Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:37]([CH2:44][CH2:45][NH2:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:9](=[O:10])[NH:46][CH2:45][CH2:44][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCOc1ccccc1
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCOc1ccccc1

Procedure:
This compound was prepared by reacting the compound of Example 63 with 2-phenoxy ethylamine.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[C:17](=[O:27])[C:18]([CH3:26])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:12]3=[CH:11][C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:28].[Na+]>>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:19][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:26])[C:17]([OH:28])=[O:27])=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc2c(c1)cc1n2C(=O)C(C)(c2ccccc2)S1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCCCOc1ccc2[nH]c(SC(C)(C(=O)O)c3ccccc3)cc2c1
Yield: 93 %

Procedure:
To 7-hexyloxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one (3.92 g), 2N sodium hydroxide (70 ml) was added, and the mixture was heated and refluxed for 1.5 hours. The reaction mixture was allowed to cool, and the deposited crystalline matter was collected by filtration. The crystalline matter was dissolved in methanol. The solution was made acidic by adding concentrated hydrochloric acid under ice cooling, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to give 3.81 g (yield: 93 %) of the desired compound as a colorless powder. The melting point was 100°-102° C.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[CH3:20][N:21]([CH3:23])/[CH:22]=[C:4]1\[CH2:5][CH2:6][CH2:7][C:2]([OH:1])([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:3]\1=[O:8]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1(O)c1cccnc1
Product: CN(C)/C=C1\CCCC(O)(c2cccnc2)C1=O

Procedure:
2-Hydroxy-2-pyridin-3yl-cyclohexanone (394 mg, 2 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (582 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 247.2 (100) [(M+H)+].
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([OH:27])[CH2:24][C@@H:23]1[C@H:28]1[O:32][C:31]([CH3:34])([CH3:33])[N:30]([C:35](=[O:37])[CH3:36])[C@H:29]1[CH2:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.C[Si](C)(C)CCOC(=O)C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][C@@H:23]1[C@H:28]1[O:32][C:31]([CH3:33])([CH3:34])[N:30]([C:35](=[O:37])[CH3:36])[C@H:29]1[CH2:38][C:39]1[CH:40]=[C:41]([F:46])[CH:42]=[C:43]([F:45])[CH:44]=1)=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)CCOC(=O)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
Add dropwise diisopropyl azodicarboxylate (0.20 mL, 1.04 mmol) to a solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluorobenzyl)-2,2-dimethyloxazolidin-5-yl]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.314 g, 0.69 mmol), acetic acid (0.06 mL, 1.04 mmol) and 4-diphenylphosphanyl-benzoic acid 2-trimethylsilanyl-ethyl ester (0.42 g, 1.04 mmol, prepared according to Synlett 2003 (4) p 473-476) in tetrahydrofuran (3 mL). Stir solution 18 hours, then add a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (3 mL) and stir 90 minutes. Add a 1N aqueous solution of sodium hydroxide (3 mL) and stir 30 minutes. Dilute with ethyl acetate and water. Evaporate the organic layer and dissolve in methanol (30 mL). Add sodium carbonate (0.365 g) and water (1 mL) and stir 18 hours. Evaporate and partition with ethyl acetate and water, wash organic layer with saturated sodium chloride solution, dry with magnesium sulfate and purify on silica gel with hexane/ethyl acetate mixtures to give the title compound as a foam (0.295 g, 95%).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.CN(CCN(C)C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].[CH3:34][Si:35](Cl)([CH3:37])[CH3:36]>C1COCC1.CCOCC>[F:20][C:21]1[C:22]([Si:35]([CH3:37])([CH3:36])[CH3:34])=[C:23]([C:31]([Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:32][CH:33]=1)[C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]
Reactant: O=C(c1cccc(F)c1)N1CCCC1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(F)c([Si](C)(C)C)c1C(=O)N1CCCC1
Temperature: -90 °C
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (23.91 mL, 31.1 mmol) was added to an ether/liquid N2 cooled (-90° C.) solution of TMEDA (3.97 g, 34.2 mmol) in THF (40 mL), followed by the addition of a solution of N-(3-fluorobenzoyl)pyrrolidine (5.0 g, 25.9 mmol) in a minimum volume of THF. The resulting reaction mixture was stirred at -90° C. for 15 min, then TMSCl (6.75 g, 62.2 mmol) was added in a single portion. The reaction was warmed to RT, quenched with dilute aq citric acid, then was extracted with ether (3×). The combined ether extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to afford 0.45 g of the title compound as an oil, a 45% yield, which solidified on standing to a white solid. m.p. 97°-100° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:18][C:19](=[O:31])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)C>>[F:28][C:26]1[CH:27]=[C:22]([CH2:21][CH2:20][C:19]([OH:31])=[O:18])[CH:23]=[C:24]([F:30])[C:25]=1[O:29][CH2:2][C:3]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1Sc1ccccc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2Sc2ccccc2)c(F)c1
Yield: 51 %

