Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].BrC1C=CC=CC=1C=O.CNC>>[Br:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: C[N+](C)=Cc1ccccc1Br
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1ccccc1Br
Agent: [Cl-]
Product: CN(C)C(c1ccccc1Br)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)C(C)C)(C)C.CS([C:33]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:36]=[CH:35][N:34]=1)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[C:33]2[N:38]=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)[CH:36]=[CH:35][N:34]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 17.4 %

Procedure:
To a mixture of ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (652 mg, 2.46 mmol) and N,N-diisopropylethylamine (570 μL, 3.28 mmol) was added 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (495 mg, 1.64 mmol) and the resultant mixture heated at 100° C. for 16 h in a reactivial. The cooled reaction mixture was diluted with CH2Cl2 (30 mL), washed with water (20 mL), the aqueous extracted with CH2Cl2 (30 mL) and the CH2Cl2 extracts combined and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluted with cyclohexane:EtOAc 10:1 afforded the title compound as a colourless gum (139 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C1(CS(NC2C=CC(C(N3C4C=CC=CC=4CN4C=CC=C4C3)=O)=CC=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=4[CH3:35])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Reactant: Cc1c(F)cccc1C(=O)Cl
Agent: O=C(c1ccc(NS(=O)(=O)Cc2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1 N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl35); 476(M+H, Cl37).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-chloro-4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].CC([O-])(C)C.[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(CO)cc1O
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCO
Product: COc1ccc(CO)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 3-hydroxy-4-methoxy-benzyl alcohol (61.67 g, 400 mmole) in 1-propanol (600 ml) was treated at 60° C. with 97% t-BuOK (55.52 g, 480 mmole), at 90° C. with benzyl chloride (66.57 ml, 560 mmole) and the resulting mixture heated under reflux for 2 hours. Then at 90° C. a second batch of t-BuOK (9.25 g, 80 mmole) was added. After a further hour at reflux a third batch of t-BuOK (9.25 g, 80 mmol) and a second batch of benzyl chloride (9.51 ml, 80 mmole) was added at 90° C. After a further 2.5 hours at reflux the mixture was cooled to room temperature and the solid filtered off. The solvents were removed in vacuo, the residue treated with water (300 ml) and one-third of the solvent removed in vacuo. Water (100 ml) was added to the residue, which was then distilled off in vacuo and the procedure repeated. The resulting suspension was filtered, the solid was collected, dried and triturated with petroleum ether (2×600 ml) to give 3-benzyloxy-4-methoxy-benzyl alcohol, (86.21 g, 88.2%) mp 62-65° C.
Reaction SMILES: Cl[C:2]1[C:3]([F:14])=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[C:5]#[N:6].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1>S1(CCCC1)(=O)=O>[F:14][C:3]1[C:2]([F:15])=[CH:9][CH:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(C(F)(F)F)ccc(Cl)c1F
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1c(C(F)(F)F)ccc(F)c1F
Temperature: 165 °C
Reaction time: 7 h
Yield: 79.3 %

Procedure:
To a solution of 35.0 g of 3-chloro-2-fluoro-6-trifluoromethylbenzo nitrile in 200 ml of sulfolane was added 36.3 g of spray-dried potassium fluoride and 4.1 g of 18-crown-6-ether, and the mixture was stirred for 7 hours at 160-170° C. under a nitrogen atmosphere. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer obtained was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. Following to the concentration of the extract, the oily product obtained was distilled under reduced pressure to obtain 25.7 g of the title compound (bp. 98-100° C. (25 mmHg) nD 20.0-1.4413).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[C:44]1([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CO.ClCCl>[N:36]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:53]3[CH2:52][CH2:51][C:50]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCCC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid pyrrolidine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with 1% methanol/dichloromethane, 1.5% methanol/dichloromethane, 2% methanol/dichloromethane, and then 1.5% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: ClCCl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([OH:15])=[O:14].[F:16][C:17]([F:25])=[C:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22]O.CN(C1C=CC=CN=1)C>O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([CH3:24])=[C:17]([F:25])[F:16])=[O:14]
Reactant: O=C(O)c1nc2ccccc2s1
Reactant: CC(CCCCO)=C(F)F
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(CCCCOC(=O)c1nc2ccccc2s1)=C(F)F
Reaction time: 20 h
Yield: 43.8 %

