2H), 2.53 (s, 3H), 2.05-2.14 (m, 1H), 1.80-1.91 (m, 4H), 1.72 (d, J=9.0 Hz, 1H), 1.34-1.43 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[C:17]([F:27])[C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:37]([O:39][C:40](=[O:43])[CH2:41]Br)[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][O:36][C:31]1[CH:30]=[C:29]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[C:17]([F:27])[C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:34]=[CH:33][C:32]=1[F:35])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CC(c1ccc(-c2ccc(F)c(O)c2)cc1Cl)C(O)(c1cc(F)c2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1cc(-c2ccc(C(C)C(O)(c3cc(F)c4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 1, step 5, 6-[2-(3-chloro-4′-fluoro-3′-hydroxy-biphenyl-4-yl)-1-hydroxy-1-trifluoromethyl-propyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with ethylbromoacetate and cesium carbonate to give the title compound as a colorless foam. MS (m/e)=614.2 [M+H+].
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]1[N:15]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]4[N:20]=[C:21]([NH2:23])[S:22][C:18]=4[CH:17]=3)[CH:13]=[N:12][CH:11]=1)[CH2:2]2.[C:26](OC(=O)C)(=[O:28])[CH3:27].[Al]>N1C=CC=CC=1>[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]1[N:15]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]4[N:20]=[C:21]([NH:23][C:26](=[O:28])[CH3:27])[S:22][C:18]=4[CH:17]=3)[CH:13]=[N:12][CH:11]=1)[CH2:4]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(-c3cncc(N4CC5CCC(CC5)C4)n3)cc2s1
Agent: [Al]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(-c3cncc(N4CC5CCC(CC5)C4)n3)cc2s1
Reaction time: 4 h
Yield: 2.8 %

