Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18].[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[N:8]([CH3:22])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18]
Reactant: CC(C)CC1NC(=O)N(c2cc(F)ccc2F)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC1C(=O)N(c2cc(F)ccc2F)C(=O)N1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
5-(2'-Methylpropyl)-3-(2,5-difluorophenyl)imidazoline-2,4-dione (3.0 g, 11.1 mmol) in DMF (15 mL) was added dropwise to an ice-cold suspension of sodium hydride (0.30 g, 12.5 mmol) in DMF (4 mL). The solution was allowed to stir for 2 hours, after which methyl iodide (1.04 mL, 2.38 g, 16.8 mmol) in DMF (5 mL) was added dropwise. The solution was stirred overnight and then diluted with water. The product was extracted with ethyl acetate (3×), and the combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated. Purification by column chromatography gave 2.7 grams of 5-(2'-methylpropyl)-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, as an oil (compound 3 under Table A).
Reaction SMILES: C(OP(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(OCC)=O)C.[CH2:22]([O:24][P:25]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:69][O:70][CH3:71])[C:37]([NH:39][CH:40]2[C:47](=[O:48])[N:46]3[CH:41]2[S:42][CH2:43][C:44]([CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[C:45]3[C:49]([O:51]CC2C=CC(OC)=CC=2)=[O:50])=[O:38])[N:35]=1)([O:27][CH2:28][CH3:29])=[O:26])[CH3:23].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.C(=O)(O)[O-]>[CH2:28]([O:27][P:25]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:69][O:70][CH3:71])[C:37]([NH:39][CH:40]2[C:47](=[O:48])[N:46]3[CH:41]2[S:42][CH2:43][C:44]([CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[C:45]3[C:49]([OH:51])=[O:50])=[O:38])[N:35]=1)([O:24][CH2:22][CH3:23])=[O:26])[CH3:29]
Reactant: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CSc4nnnn4C)CSC23)cs1)OCC
Agent: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CSC23)cs1)OCC

Procedure:
The procedure of example 68 was repeated using 350 mg of [6R-[6-α, 7-β (Z)]]-7-[[[2-[(diethoxyphosphinyl)amino]-4-thiazolyl]-(methoxyimino)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (4-methoxyphenyl)methyl ester and 0.075 ml anisole in trifluoroacetic acid for 5 minutes. The product was obtained by acidification in aqueous bicarbonate and extraction with methylene chloride in the pH range 3.2 to 3.0 to give 200 mg of the desired product; MS ((+) FAB), 648 (M+H); NMR (300 MHz, d6 -DMSO) δ 1.28 (t, 6, OCH2CH3), 3.71 (pair of doublets, 2, endocyclic-CH2S--), 3.85 (s, 3, NCH3), 3.97 (s, 3, OCH3), 4.07 (m, 4, CH2OP=O), 4.33 (m, 2, exocyclic-CH2S--) 5.01 (d, 1, 6H of 7-ACA), 5.79 (dd, 1, of 7-ACA), 7.19 (d, 1, NH).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH2:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].B#B.[Br:13]Br.C[O-].[Na+]>O1CCCC1.CO>[Br:13][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: C=Cc1cccc(CC)c1
Reactant: BrBr
Agent: B#B
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cccc(CCBr)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 3-ethyl-1-vinylbenzene (Preparation 20, 1.45 g, 10.9 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen at 0° C. was added diborane (1.0M solution in tetrahydrofuran, 4 ml, 4 mmol) dropwise over 30 min. After 30 min at room temperature, methanol (0.1 ml) was added to destroy excess diborane. The reaction mixture was cooled to 0° C., and bromine (0.59 ml, 11 mmol) and a solution of sodium methoxide in methanol (12.1 mmol) were added via separate syringes at such a rate that a pale yellow coloration was always maintained. The reaction mixture was partitioned between aqueous saturated potassium carbonate solution and hexane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica column chromatography eluting with hexane to afford the title compound (640 mg, 28%).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH3:21])[C:4]1=[O:5])[CH3:2].C([O:24]CC)C>[Os](=O)(=O)(=O)=O>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]3[O:24][CH2:19]3)[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH3:21])[C:4]1=[O:5])[CH3:2]
Reactant: C=CCCCCn1cnc2c1c(=O)n(CC)c(=O)n2CC
Reactant: CCOCC
Agent: O=[Os](=O)(=O)=O
Product: CCn1c(=O)c2c(ncn2CCCCC2CO2)n(CC)c1=O