Procedure:
To 4 ml of dichloromethane were dissolved 0.24 g (1.3 mmol) of benzothiazole-2-carboxylic acid, manufactured by a method described in “J. Amer. Chem. Soc.”, page 2328 (1949), 0.17 g (1.1 mmol) of 6,6-difluoro-5-methyl-5-hexenol and 0.13 g (1.1 mmol) of dimethylaminopyridine, followed by the addition of 0.38 g (2.0 mmol) of N-ethyl-N′-3-dimethyl-aminopropylcarbodiimide (WSC) hydrochloric acid salt at room temperature and stirring at the same temperature for 20 hours. The reaction liquid was then poured in water and extracted with dichloromethane. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain 0.15 g (yield: 43%) of 6,6-difluoro-5-methyl-5-hexenyl benzothiazole-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.BrC1C=C(C=C(OC(C)C)C=1)C(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:16][CH:13]1[CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Agent: COC(=O)c1cc(Br)cc(OC(C)C)c1
Product: COC(=O)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Prepared from methyl 3-bromo-4-hydroxybenzoate and cyclopropylmethylbromide according to the procedure for methyl 3-bromo-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C12H13BrO3: 285.1; no m/z observed, tR=3.96 min. 1H NMR (400 MHz, CDCl3) δ 8.22 (t, J=2.8 Hz, 1H), 8.02-7.88 (m, 1H), 6.91-6.81 (m, 1H), 4.02-3.91 (m, 2H), 3.88 (d, J=5.5 Hz, 3H), 1.41-1.26 (m, 1H), 0.76-0.59 (m, 2H), 0.52-0.31 (m, 2H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:5]([O:7][CH2:8][CH3:9])[CH2:6][C:3]1=[O:4]
Reactant: CN=C=O
Reactant: C=COCC
Solvent: Cc1ccccc1
Product: CCOC1CC(=O)N1C
Temperature: 130 °C
Yield: 16 %

Procedure:
A Teflon tube containing a mixture of 0.16 g (2.8 mmoles) of methyl isocyanate, 0.27 g (3.8 mmoles) of ethyl vinyl ether and 2 ml of toluene was sealed and introduced into a high-pressure reactor and the mixture was heated at 130° C. under a pressure of 8000 atmospheres for 20 hours. The reaction mixture taken out was evaporated and then purified by distillation under reduced pressure to obtain 1-methyl-4-ethoxy-2-azetidinone in a yield of 16% of the theoretical value.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>CN(C)C=O.C(OCC)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:1]2=[O:2])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (8.73 g, 53.8 mmol) was added to a solution of tert-butyl 4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate (17.2 g, 53.8 mmol) in dimethylformamide (200 mL), and stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate and extracted with water, then saturated brine. The crude product was purified by chromatography (silica gel, 0–30% ethyl acetate in methylene chloride gradient elution). The title compound was obtained as a dark solid (4.8 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:1][CH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1)(=[O:42])=[O:41]
Reactant: Cc1ccc(-c2noc(C3CC(O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2noc(C3CC(OS(C)(=O)=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.5 h