Procedure:
6-(6-(3-aza-bicyclo[3.2.2]nonan-3-yl)pyrazin-2-yl)benzo[d]thiazol-2-amine was dissolved in 0.5 mL dry pyridine in a Biotage high recovery microwave vessel with a stirbar and treated with acetic anhydride (0.020 ml, 0.22 mmol). The vessel was swept with Ar, sealed and place into a 60° C. aluminum heat transfer block. The reaction was stirred for 4 h and cooled. The solution was treated with Si Carbonate (0.31 g, 0.22 mmol) (loading=0.69 mmol g−1), and the slurry was stirred at room temperature for 30 minutes. The slurry was filtered, and the silica was washed with dry pyridine (3 mL). The solvent was removed in vacuo to afford N-(6-(6-(3-aza-bicyclo[3.2.2]nonan-3-yl)pyrazin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.0024 g, 2.8% yield). 1H NMR (400 MHz, Pyr) δ ppm 1.22-1.41 (m, 8H) 1.76 (br. s., 2H) 2.06 (s, 3H) 3.57 (d, J=4.21 Hz, 4H) 7.85 (d, J=8.51 Hz, 1H) 8.12 (dd, J=8.41, 1.86 Hz, 1H) 8.13 (s, 1H) 8.48 (s, 1H) 8.71 (d, J=1.66 Hz, 1H) 13.58 (br. s., 1H). HPLC-MS: retention time=2.18 min (95%@215 nm; 97% @254 nm; m/z=394.2, calculated for C21H23N5OS+H+=394.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:20])C(Cl)(Cl)Cl)[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:20])[N:27]([CH3:28])[CH3:26])[CH:12]=[C:11]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)N(C)C)cn1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(trichloroacetyl)-1H-pyrrole-2-carboxylate (97 mg, 0.23 mmol) in THF (2 mL) was added dimethylamine (50 μL, 0.75 mmol). The reaction mixture was stirred at room temperature. After completion (2.5 days, monitored by LCMS) a saturated aqueous solution of ammonium chloride (25 mL) was added and the mixture extracted with CH2Cl2 containing 20% of propan-2-ol (5×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give crude product mixture that was purified using flash chromatography (Biotage SP4, 12 g cartridge; 0-10% MeOH gradient in CH2Cl2) to give methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylate (45 mg, yield 56%). 1H NMR (400 MHz, d6-acetone): δ 3.12 (br s, 6H), 3.70 (s, 3H), 5.97 (s, 2H), 7.19 (d, 1H, J 2.0 Hz), 7.48 (d, 1H, J 1.9 Hz), 7.62-7.66 (m, 2H), 8.08-8.13 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[H-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.N1NC(=O)C=CC=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:7]=1
Reactant: ClCc1cccnc1
Reactant: O=c1ccc(Cl)n[nH]1
Agent: Cl
Agent: O=c1cccn[nH]1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=c1ccc(Cl)nn1Cc1cccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
6-chloro-2H-pyridazine-3-one (1.00 g) was dissolved in DMF (76 mL). To this solution, 60% sodium hydride (370 mg) was added at room temperature in an argon atmosphere and the mixture was vigorously stirred at 50° C. Meanwhile, 60% sodium hydride (370 mg) was added to a solution of 3-(chloromethyl)pyridine hydrochloride (1.51 g) in DMF at −40° C. in an argon atmosphere and the solution was allowed to warm to room temperature. Using a cannula, this solution was poured into the pyridazinone solution and the mixture was stirred first at 50° C. for 90 min and then at room temperature for 18 hours. Subsequently, a saturated ammonium chloride solution was added and the solvent was concentrated. Water was then added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification by silica gel column chromatography (ethyl acetate: petroleum ether=7:3, followed by methanol:ethyl acetate=5:95) afforded the title compound as a colorless powder (1.30 g).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.O>[CH2:29]([O:28][CH2:27][CH:22]1[CH2:23][CH2:24][N:20]([CH3:19])[C:21]1=[O:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCOCc1ccccc1
Reactant: CN1CCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CN1CCC(COCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M) (13.75 ml, 22 mmol) was added dropwise into a solution of diisopropylamine (3.08 ml, 22 mmol) in tetrahydrofuran (50 ml) with ice-cooling. After stirring at 0° C. for 30 minutes, it was cooled to −78° C., and then a solution of 1-methylpyrrolidin-2-one (1.98 g, 20 mmol) in THF (20 ml) was added dropwise. After stirring at −78° C. for 30 minutes, a solution of benzyl chloromethyl ether (3.76 g, 24 mmol) in THF (30 ml) was added dropwise. After stirring at −78° C., water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane; 4/1) to give the title compound (4.14 g, 94%) as a colorless oily matter.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[CH2:14][N:13]1[C:30](=S)[CH2:31][C:32](=[N:34][N:35](C(OC(C)(C)C)=O)[CH3:36])[CH3:33])=[O:11].C(OC(C)=O)(C)C>ClCCl>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:29])[F:27])(=[O:19])=[O:18])[CH2:14][N:13]1[C:30]1[N:35]([CH3:36])[N:34]=[C:32]([CH3:33])[CH:31]=1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=NN(C)C(=O)OC(C)(C)C
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.7 %

Procedure:
Trifluoroacetic acid (61 ul, 0.8 mmol) was added to a solution of (2S,4R)-1-[3-(tert-butoxycarbonyl-methyl-hydrazono)-thiobutyryl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (90 mg, 160 umol) in dichloromethane (0.3 ml) under an argon atmosphere. The mixture was stirred at ambient temperature for 72 h. Ice water/10% aqueous sodium carbonate solution 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted four more times with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc) to obtain the title compound (20 mg, 46 umol; 29%) as yellow solid. MS (ESI): m/z=432.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C@@H:14]3[CH2:18][CH2:17][NH:16][C:15]3=[O:19])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:20]1(CO)C=CC=C[CH:21]=1.BrC1C=CC(F)=NC=1.O[C@H]1CCNC1=O>>[CH2:5]([O:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C@@H:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:9][CH:8]=1)[C:4]1[CH:1]=[CH:3][CH:2]=[CH:21][CH:20]=1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)nc1
Reactant: OCc1ccccc1
Agent: Fc1ccc(Br)cn1
Agent: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(OCc2ccccc2)nc1

Procedure:
Following the sequence described for (R)-3-[6-(2-cyclopropyl-ethoxy)-pyridin-3-yloxy]-pyrrolidin-2-one, the title compound was prepared from phenyl-methanol, 5-bromo-2-fluoro-pyridine and (S)-3-hydroxy-pyrrolidin-2-one. MS ESI+: m/z=285 [M+H]+.