Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)=[O:21])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: N#Cc1ccc(OC(=O)Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccc(C#N)cc2)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and 4-cyanophenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-cyanophenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[S:29][C:28]3=[S:36])=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1>[Br-].[Zn+2].[Br-]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[S:29][C:28]3=[S:36])=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCn3c(=S)sc4ccccc43)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: S=c1sc2ccccc2n1CCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cn1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-6-[2-(2-thioxo-benzothiazol-3-yl)-ethyl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 3-[2-[(3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridin-6-yl]-ethyl]-3H-benzothiazole-2-thione in the form of an amorphous, colourless solid; MS: 512 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C@@H:10]([OH:27])[CH:11]=[C:12]([CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:13](OCC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[H-].C([Al+2])C(C)C.[H-].ClCCl.C(O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C@@H:10]([OH:27])[CH:11]=[C:12]([CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CCOC1CCCCO1
Agent: CC(C)C[Al+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C=C(CO)CCOC1CCCCO1
Temperature: -78 °C
Yield: 103.6 %

Procedure:
16 mg of ethyl (4S,5S)-5-tert-butoxycarbonylamino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-2-octenoate was dissolved in 0.5 ml of dichloromethane, and 13 μl of boron trifluoride ethyl ether complex was added thereto as -78° C. under stirring. The mixture was stirred for 30 minutes at the same temperature. Then, 75 μl of a 1.5M isobutyl aluminum hydride toluene solution was added to the mixture and further stirred for 45 minutes. 60 μl of a 5M acetic acid dichloromethane solution was added thereto at -78° C., and the reaction solution was raised to room temperature. 10 ml of 10% citric acid aqueous solution was added thereto and extracted with ethyl acetate. The extract was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 15 mg of (4S,5S)-5-tert-butoxycarbonylamino-1,4-dihydroxy- 2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-2-octene as a colorless oily substance.
Reaction SMILES: I[C:2]1[NH:3][C:4]([I:10])=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH:7]([C:5]1[N:6]=[CH:2][NH:3][C:4]=1[I:10])([CH3:9])[CH3:8]
Reactant: CC(C)c1nc(I)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1nc[nH]c1I
Temperature: 85 °C
Yield: 79.1 %

Procedure:
In 240 ml of ethanol was dissolved 48.1 g (0.144 mol)of 2,5-diiodo-4-isopropyl-1H-imidazole (7), followed by addition of 240 ml of water and 20.1 g (0.159 mol)of sodium sulfite. The mixture was heated at 85° C. for 35 minutes. This reaction mixture was concentrated and extracted with methylene chloride and the extract was washed with water and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was washed with ethyl acetate-diisopropyl ether and filtered to provide 26.9 g (yield 86%)of 4-isopropyl-5-iodo-1H-imidazole (4b).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]1[CH2:17][O:16][C:8]([CH3:15])([CH2:9][CH2:10][CH2:11][C:12](=O)[CH3:13])[O:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:6]1[CH2:17][O:16][C:8]([CH3:15])([CH2:9][CH2:10][CH2:11][C:12]([CH3:1])=[CH2:13])[O:7]1
Reactant: [Li]CCCC
Reactant: CC(=O)CCCC1(C)OCCO1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)CCCC1(C)OCCO1
Reaction time: 1 h
Yield: 38 %

Procedure:
To a slurry of methyl triphenylphosphonium bromide (218 g) in anhydrous tetrahydrofuran (1.8 l) cooled to 0° C. is added 1.6 M n-butyllithium (270 ml) and 2.6 M n-butyllithium (37.5 ml). After stirring for 1 hour, 6,6-ethylenedioxy-heptane-2-one (91.3 g) in anhydrous tetrahydrofuran (200 ml) is added dropwise and the mixture stirred for 1.5 hours at room temperature. The reaction mixture is then filtered and the filter cake washed with ether. The solvent is removed via distillation at atmospheric pressure. The crude residue is purified via vacuum distillation to give 6,6-ethylenedioxy-2-methyl-hept-1-ene (33.95 g, 38%) bp 75°@15 mm:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(OC(Cl)=O)C.[NH2:20][CH2:21][C:22]1[C:27]([CH2:28][CH3:29])=[N:26][C:25]2[N:30]([CH2:33][CH3:34])[N:31]=[CH:32][C:24]=2[C:23]=1[NH:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:8]([C:7]3[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=3)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[C:23]([NH:35][CH:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.8 %

Procedure:
To 3-(methoxycarbonyl)benzoic acid (1.261 g, 7.00 mmol) in DCM (35 mL) was added TEA (2.439 mL, 17.50 mmol), EtOCOCl (0.739 mL, 7.70 mmol) at 0° C. after which 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (2.379 g, 7.00 mmol) was added. This mixture was then stirred for 1 h at room temperature. The reaction mixture was diluted with DCM (35 mL) then washed with HOAc (2×20 mL, 10%), NaHCO3 (20 mL, 10%), and water (20 mL), concentrated, The residue washed with EtOAc/Hexane (10 mL, 1:1) to afford the title compound (3.5138 g, 94.2%). LC-MS m/z 466 (M+H)+.
Reaction SMILES: [C:1]([NH:9][OH:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:17]([C:19]([CH2:26][CH3:27])([C:23](Cl)=[O:24])[C:20](Cl)=[O:21])[CH3:18]>C(Cl)Cl>[C:1]([N:9]1[C:20](=[O:21])[C:19]([CH2:26][CH3:27])([CH2:17][CH3:18])[C:23](=[O:24])[O:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: O=C(NO)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccccc2)C1=O
Yield: 72.3 %