Procedure:
To a stirring suspension of N-(5-(5-(3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (220 mg, 0.565 mmol) (19) in anhydrous DCM (10 mL) at 0° C. was added DIEA (197 uL, 1.13 mmol) and methanesulfonyl chloride (542 uL, 0.678 mmol). The reaction was stirred to room for 30 minutes. The crude product was purified by silica chromatography to give 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl methanesulfonate (81). MS m/z 468.13 (M+1)+.
Reaction SMILES: C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1.[C:22]([O:26][C:27]([N:29](C(OC(C)(C)C)=O)[C:30]1[N:31]=[CH:32][C:33]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]3)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[N:34][C:35]=1[C:36]#[CH:37])=[O:28])([CH3:25])([CH3:24])[CH3:23].[OH:67][C:68]1[CH:76]=[CH:75][CH:74]=[CH:73][C:69]=1/[CH:70]=[N:71]/[OH:72]>CO.O>[C:22]([O:26][C:27]([NH:29][C:30]1[N:31]=[CH:32][C:33]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([CH:47]3[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]3)(=[O:45])=[O:46])=[CH:42][CH:43]=2)=[N:34][C:35]=1[C:36]1[O:72][N:71]=[C:70]([C:69]2[CH:73]=[CH:74][CH:75]=[CH:76][C:68]=2[OH:67])[CH:37]=1)=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: O/N=C/c1ccccc1O
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)nc1-c1cc(-c2ccccc2O)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
PIFA was added to a stirred solution of tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (150 mg,) and (E)-2-hydroxybenzaldehyde oxime in MeOH/water (0.4 mL) and the reaction mixture stirred at ambient temperature for 1.5 hours. A further portion of PIFA was added and the reaction mixture stirred at ambient temperature for a further 1.5 hours. The reaction mixture was partitioned between ethylacetate and water and the layers separated. The aqueous layer was extracted with ethylacetate (×1) and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 50% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-(2-hydroxyphenyl)isoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylate as an off-white solid (142 mg, 78%). LC/MS m/z 722.1 [M−56+1]+.
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35])=O.Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CO.O>[OH:38][N:37]=[CH:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35]
Reactant: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=NO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
In 1 ml of methanol was dissolved 0.050 g of (+)-1-formylmethyl-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one, and a solution of 0.021 g of hydroxylamine hydrochloride and 0.021 g of sodium acetate in 1 ml of water was added thereto. The resulting mixture was stirred at room temperature for 1 hour and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=1/1) to give 0.045 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[O:6][CH2:5][CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2cccc(C#N)c2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccc(CN)c2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.6 g) in tetrahydrofuran (400 ml) was added to a suspension of lithium aluminum hydride (26.3 g) in tetrahydrofuran (400 ml) with cooling on an ice-water bath under nitrogen stream for 1 hour. The mixture was stirred at room temperature for 2 hours. Ethyl acetate (200 ml) was added slowly with cooling on an ice bath and then ice-water (200 ml) was added very slowly with cooling on an ice bath. The resulting precipitate was removed by filtration. The solvent was removed under reduced pressure. Chloroform (300 ml) was added to the residue. The mixture was washed with water (100 ml) and then dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine (57.2 g) (oil).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].Br[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]Br.[OH-].[Na+]>CN(C=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[C:2]([N:1]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:18][CH:17]=[CH:16][C:15]=1[S:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: BrCCNCCBr
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)c1c(Sc2ccc([N+](=O)[O-])cc2)cccc1N1CCNCC1
Temperature: 25 °C
Yield: 82 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in DMF (40 mL) at room temperature. To this mixture bis(2-bromoethyl)amine (1.0 equiv.) was added, following the addition of NaOH (2.0 equiv.). After being stirred for 2 Hours at room temperature, the reaction mixture was poured into ice-cold water (200 mL) to get crude product. The crude solid was filtered and washed several times with water and purified by silica gel column chromatography (1:3 v/v ethyl acetate/petroleum ether) to provide a yellow solid (380.9 mg, 82% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH3:20][CH:19]([NH:22][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:18][CH:17]=1)[CH3:21]
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
reacting 1-{4-[2-(Cyclopropylmethoxy)ethyl]phenoxy}-2,3-epoxypropane with isopropylamine to produce Betaxolol; and
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:21][CH2:22][CH:23]([CH2:41][O:42][CH2:43][CH:44]1[O:46][CH2:45]1)[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O.O1CCOCC1>[CH2:5]([O:21][CH2:22][CH:23]([CH2:41][O:42][CH2:43][CH:44]([OH:46])[CH2:45][N:1]=[N+:2]=[N-:3])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCOCC(COCC1CO1)OCCCCCCCCCCCCCCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCC(O)CN=[N+]=[N-])OCCCCCCCCCCCCCCCC
Yield: 62 %

Procedure:
A solution of sodium azide (0.5 g., 7.7 mmoles) in water (5 ml.) was added to a refluxing solution of 1,2-di-O-(n-hexadecyl)-3-O-(2,3-epoxypropyl)-glycerol (3.3 g., 5.5 mmoles) in 1,4-dioxane (100 ml.), and the resulting solution stirred at reflux for 16 hours. Since the reaction was not yet complete, additional sodium azide (0.5 g., 7.7 mmoles) was added and the reaction stirred at reflux for another 16 hours. The reaction solution was then cooled, concentrated in vacuo, diluted with water (100 ml.) and extracted with ether (3×100 ml.). The combined ether extract was washed with water (100 ml.), dried (MgSO4), filtered and evaporated in vacuo to an oil which solidified on standing [2.2 g., 62% yield, ir (CHCl3) 2105 cm-1 ].