Procedure:
3-Chloromethyl-2-phenylsulfanyl-pyridine obtained in Step C of Preparation Example 15 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (21 mg, 0.09 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (19 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:13].[Br:14]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[Br:14][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:12])[C:3]=2[O:2][CH3:1])[C:7]1=[O:13]
Reactant: COc1c(C)ccc2c1CCC2=O
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(C)ccc2c1CC(Br)C2=O
Temperature: 22.5 °C
Yield: 44.2 %

Procedure:
To a stirred solution of 4-Methoxy-5-methyl-indan-1-one (5.0 gm, 0.0284 mole) in Acetic acid (65 ml) and Hydrobromic acid (1 ml), a solution of Bromine (1.47 ml, 0.0284 mole) in 5 ml Acetic acid was added at 10-20° C. The reaction mixture was stirred at 20-25° C. for an hour. Then it was poured into saturated solution of Sodium bicarbonate and extracted with Diethyl ether (3×100 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give crude product which was purified over column chromatography using Ethyl acetate:Hexane (5:95) as a mobile phase. The collected fractions were distilled to give 3.2 gm of desired product as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13])=[CH:8][CH:7]=[C:6](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]=2>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6](/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(/C=C/c3ccccc3)ccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(O)=C(C(=O)NCC(=O)O)C(=O)c2ccc(/C=C/c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E)-tert-butyl 2-(2-hydroxy-1,1-dimethyl-4-oxo-7-styryl-1,4-dihydronaphthalene-3-carboxamido)acetate (120 mg, 268 μmol) was dissolved in TFA (2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, suspended in hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated; 391.4: Observed; 392.0.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:6][CH:5]=1.N1C2C(=CC=CC=2)C=CC=1>CCOCC>[Br:1][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[O:15]1
Reactant: C=CCCC(O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Clc1ccc(C2CCC(CBr)O2)cc1
Yield: 18.1 %

