Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: O=C(O)Cc1ccccc1F
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccccc1F
Temperature: 68 °C

Procedure:
To a stirred solution of 2-fluorophenylacetic acid (9.6 g, 62 mmol) in MeOH (100 mL) was added concentrated HCl (0.7 mL, 19 mmol). The solution was heated at 68° C. for 4 hours, and then the reaction was concentrated in vacuo to remove MeOH. The residue was dissolved in ether and then washed with saturated NaHCO3 solution (1×50 mL). The organic extracts were separated, dried with Na2SO4, filtered and concentrated to give a yellow oil (10 g). MS m/e=169.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13]C(=O)C.[OH-].[K+]>CCO.O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: COc1cc(OC)c(Cl)c(NC(C)=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(N)c1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a suspension of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-acetamide (f) (6.50 g, 24.61 mmol) in a mixture of EtOH (80 mL) and water (30 mL), KOH (20 g) is added, and the mixture is stirred 2 days at 80° C. After the solvent (EtOH) is removed under vacuum, water (˜15 mL) is added, and a white solid is collected by filtration and washed with water and dried to give final product g: 1H NMR 600 MHz (CDCl3) δ 6.03 (s, 1H), 4.55 (s, 2H), 3.88 (s, 6H); MS m/z 222.00 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl>[OH-].[Na+]>[CH2:12]([O:11][C:9]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
3-Azetidinecarboxylic acid (4.0 g, 39.6 mmol) was dissolved in 1N sodium hydroxide solution (40 mL) and cooled to 0° C. Benzyl chloroformate (5.9 mL, 41 mmol) was added followed by further 1N sodium hydroxide solution (41 mL) dropwise. The mixture was stirred vigorously for 16 hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2×100 mL) and the extracts dried over MgSO4. Concentration yielded the title compound (9.3 g, 39.6 mmol, 100%).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([OH:15])=O)[CH:12]=[C:7]2[CH:6]=[C:5]1[CH3:26])[CH:2]=[CH2:3].[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>>[CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([N:32]3[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]3)=[O:15])[CH:12]=[C:7]2[CH:6]=[C:5]1[CH3:26])[CH:2]=[CH2:3]
Reactant: CCN1CCNCC1
Reactant: C=CCn1c(C)cc2cc(C(=O)O)nc(N3CCc4ccccc4C3)c21
Product: C=CCn1c(C)cc2cc(C(=O)N3CCN(CC)CC3)nc(N3CCc4ccccc4C3)c21
Yield: 49 %

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 922 and 1-ethylpiperazine, the titled compound was obtained as a white solid. (Yield: 49%)
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH2:6][C:7]([I:11])=[C:8]([I:10])[I:9].[I-].[Na+]>CC(C)=O>[I:11][C:7](=[C:8]([I:10])[I:9])[CH2:6][S:1][C:2]#[N:3]
Reactant: ClCC(I)=C(I)I
Reactant: N#C[S-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#CSCC(I)=C(I)I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
9.14 g (0.113 mole) of sodium thiocyanate are dissolved in 200 ml of acetone; 51.4 g (0.113 mole) of 3-chloro-1,1,2-triiodo-1-propene are then added. In addition, 0.2 g of sodium iodide are also introduced as the catalyst. The reaction mixture is stirred at room temperature for 12 hours.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-oxo-3-phenylpropionate (28.6 g, 145 mmol) in 1,2-dimethoxyethane (1.50 ml) was added sodium hydride (60% in oil, 5.65 g, 141 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hr. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (33.8 g, 141 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 2 hrs. The reaction solution was poured into water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (45.4 g, 75%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[CH3:11][Si](C[Mg]Cl)(C)C.C(OCC)C>C1COCC1>[CH2:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH:9]=[CH2:11]
Reactant: O=CCCc1cccnc1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCc1cccnc1
Reaction time: 0.25 h

