Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[BrH:15].[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:15][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH:1]1[CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC1CC1)C(C)=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC1CC1)C(=O)CBr
Temperature: 0 °C

Procedure:
A solution of ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(358 mg) and pyridinium hydrobromide perbromide (633 mg) in acetic acid (2 ml) was heated at 50° C. for 30 minutes. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-bromo-2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(470 mg). To a solution of the compound obtained above in N,N-dimethylacetamide (2.2 ml) was added thiourea (126 mg) at ambient temperature. The mixture was stirred at the same temperature for an hour. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using a mixture of chloroform and ethyl acetate (4:1 V/V) as an eluent to give ethyl 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(177 mg) as a crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].C(N(C(C)C)C(C)C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)c1ccccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCOS(C)(=O)=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of (S)-tert-butyl 1-(2-bromophenyl)-4-hydroxybutylcarbamate (compound 5; 59.4 mmol, 20.44 g) in dry methylene chloride (500 mL) cooled in an ice bath was added N-ethyldiisopropylamine (119 mmol, 15.35 g) followed by the slow addition of methane sulfonyl chloride (60.0 mmol, 6.87 g) under nitrogen maintaining the reaction temperature below 5° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and left to stir for two days. The reaction mixture was evaporated at 45° C. under vacuum and residue taken up in methylene chloride (500 mL) washed with 0.5% citric acid, dried over magnesium sulfate with activated charcoal, filtered through a bed of dicalite and evaporated to give a slightly oily solid which was triturated with heptane to give (S)-4-(2-bromophenyl)-4-(tert-butoxycarbonylamino)butyl methanesulfonate 23.25 g) as a pale brown solid, MS (ES): m/z [M+H]+ 422 and 424.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[S:20][C:19]([C:21]([N:36]3[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:38][CH2:37]3)=[O:23])=[N:18][N:17]=2)(=[O:11])=[O:12])=[C:5]([CH3:25])[CH:4]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Reactant: C1CCN(CCN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCN4CCCC4)CC3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (125 mg, 0.32 mmol), 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (71 mg, 0.39 mmol), trimethylaluminium (2 M in toluene, 0.35 mL) and THF (10 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:24]=[N:23][NH:22][C:21]=1[C:25](O)=[O:26]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[NH:22][N:23]=[CH:24][C:20]=3[Cl:19])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1[nH]ncc1Cl
Product: C[C@]1(c2cc(NC(=O)c3[nH]ncc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-2H-pyrazole-3-carboxylic acid following procedure I yielded the title compound. MS (ISP): m/z=388.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13].[CH3:14][N:15]([CH3:18])[CH:16]=O>C(OCC)C>[CH3:14][N:15]([CH:18]=[C:4]1[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2](=[O:13])[CH2:3]1)[CH3:16]
Reactant: O=C1CCC(=O)c2ccccc2N1
Reactant: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Temperature: 90 °C
Yield: 79 %

Procedure:
A mixture of 0.250 g (1.43 mmol) of 3,4-dihydro-1H-1-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N,N-dimethylformamide, dimethylacetal is heated at 90° C. for 1.5 hour. The mixture is cooled, diluted with diethylether and filtered. The solid is washed well with diethylether and dried to give 0.26 g of tan crystals, m.p. 203°-205° C.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].N[C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[C:16]#[N:17].[BrH:20]>C(O)(=O)C>[Br:20][C:11]1[CH:12]=[CH:13][C:14]([CH3:19])=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: Cc1ccc(N)cc1C#N
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(Br)cc1C#N
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