Procedure:
16 g (0.1 mole) of bromine are added dropwise to 17.3 g (0.1 mole) of 5-(4-chlorophenyl)-pent-1-en-5-ol in 50 ml of absolute ether at 0° C. When the addition has ended, 13 g (0.1 mole) of quinoline are added, whereupon the temperature rises to 15° C. and quinoline hydrobromide precipitates. The precipitate is filtered off with suction, the filtrate is evaporated in vacuo and the residue is heated on a waterbath for 1 hour. After cooling, the residue is taken up in ether, the mixture is washed with 15% strength hydrochloric acid and with water, dried over sodium sulphate and concentrated in vacuo and the residue is distilled under a high vacuum. 5 g (18% of theory) of 2-bromomethyl-5-(4-chlorophenyl)tetrahydrofuran of boiling point 145° C./0.13 mbar are obtained. ##STR111##
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:40](=[O:41])[CH2:39][CH2:38][N:37]([CH2:43][CH2:44][OH:45])[C:35](=[O:36])[O:34][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00013 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000163 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.031 g, 0.000163 mol), N,N-diisopropylethylamine (0.031 g, 0.00024 mol) and 1-hydroxy-7-azabenzotriazole (0.018 g, 0.00013 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.050 g, 0.000083 mol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:19]([OH:21])=O)[CH:6]=1)=[O:4].C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:19]([N:33]=[N+:34]=[N-:35])=[O:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)nn1Cc1ccc(OC)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)N=[N+]=[N-])nn1Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
In a round bottom flask, 1-(4-methoxy-benzyl)-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (105, 5.48 g, 18.9 mmol) was combined with 20 mL of toluene and thionyl chloride (6 mL, 80 mmol). The reaction was heated at reflux for 40 minutes, then concentrated 2× from toluene and the resulting solid dried under vacuum. This was dissolved in 30.0 mL of acetone and sodium azide (3.8 g, 58 mmol) in 10.0 mL of water was added and stirred for 1 minute. The reaction was poured into 250 mL of ice water and stirred slowly. The resulting precipitate was collected by filtration and dried under vacuum to provide the desired compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:13]=1)=[O:10]
Reactant: Cc1cc(C#Cc2ccccc2)nc(NC(=O)C(C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#Cc2ccccc2)nc(NC(=O)C(C)N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl-N-[1-[[4-methyl-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate D3b (2 mg, 5 μmol) and DCM:TFA (9:1, 400 μl) is stirred at RT for 4 hours. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. Yield: 1.5 mg (quant.). HPLC-MS: M+H=280; tR=1.77 min (*Method—1).
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[S:18])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(O[C@@H:26]1[NH:29][C:28](=[O:30])[C@H:27]1[O:31][CH3:32])(=O)C.O1CCOCC1.C(Cl)Cl>P([O-])([O-])([O-])=O>[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([S:18][C@H:26]2[NH:29][C:28](=[O:30])[C@@H:27]2[O:31][CH3:32])=[O:19])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CO[C@@H]1C(=O)N[C@H]1OC(C)=O
Reactant: O=C(NCCCC([O-])=S)OCc1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 55b), an aqueous solution of 480 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt is added to 159 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 6 ml of a phosphate buffer of a pH of 7 and 0.4 ml of dioxan. After working up and chromatography over silica gel, the title compound with the following IR spectrum (CH2Cl2) is obtained:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36]>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CNCCCO
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 3-(methylamino)propan-1-ol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.76 (s, 1H), 4.52 (br, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 3.40 (t, 2H), 2.31 (t, 2H), 2.25 (t, 2H), 2.09 (s, 3H), 1.74 (m, 2H), 1.52 (m, 2H), 1.39 (m, 4H), 1.29 (m, 2H); MS (ESI): 523.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.551 g, 2.54 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (30 mL) at 0° C. A 1.0 M ZnCl2 solution in diethyl ether (2.903 mL, 2.903 mmol) was added cautiously over 10 minutes, after addition the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (I75) (0.705 g, 2.42 mmol) in 1:1 t-BuOH:1,2-dichloroethane (15 mL) was added drop-wise over 15 minutes at 0° C., a solution of NEt3 (0.405 mL, 2.903 mmol) in 1:1 t-BuOH:1,2-dichloroethane (15 mL) was added drop-wise over 15 minutes and the reaction was allowed to warm to room temperature and was stirred for 18 hours. The organic solvents were evaporated in vacuo and the crude oily solid was suspended in water (200 mL), the suspension was sonicated for 30 minutes and the product was separated by filtration, the solid was washed with water (10×20 mL) and dried under a high vacuum. The material was further purified by silica gel chromatography using a gradient of 0-50% ethyl acetate in petroleum benzine 40-60° C. to give the title compound (I76) (0.730 g, 64%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.41 (s, 1H), 8.71 (s, 1H), 7.46 (d, J=7.7 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 6.84 (d, J=7.1 Hz, 1H), 3.60 (d, J=12.4 Hz, 2H), 2.69 (t, J=10.9 Hz, 2H), 1.78 (d, J=10.9 Hz, 2H), 1.54-1.34 (m, 11H). LCMS Method C: rt 6.36 min; m/z 474.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH:14]=O)[N:9]=[CH:8][CH:7]=[CH:6]2.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:14][CH2:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][C:3]=3[O:2][CH3:1])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: COc1cc2cccnc2cc1CC=O
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2cccnc2cc1CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde and 0.63 g of 1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 20 ml of methylene chloride. Thereafter, 0.42 ml of acetic acid and 0.74 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), so as to obtain 445 mg of the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([CH3:22])[NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH:8]C(OC(C)(C)C)=O.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([CH3:22])[NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH2:8]
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#COC[C@H](N)C(=O)NC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Purified N-tert-butoxycarbonyl O-propynyl-L-seryl α,α-dimethylglycine methyl ester 14 (2.27 g, 6.63 mmol) was dissolved in 50% (v/v) TFA in CH2Cl2 and the reaction mixture stirred for 1 h 10 min at room temperature. The solvent and bulk of excess TFA were evaporated and CH2Cl2 (3×20 mL) added and evaporated. Diethyl ether (25 mL) was added causing a white solid to precipitate on standing. The Et2O was decanted off and the residue washed with more Et2O (2×25 mL). After decantation of the Et2O the residue was dried under high vacuum affording the title compound as a white solid (2.10 g, 89%); 1H NMR (200 MHz, DMSO-d6) δ 8.95 (s, 1H, NH), 8.31 (br s, 3H, NH3+), 4.20 (d, J=2.4 Hz, 2H, CH2CCH), 4.02 (dd, J=5.8, 3.8 Hz, 1H, CαH or CHH), 3.88-3.67 (m, 2H, CH2 or CαH/CHH), 3.57 (s, 3H, OCH3), 3.52 (t, J=2.3 Hz, 1H, CCH), 1.39 (s, 3H, CH3), 1.36 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 173.9, 165.7, 158.3 (q, JCF=31 Hz), 117.2 (q, JCF=298 Hz), 79.5, 78.0, 68.0, 58.1, 55.5, 52.1, 52.0, 24.7; HRMS (m/z): M+ calcd. for C11H19N2O4, 243.1344. found, 243.1335; Anal. Calcd. for C13H19F3N2O6: C, 43.82; H, 5.38; N, 7.86. Found: C, 43.8; H, 5.4; N, 7.8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[C:17]1([N:23]2[C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:11]1([C:8]2[N:6]3[CH:7]=[C:2]([C:27]4[N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=[CH:25][CH:26]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2ncc(-c3ccccc3)n2c1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Product: c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccccc4)cn23)cc1

Procedure:
The title compound, off-white solid (48 mg, 39%), MS (ISP) m/z=337.5 [(M+H)+], mp 139° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-phenyl-imidazo[1,2-a]pyridine (intermediate G) (0.1 g, 0.366 mmol) and 1-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate D) (0.12 g, 0.44 mmol).