Procedure:
3-(Pyridin-3-yl)propanal (10 g, 74 mmol) is dissolved in THF (200 ml), and thereto is added a solution of trimethylsilylmethyl magnesium chloride in diethyl ether (100 ml, 100 mmol) under ice-cooling, and the mixture is stirred for 15 minutes. The reaction is quenched with a saturated brine (10 ml), and the mixture is extracted with ethyl acetate (300 ml×2), washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added THF (50 ml) and conc. sulfuric acid (5 ml), and the mixture is heated under reflux for 20 minutes. After being allowed to cool, the reaction solution is neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (200 ml×2). The organic layer is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(3-butenyl)pyridine (6.5 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:23](=O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][NH2:31])[CH3:29].N1C=CC=CC=1>C(O)C>[CH2:28]([O:30]/[N:31]=[C:23](\[C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)/[CH2:24][CH3:25])[CH3:29]
Reactant: CCON
Reactant: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCO/N=C(/CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-one (250 mg, 0.612 mmol), O-ethylhydroxylamine hydrochloride (179 mg, 1.84 mmol) and pyridine (1.5 mL) in ethanol (6.0 mL) was stirred at 80° C. for 26 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compounds as a colorless crystal respectively (E (Example 123): 111 mg, 0.246 mmol, 40%, Z (Example 124): 31.0 mg, 0.0686 mmol, 11%).
Reaction SMILES: N#N.[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCN(CC)CC>CN(C=O)C>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:3][C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.09 mmol) in dry DMF (25 mL) was added trimethylsilyl chloride (5.77 mL, 45.17 mmol) followed by Et3N (8.38 mL, 60.23 mmol) at rt. The reaction mixture was stirred at 80° C. for 24 h. The mixture was then cooled to rt, diluted with hexanes and washed with sat. aq. NaHCO3. The layers were separated and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes/EA, 9:1) to afford tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil. Rf (Hexanes/EA, 9:1)=0.50.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2cc(O)ccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl6-hydroxyindazole-3-carboxylate (1.457 g) which can be prepared according to the method described in Reference example 17, etc. was dissolved in dehydrated DMF (15.6 mL; manufactured by Kanto Chemical Co., Inc.), added with imidazole (1.425 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (4.06 mL), followed by stirring overnight at room temperature. The reaction solution was poured to a saturated aqueous solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with brine and insoluble matters were filtered using Celite. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=81:19→60:40) to obtain the title compound (1.467 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:13]([SH:24])=[N:14][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II>>[N:18]1([C:15]2[N:14]=[C:13]3[S:24][N:9]([CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:10](=[O:11])[C:12]3=[CH:17][N:16]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(NCCN1CCCCC1)c1cnc(N2CCOCC2)nc1S
Agent: II
Product: O=c1c2cnc(N3CCOCC3)nc2sn1CCN1CCCCC1
Yield: 50.3 %

Procedure:
Using the procedure of Example 20, 5.2 g (14.8 mmol) of 4-mercapto-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide were treated with 3.81 g (15.0 mmol) of iodine to give 2.6 g of the title compound after recrystallization from aqueous isopropanol, mp 98°-100° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:17]=4[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl[C:27]1[N:32]=[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]2[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:30]([Cl:45])=[CH:29][N:28]=1>>[Cl:45][C:30]1[C:31]([NH:33][C@@H:34]2[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]2[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[N:32][C:27]([NH:25][C:22]2[CH:23]=[CH:24][C:17]3[CH2:16][CH2:15][CH:14]([N:11]4[CH2:12][CH2:13][CH:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH2:9][CH2:10]4)[CH2:20][CH2:19][C:18]=3[CH:21]=2)=[N:28][CH:29]=1
Reactant: CN1CCN(C2CCN(C3CCc4ccc(N)cc4CC3)CC2)CC1
Reactant: CS(=O)(=O)NC1CCCCC1Nc1nc(Cl)ncc1Cl
Product: CN1CCN(C2CCN(C3CCc4ccc(Nc5ncc(Cl)c(N[C@@H]6CCCC[C@H]6NS(C)(=O)=O)n5)cc4CC3)CC2)CC1

