Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH:22]=[O:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C=O)C1
Temperature: -78 °C

Procedure:
To 40 mL dry DCM was added 2.19 mL (30.8 mmol) DMSO. The solution was cooled to −78° C. under nitrogen and 1.95 mL (23.1 mmol) oxalyl chloride was added dropwise. A solution of 2.88 g (15.4 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 20 mL dry DCM was added quickly via syringe followed by 10.5 mL (77 mmol) triethylamine. The mixture was allowed to warm to room temperature and then quenched by extraction with 1 M HCl (2×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the product which was used in the next step without further purification.
Reaction SMILES: [O-:1][S:2]([O-:5])(=O)=O.[Na+].[Na+].[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([NH2:18])[CH:12]=1.[CH3:20]CN(CC)CC.[Na+].[Cl-]>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([NH:18][S:2]([CH3:20])(=[O:5])=[O:1])[CH:12]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)([O-])[O-]
Reactant: COC(=O)c1ccc(Br)c(N)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add Na2SO4 (0.12 mmol) to a suspension of 4-Bromo-3-amino-benzoic acid methyl ester (0.1 mmol) and Et3N (0.1 mmol) in dichloromethane at 0° C. Stir 4 h at RT. Add a saturated solution of NaCl (15 mL), and extract with dichloromethane (2×50 mL). Dry over NaSO4, filter and evaporate to dryness. Purify the residue utilizing flash chromatography (Silica gel-hexane/EtOAc) to provide the title compound.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[C:4](=O)[O:3]1.[NH2:20][OH:21]>C1COCC1>[OH:6][CH:5]([CH:7]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1)[C:4]([NH:20][OH:21])=[O:3]
Reactant: CC1(C)OC(=O)C(C2Sc3ccccc3NC2=O)O1
Reactant: NO
Solvent: C1CCOC1
Product: O=C(NO)C(O)C1Sc2ccccc2NC1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The crude 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-4H-benzo[1,4]thiazin-3-one (0.036 mmol) is dissolved in 0.5 mL of THF and 0.5 mL of NH2OH (1N in MeOH) is added to the mixture. After the addition, the mixture is stirred at 60° C. for 3 hours. The solvent is then removed under vacuum and the residue is purified by preparative thin layer chromatography (silica gel, 10% MeOH/CH2Cl2) to provide the title compound 2,N-dihydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetamide. Yield: 70%. 1H NMR (400 MHz, MeOD) δ 7.30 (dd, 1H, J=1.29 Hz, J=8.0 Hz), 7.18, (dt, 1H, J=1.3 Hz, J=8.0 Hz), 7.01 (dt, 1H, J=1.3 Hz, J=8.0 Hz), 6.95 (dd, 1H, J=1.3 Hz, J=8.0 Hz), 4.74 (d, 1H, J=3.80), 3.97 (d, 1H, J=3.8). MS: (ES+): 255.1[M+1].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28](Br)([CH3:30])[CH3:29]>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:28]([CH3:30])[CH3:29])[N:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1n[nH]c2ccccc12
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
A solution of N-(1-benzylpiperidin-4-yl)-indazole-3-carboxamide (3.34 g, 10.0 mmol) in dry DMF (70 ml) under argon atmosphere was added sodium hydride (0.25 g, 10.0 mmol) and stirred at room temperature for 3 h. The mixture was added isopropylbromide (1.37 g, 11.0 mmol) and stirred for additional 24 h. The reaction mixture was evaporated in vacuo and the residue added EtOAc (100 ml). The organic layer washed with brine (50 ml) and H2O (2×50 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave an oil that solidified upon standing. The oil was separated with flash chromatography (SiO2, Et2O/Hexane (2:1) to leave the product as a solid (1.22 g, 32.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]([OH:29])([CH3:28])[CH2:22]OS(C)(=O)=O)=[CH:15][C:14]=1[C:31]([F:34])([F:33])[F:32])#[N:12].Cl.C>O.C(O)(C)C>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]([OH:29])([CH3:28])[CH2:22][S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:14]=1[C:31]([F:32])([F:34])[F:33])#[N:12]
Reactant: Fc1ccc(S)cc1