Conc. sulfuric acid (60 mL) is added to sodium nitrite (5.75 g, 83.4 mmol). The temperature rises to 70° C. and solution is effected. After cooling to 20-40° C., the above solution is added dropwise to a mechanically stirred solution of 5-amino-2-methylbenzonitrile (10.0 g, 75.8 mmol) in acetic acid (150 mL). The temperature is maintained at 20-40° C. throughout the addition. The reaction mixture is cooled to 16-20° C. and a solution of cuprous bromide (24 g, 167 mmol) in conc. hydrobromic acid (150 mL) is added keeping the temperature between 16-20° C. After 45 min, the reaction mixture is poured onto ice (500 g) and the solids are collected by filtration then dissolved in dichloromethane (600 mL), washed with brine, dried, filtered and concentrated to give 5-bromo-2-methylbenzonitrile (see also, Dressler, J. et al. EP 0 594 019) (11.5 g, 77%) as a brown solid. 1H NMR (CDCl3, δ ppm): 7.72 (1H, s), 7.60 (1H, dd), 7.20 (1H, dd), 2.50 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1cccc(C(=O)O)c1Cl
Product: Cc1cccc(C(=O)NCC2(c3ccc(C(F)(F)F)nc3)CCC(F)(F)CC2)c1Cl

Procedure:
From 2-chloro-3-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=447.1, tR (minutes, Method D)=0.80
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[I:8].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([C:5]1[C:6]([CH3:9])=[C:7]([I:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(O)cc(C)c1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)c(Cc2ccccc2)c(C)c1I
Temperature: 25 °C
Yield: 68 %

Procedure:
0-Benzyl-3,5-dimethyl-4-iodophenol was prepared as follows: In a 500 ml round-bottom flask were placed 30.0 g (121 mmol) of 3,5-dimethyl-4-iodophenol, 190 ml acetone, 16.9 g (122 mmol) potassium carbonate and 20.7 g (121 mmol) benzyl bromide. The mixture was refluxed for 15 hours, cooled, filtered and the precipitate washed with acetone. The combined filtrate was evaporated under reduced pressure to yield an orange oil which slowly crystallized. This was dissolved in methylene chloride and water and the methylene chloride layer sequentially washed with 5% sodium hydroxide, saturated sodium bisulfite and water. After drying over magnesium sulfate and filtering, the methylene chloride was removed under reduced pressure. The resulting solid was recrystallized from hot methanol, cooled to room temperature and then in ice, collected and washed with cold methanol to yield 27.9 g (68% yield) of white plates, mp 56-57, which were identified as O-Benzy13,5-dimethyl-4-iodophenol. 1H NMR analysis indicated: (δ, CDCl3) 7.68 (m, 5H), 6.62 (s, 2H), 4.88 (s, 2H) and 2.39 (s, 6H). Mass spectrum analysis indicated: (m/e) 338 (M+) and 91.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a mixture of 152 g (1.0 mole) of methyl salicylate and 500 ml of chloroform were added dropwise with stirring a solution of 172 g (1.08 mole) of bromine in 300 ml of chloroform at about 10° C. over a period of 6 hours. After the addition, the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and then with an aqueous solution of sodium bicarbonate. Removal of the solvent gave 230 g of substantially pure methyl 5-bromosalicylate in 99.6% yield, M.P. 59° to 61.5° C.
Reaction SMILES: O[CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][CH2:7]1.Cl.[OH-].[Na+].CCOCC>C(O)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]=[CH:2][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)[CH2:11][CH2:10]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(C(O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CCc2cc(C=CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1.9 Grams of 6-{1-hydroxy-4-[4-(3-chlorophenyl) -1- piperazinyl]butyl}-3,4-dihydrocarbostyril was dissolved in 50 ml of acetic acid and further 2 ml of concentrated hydrochloric acid was added to this solution. The solution was stirred at 80° C. for 30 minutes and the reaction mixture was concentrated under a reduced pressure to dryness to obtain a residue. To the residue was added 10N-NaOH and ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and separated by a silica-gel chromatography. Recrystallized from ethanol-chloroform to obtain 6-{4-[4-(3-chlorophenyl)-1-piperazinyl]-1- butenyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 1.6 g. Melting point: 175° -176° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.Cl[CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:20]([C:18]1[N:19]=[C:15]([CH2:14][O:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cc(O)ccn1