Procedure:
A mixture consisting of 1.37 g (0.0100 mol) of benzohydroxamic acid, 10 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round-bottom flask. The mixture was cooled in an ice bath and 2.00 g (0.101 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period. The reaction mixture was stirred for one hour at room temperature after which time all the benzohydroxamic acid had dissolved. The solution was evaporated under reduced pressure, and to the residue was added 100 ml of cold water. The insoluble viscous oil was rubbed with a glass rod to effect solidification. The solid was filtered and dried to give 1.89 g (75.9%) of crude 2-benzoyl-4,4-diethylisoxazolidine-3,5-dione: mp 76°-79° C. Recrystallization of 1.72 g of crude isoxazolidine-3,5-dione from 20 ml of absolute ethanol gave 1.56 g of pure 2-benzoyl-4,4-diethylisoxazolidine-3,5-dione: mp 87°-88° C. (lit 87°-88° C.) G. Zinner and R. Moll, Arch. Pharm., 299, (6), 562-8(1966), CA 65 10575f; IR (Nujol) 1817 (s, C=O), 1762 (s, C=O), 1714 (s, C=O) and 694 (s, aromatic C--H bend) cm-1 : NMR (acetone-d6 ) δ7.46 (m, 5, aromatic C--H), 1.87 (q, 4, CH2), 1.00 (t, 6, CH3).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:17][C@H:18]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH3:25])[CH2:20][NH:19]1.[Cl-].[NH4+]>C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][C@@H:21]([CH3:25])[CH2:22][CH2:23][CH2:24][C@@H:18]2[CH3:17])[C:7]=1[F:8]
Reactant: C[C@H]1CCC[C@H](C)NC1
Reactant: Fc1c(Cl)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C[C@H]1CCC[C@H](C)N(c2ncnc(Cl)c2F)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Into 3 ml of acetonitrile were added 0.2 g of 4,6-dichloro-5-fluoropyrimidine, 0.50 g of potassium carbonate and 0.27 g of trans-2,6-dimethylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.31 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-trans-2,6-dimethylhexahydro-1H-azepine.
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24]([N:26]4[CH2:32][CH2:31][CH2:30][C:29]([F:34])([F:33])[CH2:28][CH2:27]4)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:29]1([F:33])[CH2:30][CH2:31][CH2:32][N:26]([C:24]([CH:22]2[CH2:23][N:20]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:36][CH2:35][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:21]2)=[O:25])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)N4CCCC(F)(F)CC4)C3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CN(c2c3c(nc4ccnn24)CCNCC3)C1)N1CCCC(F)(F)CC1
Reaction time: 8 h

Procedure:
To 190 mg (0.38 mmol) 10-[3-(4,4-Difluoro-perhydro-azepine-1-carbonyl)-azetidin-1-yl]-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 5 mL DCM was added 0.38 mL TFA and stirring was continued overnight at room temperature. To neutralize TFA sat. NaHCO3-solution was added, the organic layer separated and dried over Na2SO4. After filtration and evaporation of the solvent was the residue purified by HPLC.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[S:10](=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:39])[CH2:25][CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36](O)=[O:37])[CH3:27]>>[CH3:39][N:24]([CH3:23])[CH2:25][CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([N:13]1[CH2:14][CH:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][S:10](=[O:16])[CH:11]2[CH2:12]1)=[O:37])[CH3:27]
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: CC(CN(C)C)Oc1ccccc1CC(=O)O
Product: CC(CN(C)C)Oc1ccccc1CC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCS2=O
Yield: 9.7 %

Procedure:
By carrying out the procedure according to that described in Example 8 below, using 1.82 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide and 1.39 g of [(3-dimethylamino-2-propoxy)phenyl]acetic acid, 0.3 g of (1RS,4aRS,7aRS)-6-{[(3-dimethylamino-2-propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained in the form of white crystals; melting point 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[NH:14][C:13](=[O:19])[C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].[CH3:21]I>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[N:14]=[C:13]([O:19][CH3:21])[C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: CI
Reactant: Cc1[nH]c(=O)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(C)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Temperature: 50 °C

Procedure:
Compound 5-1 (3.2 g; 9.71 mmol), methyl iodide (1.21 mL; 19.4 mmol), silver carbonate (8.03 g; 29.1) mmol) and chloroform (100 mL) were added to a sealed vessel. The contents of the sealed vessel were heated at 50° C. overnight in the absence of light. The reaction mixture was cooled to room temperature, filtered to remove insoluble material, and the filtrate concentrated in vacuo. The crude material was purified via silica gel chromatography (0-15% EtOAc in hexane) to give the title compound. MS M+1=344.8. 1H NMR (CDCl3): 2.58 (s, 3H), 4.06 (s, 3H), 6.96 (m, 1H), 7.20 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccccc2)c(=O)c2ccccc2n1-c1ccccc1