Reactant: CC(O)(COS(C)(=O)=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(O)(CSc1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, to a solution of 25.6 g (0.20 mol) of 4-fluorthiophenol in 500 ml of isopropanol 8.4 g (0.20 mol) of sodium hydroxide in 400 ml of water was added. The mixture was stirred at 25° C. for 2 h, then 58.6 g (16 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2-hydroxy-3-(methanesulfonyloxy)-2-methyl-propionamide in 500 ml of isopropanol was added. Then the mixture was stirred at 25° C. for 5 h, then the pH was adjusted to neutral with concentrated hydrochloric acid and treated with charcoal at reflux temperature. Most of the isopropanol was evaporated in vacuum and 250 ml of 2% aqueous sodium hydroxide solution was added to the residue under vigorous stirring, then the crystalline mixture was left for 1 h, then filtered and washed with water. The dried crystals were recrystallized from a 1:4 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: CS(N)(=O)=O.C1(S(N)(=O)=O)CC1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:40]1([C:43]2[C:44]([O:53][CH:54]3[CH2:59][CH2:58][C:57]([F:61])([F:60])[CH2:56][CH2:55]3)=[CH:45][C:46]([F:52])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[CH2:42][CH2:41]1.[N:62]1([S:66]([NH2:69])(=[O:68])=[O:67])[CH2:65][CH2:64][CH2:63]1>>[N:62]1([S:66]([NH:69][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH:40]3[CH2:41][CH2:42]3)[C:44]([O:53][CH:54]3[CH2:59][CH2:58][C:57]([F:60])([F:61])[CH2:56][CH2:55]3)=[CH:45][C:46]=2[F:52])(=[O:68])=[O:67])[CH2:65][CH2:64][CH2:63]1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with cyclopropanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.092 g, 46%): 1H NMR (300 MHz, DMSO-d6) δ 11.58 (br s, 1H), 7.14-7.06 (m, 2H), 4.80 (br s, 1H), 4.00 (t, J=7.7, 7.7 Hz, 4H), 2.18-1.87 (m, 11H), 0.89-0.82 (m, 2H), 0.67-0.61 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −92.0 (d, J=232 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −112.7 (s, 1F); MS (ES−) m/z 431.1 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.[CH:35]1[CH:40]=[C:39]2N=N[N:43](O)[C:38]2=CC=1.O.CCN(C(C)C)C(C)C.C[C@H]1C[C@@H]1N.Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:43][C@H:38]4[CH2:39][C@@H:40]4[CH3:35])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H]1C[C@@H]1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H]1C[C@@H]1NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
Combine 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94 mg, 0.490 mmol), HOBT hydrate (75 mg, 0.490 mmol) in DMF (1 mL) and added Hunig's base (127 mg, 0.980 mmol). Then (1s,2s)-2-methylcyclopropanamine (34.8, 0.490 mmol) was added and the mixture was stirred at 60° C. for 3 h. The reaction mixture was diluted with water (4 mL) and acidified with 1N HCl to pH=5-6 to give a solid. The solid was collected by filtration, washed with water (2 mL), and recrystallized from hot MeOH (3-6 mL) to give the title compound (79.2 mg, 67.5% yield) as a white solid. MS m/z [M+H]+ 360.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:13][CH:12]=1)(=[O:9])[CH3:8].[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14](/[CH:15]=[CH:16]/[C:17]([NH:22][C:23]2[CH:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:19])=[CH:20][CH:21]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 3.9 μL of N,N-dimethylformamide and 0.094 mL of oxalyl chloride were added to 206 mg of 4-acetoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 86 mg of tert-butyl 2-amino-4-phenoxybenzoate, 3.0 mL of methylene chloride and 0.67 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-((E)-3-(4-acetoxyphenyl)acrylamido)-4-phenoxybenzoate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]([CH2:34][CH2:35][CH2:36][CH3:37])[O:29][C:30]2=[O:31])=[CH:26][CH:25]=1.N1C=CC=CC=1>CCOCC>[CH2:34]([CH:28]1[C:27]2[C:32](=[CH:33][C:24]([NH:23][C:8](=[O:10])[C:7]3[CH:11]=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=3)=[CH:25][CH:26]=2)[C:30](=[O:31])[O:29]1)[CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC1OC(=O)c2cc(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc21

Procedure:
2.50 g (10 mmol) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid are heated with 2.5 ml of thionyl chloride under reflux for 30 minutes. The reaction mixture is evaporated in vacuo and the residue is mixed with petroleum ether to remove the excess of thionyl chloride. 2.05 g (10 mmol) of compound obtained in Example 4 are mixed with 8.6 g of dry pyridine and dried ether. To this suspension there is added, dropwise, the ethereal solution of acyl chloride prepared above; the reaction mixture is refluxed for 30 minutes. The solvents are removed in vacuo. The residue is washed with water and dried. The title compound is crystallised from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6][C@@H:5]1[OH:25])[CH3:2].[CH2:26](O)[CH2:27][OH:28].C([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:26]1[CH2:27][O:28][C:14]2([CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([C:18](=[O:23])[CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:22])[C@H:7]([CH2:6][C@H:5]([OH:25])[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21]2)[CH2:8][CH2:9]4)[O:24]1
Reactant: OCCO
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O
Reaction time: 8 h

Procedure:
A solution of 2β-ethoxy-3α-hydroxy-5α-androstane-11,17-dione (8 g) in chloroform (80 ml) containing ethylene glycol (13 ml), ethyl orthoformate (8.3 ml) and p-toluene sulphonic acid (160 mg) was kept at room temperature overnight. The reaction mixture was washed with sodium bicarbonate solution and water, dried (Na2SO4) and evaporated in vacuo. Purification of the residual froth (8.6 g) by preparative thin layer chromatography over silica (acetone-petroleum ether 3:7) and crystallization from ethyl acetate-petroleum ether afforded the title compound m.p. 142°-145°, [α]D +18.2°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH:42]([C:44]1[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[N:48][CH:49]=1)[NH2:43].NN>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:42]([C:44]3[CH:49]=[N:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[N:43]=[C:17]([OH:19])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cn1
Reactant: O=C(O)C#Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: NN
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propiolic acid (1 g) and 1-hydroxybenzotriazole hydrate (643 mg) in N-methylpyrrolidone (10 ml) was added WSCD-HCl (912 mg) and the mixture was stirred at room temperature for 10 min. In another flask, diisopropylethylamine (2.31 g) was added to a suspension of 5-hydrazino-2-methoxypyridine dihydrochloride (1.26 g) in N-methylpyrrolidone (4 ml) and stirred at room temperature until all 5-hydrazino-2-methoxypyridine dihydrochloride was dissolved. Thus obtained hydrazine solution was added to the reaction flask and the mixture was stirred at room temperature for 1.5 hrs.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CCOCC>[Si:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 4-hydroxybenzyl cyanide 77 (2.0 g, 15.0 mmol) in DMF (10 ml) was added t-butyldimethylsilyl chloride (2.5 g, 16.5 mmol). The reaction mixture was cooled to 0° C. and imidazole (2.3 g, 33.0 mmol) was added and then the mixture was allowed to warm to ambient temperature. After stirring for 3 hours, the reaction mixture was diluted with ether and washed with 0.5 M HCl, sat. aq. NaHCO3, water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (8:1)) to give 78 as a clear oil (3.6 g, 98% yield). 1H-NMR (400 MHz, chloroform-d) δ7.87 (d, J=8.5 Hz, 2 H), 6.86 (d, J=8.5 Hz, 2 H), 3.54 (s, 2 H), 0.98 (s, 9 H), 0.23 (s, 6 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[CH3:2][O:3][C:4](=[O:13])[CH:5]([N:12]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C(N)c1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(N=Cc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 8 (40.3 g, 0.2 mol) in dichloromethane (600 mL) was added triethyl amine (24.24 g, 0.24 mol) dropwise. After stirring for 30 min, benzaldehyde (21.2 g, 0.2 mol) was added dropwise, followed by the addition of MgSO4 (240 g, 2 mol). The mixture was stirred overnight. After filtration, the filtrate was evaporated to give compound 9 (49 g, 96.8%). 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 5.22 (s, 1 H), 7.30-7.39 (m, 6 H), 7.53-7.56 (m, 2 H), 7.82-7.85 (m, 2 H), 8.34 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:20]([O:22][CH3:23])=[O:21].[K+].C1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:38])=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([Cl:38])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(N=Nc2ccc(S(=O)(=O)[O-])cc2)ccc1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(N=Nc2ccc(S(=O)(=O)Cl)cc2)ccc1O