Reactant: CC(C)c1csc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2nc(C(C)C)cs2)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Ethyl 4-hydroxy-2-pyridinecarboxylate (19.5 g, 0.057 mol) dissolved in dimethylformamide (200 ml) was added with a solution of 2-(chloromethyl)-4-isopropyl-1,3-thiazole (11 g, 0.063 mol) in dimethylformamide (150 ml). The mixture was added with potassium iodide (9.5 g) and potassium carbonate (12 g) at room temperature, then heated to 110° C. and stirred for 1 hour. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with chloroform and washed with water. The resulting organic layer was washed with saturated brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform) to obtain 8.049 g (46%) of the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A solution of 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (190 mg, 606 μmol) and 6-methoxypyridin-3-amine (94.1 mg, 758 μmol) (Aldrich, St. Louis, Mo.) in THF (2.0 mL) was cooled in an ice bath and treated with LiHMDS (3.0 mL, 3.0 mmol)(a 1.0 M in THF solution). A blood-red solution was obtained. The mixture was stirred for 1 h, and then quenched with water (0.1 mL). The mixture was extracted into EtOAc from saturated aqueous NaHCO3, concentrated and purified by flash chromatography on silica (25 to 50% EtOAc/hexane; yellow band from column) to give 6-methoxy-N-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (96.3 mg, 38.0% yield) as a yellow crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 12.50 (s, 1H); 9.72 (dd, J=7.82, 1.71 Hz, 1H); 8.87 (s, 1H); 8.53 (d, J=2.69 Hz, 1H); 8.32 (dd, J=4.65, 1.96 Hz, 1H); 8.18 (dd, J=8.93, 2.81 Hz, 1H); 7.01 (dd, J=7.82, 4.65 Hz, 1H); 6.85 (d, J=9.05 Hz, 1H); 5.80-5.89 (m, 1H); 3.97-4.12 (m, 1H); 3.85 (s, 3H); 3.67-3.82 (m, 1H); 2.89 (s, 3H); 2.27-2.38 (m, 1H); 1.93-2.12 (m, 2H); 1.72-1.88 (m, 1H); 1.55-1.70 (m, 2H). m/z (ESI, +ve) 418.1 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].C(OCC)(=O)C.[ClH:31]>C(Cl)Cl>[ClH:31].[NH2:11][CH:3]([C:1]#[N:2])[C:4]([NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)(C)NC(=O)C(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C(N)C#N
Temperature: 60 °C

Procedure:
2-Cyano-N-(1,1-dimethylethyl)-2-[(diphenylmethylene)amino]acetamide 4 (900 g, 2.818 mol), ethyl acetate (4.5 L) and aqueous HCl (1 N, 4.5 L) were placed into a 12 L three-necked flask equipped with a nitrogen inlet, a gas outlet tube, reflux condenser, thermometer, mechanical stirrer, and maintained under a positive pressure of nitrogen. The mixture was heated on an oil bath at 60° C. for 4 hours with vigorous stirring, gradually cooled to room temperature, and then slowly diluted with CH2Cl2 (4 L). (Thin layer chromatography (EtOAc/hexanes=1/4) indicated no more starting material was present.) The resulting layers were separated and the aqueous phase was extracted with CH2Cl2 (4 L). The combined organic solutions were extracted with aqueous HCl (1N, 2×0.5 L). The aqueous extracts were combined and concentrated under reduced pressure to yield 490 g (2.557 mol) of 2-amino-2-cyano-N-(1,1-dimethylethyl)-acetamide hydrochloride 5.HCl.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([OH:30])=[O:29])(=[O:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@@H:49](O)[CH2:48]2>C1COCC1>[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@@H:49]([O:29][C:28](=[O:30])[CH:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17](=[O:19])[CH3:18])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:48]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(=O)c1ccccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
PS-DCC (890 mg, 1.184 mmol, loading: 1.33 mmol/g) is suspended in dry THF (10 mL). (2-Acetyl-phenylamino)-phenyl-acetic acid hydrochloride (I63) (181 mg, 0.59 mmol), HOBt (181 mg, 1.18 mmol), and (R)-quinuclidin-3-ol (226 mg, 1.78 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated. The resulting crude oil is purified by flash chromatography (DCM/MeOH=9/1) to afford the title compound as a colorless oil (239 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: C([O:3][C:4]([C:6]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[N+:17]([O-])=O)[CH2:8][CH2:7]1)=O)C>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:6]3([CH2:8][CH2:7]3)[C:4](=[O:3])[NH:17][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Nc2cc(Br)ccc2OC12CC2