Procedure:
The same compound was also obtained by hydroxylation of 1,3-diethyl-7-(5-hexenyl)xanthine ##STR19## with osmium tetroxide: 0.73 g of 1,3-diethyl-7-(5-hexenyl)xanthine in 11 ml of diethyl ether was added dropwise with stirring in 5 minutes to 0.65 g of osmium tetroxide in 11 ml of diethyl ether at room temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9]([CH:12]=O)[CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:8]=1
Reactant: O=Cc1csc(-c2ccccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1csc(-c2ccccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyridinyl)-3-thiophenecarboxaldehyde (prepared as described in Reference Example 94) or the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: COCCOCCl
Reactant: COC(=O)C(O)c1ccc(OCc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOC(C(=O)OC)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-hydroxyacetate (0.507 g, 1.75 mmol) was dissolved in tetrahydrofuran (9 ml), and sodium hydride (0.09 g, 2.27 mmol) was added thereto while being cooled with ice. The mixture was stirred for 30 minutes at room temperature, and 2-methoxyethoxymethylchloride (0.26 ml, 2.27 mmol) was added thereto while being cooled with ice. After being stirred for 62 hours at room temperature, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-[(2-methoxyethoxy)methoxy]acetate (0.421 g, 64%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(O)C=CC=CC=1.[H][H]>[Ni].C(O)C>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: Oc1ccccc1
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](O)CC2)CC1

Procedure:
Ten % by weight (20 g) of Raney nickel was added to 4-(trans-4'-pentylcyclohexyl)phenol (200 g), and ethanol (1.8 l) was added to dissolve the phenol, followed by absorbing 3 mols of hydrogen based on one mol of the raw material phenol, into the solution at 100° C. under a hydrogen pressure of 20 Kg/cm2G. After completion of the hydrogenation, the catalyst was filtered off and ethanol was vaporized to concentrate the solution so as to give a volume of about 0.3 l, followed by adding fresh ethanol, recrystallization and filtration to obtain trans-4-(trans-4'-pentylcyclohexyl)cyclohexanol (77 g) (yield: 37.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[C:54]([O:58][C:59]([N:61]1[CH2:65][CH2:64][C:63]([C:67]#[CH:68])([OH:66])[CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[C:15]([C:9]1[N:8]=[C:7]2[C:6]3[CH:18]=[C:2]([C:68]#[C:67][C:63]4([OH:66])[CH2:64][CH2:65][N:61]([C:59]([O:58][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:60])[CH2:62]4)[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][N:11]2[CH:10]=1)(=[O:16])[NH2:17]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CCN(C(=O)OC(C)(C)C)C1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1
Yield: 28.5 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure H. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (100 mg, 0.32 mmol) in N,N-Dimethyl-formamide (3 mL) were added 1,3-bis(diphenylphosphino)-propane (26 mg, 0.064 mmol), Pd(OAc)2 (7.2 mg, 0.032 mmol), K2CO3 (110 mg, 0.8 mmol), 3-Ethynyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (136 mg, 0.64 mmol) and CuI (12 mg, 0.064 mmol). Then the solution was bubbled N2 for 5 min and microwaved for 1 h at 120° C. under nitrogen. The reaction mixture was filtrated and the filtrate was purified by column to afford crude titled compound (40 mg, 28%). LCMS=383.0 [M-56]+.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:9][CH:8]=1)([CH3:6])=[O:5])#[N:2].[C:25](N=S(C1C=CC(CN2C(=O)C3C(=CC=CC=3)C2=O)=CC=1)CC)#N>>[C:1]([N:3]=[S:4]([C:7]1[CH:24]=[CH:23][C:10]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:9][CH:8]=1)([CH2:6][CH3:25])=[O:5])#[N:2]
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CCS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Product: CCS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
The title compound is prepared in analogy to preparation 6c, substituting 2-(4-(N-cyano-S-methylsulfinimidoyl)benzyl)isoindoline-1,3-dione with 2-(4-(N-cyano-S-ethylsulfinimidoyl)benzyl)isoindoline-1,3-dione (preparation 13a). ESI mass spectrum: [M+H]+=354; r.t. HPLC: 3.33 min (LCMS-FA-8).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:12][O:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5](/[CH:4]=[CH:3]/[CH2:2][OH:1])[CH:6]=2)=[CH:18][CH:17]=1
Reactant: OC/C=C/c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cccc(/C=C/CO)c2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of (E)-3-(3-Hydroxy-propenyl)-phenol (0.5 g, 3.33 mmol), methyl 4-(bromomethyl) benzoate (763 mg, 3.33 mmol) and potassium carbonate (1.8 g, 13.3 mmol) in acetone (40 ml) was stirred at room temperature over night. The reaction mixtyre was added water (30 ml) and acidified with 1N HCl and extracted with ethyl acetate (90 ml). The organic phase was washed with water, brine and dried with sodium sulphate and evaporated and dried in vacuo yielding 954 mg (96%) (E)-4-[3-(3-Hydroxy-propenyl)-phenoxymethyl]-benzoic acid methyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][Br:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.O[Li].O.O.Cl>C1COCC1.CO>[Br:20][CH2:19][CH2:18][CH2:17][O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)oc2cccc(OCCCBr)c12
Temperature: 0 °C
Reaction time: 7 h
Yield: 112.9 %