Procedure:
17.6 g of potassium 4-(4-hydroxy-3-carbomethoxy-phenylazo)-benzenesulphonate, 30 ml of benzene, 2 ml of dimethylformamid and 6 ml of thionyl chloride are heated to the boiling point under reflux for 30 min. The mixture is cooled, and cold water and 100 ml of petroleum ether are added with rapid stirring. The product is filtered off and washed with water and dried, whereupon 15.4 g of the title compound are obtained. The melting point is 137° - 138° C. after recrystallization.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.CCN(CC)CC.[Li+].[Cl-]>CC#N>[Si:1]([O:8][C@H:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH:22]=2)[C@@H:13]1[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:41][CH:42]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Temperature: 35 °C

Procedure:
Methyl {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetate (530 mg, 0.73 mmol) was dissolved in 15 ml MeCN. Water (0.2 ml), Et3N (1.0 ml, 7.2 mmol) and LiCl (630 mg, 14.9 mmol) were added and the mixture was stirred at 35° C. over night. The mixture was filtered and concentrated. The residue was extracted between EtOAc and 0.3 M KHSO4. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine (2×) and concentrated. The brown residue was purified by preparative HPLC on a C8 column (150×30 mm) using a gradient from 20-60% MeCN in 0.1 M ammonium acetate as eluent. The title compound was obtained in 170 mg (33%) as a slightly brownish solid. M/z: 711.2 (M−1). 1H-NMR (400 MHz, DMSO-d6) δ: −0.18 (s, 3H), −0.04 (s, 3H), 0.78 (s, 9H), 2.93 (ddd, 2H), 2.98 (s, 3H), 4.01 (d, 2H), 4.29 (d, 1H), 4.67 (s, 2H), 4.88-4.94 (m, 1H), 5.11 (d, 1H), 6.93 (d, 2H), 7.09-7.18 (m, 2H), 7.21 (d, 2H), 7.32-7.42 (m, 6H), 7.58 (t, 1H), 12.97 (brs, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:30])[CH2:26][N+:27]([O-])=O)[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(=O)C>CO.[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:30])[CH2:26][NH2:27])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)C[N+](=O)[O-])N1CCc2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)CN)N1CCc2ccccc2C1=O
Reaction time: 4 h

Procedure:
A mixture of 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-4-hydroxy-5-nitro-pentanoic acid, tert-butyl ester (2.55 g, 6.05 mMol) and 10% Pd on charcoal (1.5 g) in 100 mL of methanol containing 5 mL of 10% aqueous acetic acid was hydrogenated at room temperature for 4 hours. Filtration and evaporation of the solvent under reduced pressure gave of 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-amino-4-hydroxy-pentanoic acid, tert-butyl ester hydroacetate (2.7 g).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([CH2:45][C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:46](=[O:47])[CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)Cc1ccccc1)CC2(C)C
Temperature: 25 °C
Yield: 11.3 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (9.2 mg, 0.021 mmol) in CH2Cl2 (5 mL) was added Et3N (8.98 μl, 0.064 mmol) followed by 2-phenylacetyl chloride (4.26 μl, 0.032 mmol) and the mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product was dissolved in MeOH and repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm) to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-phenylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.3 mg, 10% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 7.38-7.60 (1H, m), 7.00-7.40 (7H, m), 6.97 (1H, d, J=7.02 Hz), 4.75-4.85 (1H, m), 4.35-4.47 (0.5H, m), 4.17-4.34 (1H, m), 3.98 (0.5H, d, J=16.48 Hz), 3.77-3.93 (1.5H, m), 3.57-3.77 (3H, m), 3.53 (0.5H, d, J=13.12 Hz), 1.22-1.42 (9H, m), 1.11-1.22 (3H, m), 0.87-1.04 (9H, m). LCMS (M+H) calcd for C33H40FN2O4: 547.29. found: 547.4.