Procedure:
3-(Benzoylamino-methyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from an over-reduced batch of intermediate I and benzoyl chloride. MS calcd. for C25H21N2O4 [(M+H)+] 413.1, obsd. 412.9
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH2:27])=[O:26])[CH:20]=2)[CH:12]=1)(=O)C.Cl.CCOCC>O>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][C:19]1[CH:20]=[C:21]([C:25]([NH2:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)Oc1cccc(COc2cccc(C(N)=O)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: NC(=O)c1cccc(OCc2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
A solution of K2CO3 (500 mg, 3.62 mmol, 5.75 equiv.) in water (5 ml) was added to a solution of 3-[3-(aminocarbonyl)phenoxy]methylphenyl acetate (180 mg, 0.63 mmol, 1 equiv.) and the mixture was stirred at r.t., under N2, for 3 h; The mixture was acidified with 10% HCl solution to pH 1, and was extracted with EtOAc (2×30 ml). The combined organic extracts were washed with water (30 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure, to give a clear oil residue which, after trituration with Et2O, solidified to a white solid (70 mg, 46% yield). Mp 122-123° C., HPLC-MS (method 1): m/z 244 [M+H]+. Rt=2.92 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C@@H:16]([CH3:19])[CH2:17][OH:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C@@H:16]([CH3:19])[CH2:17][O:18][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)Nc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of (2S)-2-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (30.0 g, 92.0 mmol) dissolved in 100 mL of anhydrous pyridine was treated with tert-butyldimethylsilyl chloride (15.2 g, 101.2 mmol) and a catalytic amount of DMAP (112 mg, 0.92 mmol). After stirring overnight at ambient temperature under an atmosphere of N2, the reaction mixture was concentrated under reduced pressure. The resulting solid was partitioned between CH2Cl2 (500 mL) and H2O (500 mL). The layers were separated and the organic portion was concentrated under reduced pressure to give 40.5 g of 7-bromo-N-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-nitroquinolin-4-amine as a yellow, crystalline solid.
Reaction SMILES: [ClH:1].[C:2]1([O:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:11]2[C:6](=C[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]1([O:28]C2CCN(CC3C=CC=CC=3)C2)C2C(=CC=CC=2)C=CC=1>>[ClH:1].[CH3:18][O:28][C:3]1[C:2]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:8][CH2:9][CH2:10]2
Reactant: c1ccc2c(OC3CCNC3)cccc2c1
Reactant: c1ccc(CN2CCC(Oc3cccc4ccccc34)C2)cc1
Agent: Cl
Product: COc1ccc2c(c1O[C@@H]1CCNC1)CCC2

Procedure:
(rac)-3-[(1-Naphtalenyl)oxy]pyrrolidine hydrochloride m.p. 222° C., starting from (rac)-3-[(1-naphtalenyl)oxy]-1-(phenylmethyl)-pyrrolidine.
Reaction SMILES: [H-].[CH2:2]([Al+]CC(C)C)[CH:3](C)C.CO[C:13](=O)[C@@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[Si:17]([O:16][CH2:15][C@H:14]([CH3:24])/[CH:13]=[CH:2]/[CH3:3])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Product: C/C=C/[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminum hydride (1 M solution in hexane, 86 mL) was added to a solution of (S)-3-(tert-butyldimethylsilyloxy)-2-methylpropionic acid methyl ester (20 g, 86.1 mmol) in dichloromethane (400 mL) at −78° C., and the mixture was stirred at the same temperature for two hours. A saturated potassium sodium tartrate solution was added to the reaction mixture which was then stirred while heating to room temperature. The organic layer was separated, and then the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (200 mL). Triphenylphosphonylideneacetic acid methyl ester (32 g, 94.7 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, and then the solvent was evaporated under reduced pressure. Hexane was added to the resulting residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 25 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:21].[OH-:22].[Na+]>O1CCOCC1>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:12])[C:9]([OH:21])=[O:22]
Reactant: [OH-]
Reactant: C[C@H]1[C@@H](CCCc2cccs2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1cccs1)C(=O)O
Temperature: 23 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(thiophene-2-yl)-1-propyl)-4-methylazetidin-2-one (91 mg, 0.295 mmol) in dioxane (1 mL) is added 1 M aqueous sodium hydroxide (0.44 mL). The solution is stirred at 23° C. for 18 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(thiophene-2-yl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (91 mg, 94% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NCC(O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 14, 1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester, according to the procedure of Example 1 as an off-white solid; mp 74-83° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.10-1.20 (m, 6H), 1.20-1.90 (m, 8H), 2.60-3.40 (m, 6H), 3.80-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.75 (d, 1H), 6.84 (t, 2H), 7.00 (d, 2H), 7.57 (d, 2H), 10.57 (br s, 1H), 10.70 (br s, 1H); MS (ES) m/z: 602.1 (MH+); HRMS Calcd. for C29H40N5O7S (MH+): 602.2634. Found: 602.2642.