Procedure:
The title compound was prepared from 7-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 179 heating at 140° C. Product was isolated as an off-white solid (10 mg, 9%). LCMS (m/e) 645 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 9.32 (m, 2H), 7.97 (s, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 7.06 (d, 1H, J=7.8 Hz), 6.95 (m, 1H), 3.38-2.82 (m, 8H), 2.94-3.02 (m, 8H), 2.67-2.77 (m, 8H), 2.33 (m, 2H), 1.95-2.06 (m, 4H), 1.72 (m, 4H), 1.15-1.44 (m, 8H).
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][CH2:7][C:8]([NH2:10])=[NH:9].[CH2:11]([O:13][CH2:14][C:15](=O)[CH2:16][C:17](OCC)=[O:18])[CH3:12]>CO>[CH2:11]([O:13][CH2:14][C:15]1[N:10]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=[C:17]([OH:18])[CH:16]=1)[CH3:12]
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: COCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOCc1cc(O)nc(COC)n1
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Sodium methylate (6.5 g, 0.12 mole) was added to a solution of methoxyacetamidine hydrochloride (6.23 g, 0.05 mole) and ethyl ethoxyacetoacetate (8.72 g. 0.05 mole) in methanol (50 ml) at room temperature, and the resulting white suspension liquor was stirred at 45° to 50° C. for 4 hours. The reaction mixture was treated in the same manner as in Example 5. Recrystallization from ether gave 8.5 g of 6-(ethoxymethyl)-4-hydroxy-2-(methoxymethyl)pyrimidine as white needle-like crystals (m.p. 96.5°-98° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[N:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[N:17]=[C:16]([N:24]3[CH2:48][CH2:47][C:27]4([CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:33])[CH:29]([C:42]([O:44]CC)=[O:43])[CH2:28]4)[CH2:26][CH2:25]3)[CH:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:49]2[CH:53]=[CH:52][C:51]([CH3:54])=[N:50]2)[CH:3]=1.C1COCC1.[Li+].[OH-]>O>[CH2:35]([O:34][C:32]([N:30]1[CH:29]([C:42]([OH:44])=[O:43])[CH2:28][C:27]2([CH2:26][CH2:25][N:24]([C:16]3[CH:15]=[C:14]([O:13][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N:49]4[CH:53]=[CH:52][C:51]([CH3:54])=[N:50]4)[C:9]([F:10])([F:11])[F:12])[N:19]=[C:18]([S:20]([CH3:23])(=[O:21])=[O:22])[N:17]=3)[CH2:48][CH2:47]2)[CH2:31]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)C1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(S(C)(=O)=O)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(S(C)(=O)=O)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.10 g, 2.65 mmol) in 2:1 THF:H2O (90 mL) was added LiOH (127 mg, 5.3 mmol), and the reaction was stirred at RT for 21 h, after which additional LiOH (65 mg, 2.6 mmol) was added, and the reaction was stirred for 8 h longer. The reaction was then quenched with 1 N HCl to pH<1, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([O:11]S(C(F)(F)F)(=O)=O)=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32): (500 mg, 0.938 mmol) in THF (5 ml) was added TBAF (1.0 M in THF, 4 ml) slowly. The reaction mixture was stirred at rt for 1 h. The reaction mixture was washed by a mixture of H2O (20 ml) and HOAc(200 ul), extracted by EtOAc, the organic phase was washed by sat. NaHCO3, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75A (380 mg). LCMS-ESI+: calc'd for C16H20BrNO4S: 402.0 (M+H+). Found: 401.9 (M+H+).
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[C@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23]
Reactant: [H][H]
Reactant: O=C(N[C@@H]1C(=O)N[C@H]1Oc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N[C@H]1Oc1ccccc1