Temperature: 60 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.5 g, 10.6 mmol) in glacial acetic acid (40 mL) was added iron powder (5.9 g, 106.1 mmol) at room temperature and the reaction mixture was heated at 60° C. for 3 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through celite bed. The filtrate was concentrated, and the resulting residue was taken in ethyl acetate and washed with water and saturated sodium bicarbonate solution, then the organic layer was dried over sodium sulfate, concentrated and the resulting residue was purified by silica gel column chromatography to furnish 6-bromospiro[4H-1,4-benzoxazine-2,1′-cyclopropane]-3-one (2.51 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][C@H:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:8]2)[NH:4][C:3]1=[O:20].[NH2:21][OH:22]>C(O)C.O>[OH:22]/[N:21]=[C:16](\[NH2:17])/[C:15]1[CH:18]=[CH:19][C:12]([C@H:9]2[CH2:10][CH2:11][C:5]3([NH:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]3=[O:7])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: NO
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(C#N)cc3)C2)C1=O
Solvent: CCO
Solvent: O
Product: CN1C(=O)NC2(CC[C@H](c3ccc(/C(N)=N/O)cc3)C2)C1=O
Temperature: 60 °C
Yield: 97.9 %

Procedure:
4-((7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)benzonitrile (0.88 g, 3.27 mmol) was suspended in ethanol (20 ml). To this was added hydroxylamine (0.240 ml, 3.59 mmol) as 50% weight solution in water, and the reaction was heated to 60° C. under an atmosphere of nitrogen for about 20 hours. The reaction mixture was left to cool down to ambient temperature. Solvent was partially removed. The resulting white precipitate was filtered, rinsed with cold ethanol and vacuum-dried to afford (Z)-N′-hydroxy-4-{(7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl}benzimidamide as light brown solid (1.12 g, 3.20 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:12][OH:13])([CH2:8][N:9]=[N+:10]=[N-:11])[CH2:4][N:5]=[N+:6]=[N-:7].S(=O)(=O)(O)O.[OH-].[Ca+2].[OH-].[CH3:22][C:23]([CH3:25])=O>>[N:5]([CH2:4][C:3]1([CH2:8][N:9]=[N+:10]=[N-:11])[CH2:12][O:13][C:23]([CH3:25])([CH3:22])[O:1][CH2:2]1)=[N+:6]=[N-:7]
Reactant: CC(C)=O
Reactant: [N-]=[N+]=NCC(CO)(CO)CN=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: CC1(C)OCC(CN=[N+]=[N-])(CN=[N+]=[N-])CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 mole of compound 1 was dissolved in 500 ml of dry acetone. After addition of 10 ml of concentrated sulfuric acid, the reaction mixture was stirred at room temperature for 2 hours. It was neutralized with calcium hydroxide and filtered and the filtrate and was concentrated to a syrup in vacuo. The crude product was further purified by column chromatography (eluting agent: chloroform/ethyl acetate 9:1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([N:23]2[CH2:28][C:27]3([CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]4[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=4)[CH:41]=O)[CH2:30][CH2:29]3)[O:26][CH2:25][CH2:24]2)=[O:22])[N:20]=1.[NH2:46][CH2:47][C@@H:48]([C:57]1[CH:66]=[CH:65][C:64]([OH:67])=[C:63]2[C:58]=1[CH:59]=[CH:60][C:61](=[O:68])[NH:62]2)[O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51].C(O)(=O)C>CO>[Si:50]([O:49][C@H:48]([C:57]1[CH:66]=[CH:65][C:64]([OH:67])=[C:63]2[C:58]=1[CH:59]=[CH:60][C:61](=[O:68])[NH:62]2)[CH2:47][NH:46][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([O:37][CH2:36][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][C:27]3([O:26][CH2:25][CH2:24][N:23]([C:21]([C:19]4[N:20]=[C:16]([CH3:15])[S:17][CH:18]=4)=[O:22])[CH2:28]3)[CH2:29][CH2:30]2)[CH:39]=1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(C=O)c4)CC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.113 g) was added in one portion to a stirred solution at 0° C. of 3-(3-(4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)propoxy)benzaldehyde (example 95, step b) (0.157 g), (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.118 g) and acetic acid (0.020 mL) in methanol (7 mL). The resulting mixture was stirred at 20° C. for 2 hours. Most of the methanol was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous phosphate buffer (pH=7.2), the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 8% methanol and 1% ‘880’ aqueous ammonia in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.160 g.