Procedure:
(3S, 4S)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (140 mg, 0.45 mmole) is hydrogenated with 100 mg of 10% palladium on activated carbon in ethyl acetate (20 ml) at 50 psi hydrogen pressure at room temperature for 2 hours. After removal of catalyst by filtration, deprotected (3S, 4S)-3-amino-4-phenoxy-azetidin-2-one in ethyl acetate is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[C:23]#[N:24])=[CH:17][CH:16]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[C:23]#[N:24])=[CH:19][CH:20]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a 20 ml vial, 3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile (0.04 ml, 0.04 mmol) was dissolved in DCM (3 ml) and the reaction mixture was cooled to 0° C. TFA (2 ml, 0.0238 mole) was added drop wise at 0° C. and there reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated and the residue was neutralized by NaHCO3 to pH 7-8 and the aq. layer was extracted with EtOAc. The organic layer was evaporated and the residue was dissolved in methanol. HCl and water were added and the solution was stirred at RT overnight and then neutralized with NaHCO3 to pH7-8. The crude product which precipitated was filtrated, washed with water and dried. The crude product was dissolved in a mixture of EtOAC and CH2Cl2, loaded on TLC plate and flashed with EtOAc:hexane=85:15 to yield 0.014 g of 3-[4-[[7-(2,2-dimethylpropanoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[OH:16])(=[O:3])[CH3:2].[O-2].[Ba+2].[OH-].[Ba+2].[OH-].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([NH:4][C@H:5]1[C@@H:12]([O:13][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:11]([CH2:14][O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[O:16][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](NC(C)=O)[C@H]1O
Agent: [Ba+2]
Agent: [O-2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](NC(C)=O)[C@H]1OCc1ccccc1

Procedure:
Dissolve 15 g. of methyl 3-acetamido-3-deoxy-β-D-galactopyranoside in DMF (300 ml.). To the solution add barium oxide (111 g.) and barium hydroxide (51 g.) and cool to 0°. With rapid stirring add benzyl bromide (150 ml.) dropwise. Allow the mixture to stir for a further 4 hours at 0° and then 16 hours at room temperature. Dilute the reaction mixture with 750 ml. of chloroform and filter. Concentrate the filtrate at 60° in vacuo to a yellow syrup, and extract this syrup with 500 ml of ethyl acetate. Filter the extract and concentrate in vacuo to a residue. Dissolve the residue in chloroform (200 ml.), wash the solution with 3 × 100 ml. of water then dry the chloroform phase over MgSO4. Remove the MgSO4 by filtration, then add hexane to the filtrate till crystals appear. After standing to complete the crystallization, filter off the product and dry to obtain methyl 3-acetamido-3-deoxy-2,4,6-tri-O-benzyl-β-D-galactopyranoside, 29.53 g. m.p. 147°-151°, [α d26 +52.5°.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)COC1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)COC1CCC(N)CC1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
Tert-butyl 2-[4-(dibenzylamino)cyclohexoxy]acetate (6 g, 15 mmol, 1 eq.) was dissolved in methanol (200 mL) and pumped through the H-Cube® hydrogenation instrument containing a 10% Pd(OH)2 catalyst cartridge (CatCart) and using full hydrogen flow, ambient pressure, at 40° C. for 3 hours. The solvent was removed under vacuum to provide tert-butyl 2-(4-aminocyclohexoxy)acetate (3.3 g, 98%); (CI, m/z): [M+H]+ 230; 1H NMR (400 MHz, CDCl3): δ 3.99 (s, 2H), 3.31 (tt, J=10.7, 4.2 Hz, 1H), 2.71 (tt, J=10.8, 3.9 Hz, 1H), 2.00-2.11 (m, 2H), 1.83-1.93 (m, 2H), 1.46-1.51 (m, 9H), 1.29-1.44 (m, 4H), 1.06-1.19 (m, 2H).