Procedure:
4-(3-Bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (27.3 g), the compound in Example 5-a, was dissolved in THF (546 ml) and cooled at 0° C. To the solution were added LiOH.H2O (6.72 g), water (410 ml) and MeOH (135 ml). The mixture was stirred at room temperature for seven hours. To the reaction mixture was added 1N-HCl (133 ml). After evaporating the organic solvent, the mixture was mixed with ethyl acetate (1,400 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to give colorless needles. The colorless needles were washed with ethyl acetate-hexane (2:8) to obtain pure 4-(3-bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid (28.3 g). FAB-MS: m/z 312 (M+); 1H-NMR (CDCl3): δ 2.43 (2H, quintet, J=6.5 Hz), 2.78 (3H, s), 3.66 (2H, t, J=6.5 Hz), 4.25 (2H, t, J=6.5 Hz), 6.67 (1H, d, J=8 Hz), 7.17 (1H, d, J=8 Hz), 7.38 (1H, t, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[Br-:12].[C:13]1([PH+:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:12].[CH3:1][C:2]1[S:3][C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COc1sc(C)c(CO)c1C
Agent: [Br-]
Solvent: CC#N
Product: COc1sc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C

Procedure:
6.1 G. (35.5 mmol) of 2,4-dimethyl-3-hydroxymethyl-5-methoxythiophene were added at 35° C. with vigorous stirring to a suspension of 13.4 g. (39.0 mmol) of triphenylphosphonium bromide in 250 ml. of acetonitrile. The deep purple color which was formed immediately, disappeared after some minutes. The reaction mixture was stirred for 3 hrs. The solvent was evaporated to a volume of about 25 ml. and an excess of cold ether was added. The solvent then was decanted from the resulting oily precipitate which was dissolved in warm acetone and again precipitated by adding cold ether. The solvent was decanted and the resulting oily residue was dried in high vacuum to yield (2,4-dimethyl-5-methoxy-3-thenyl)-triphenylphosphonium bromide.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([CH:22]([CH:28](OC)OC)[CH:23](OC)OC)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH:33]C(=O)C2C=CC=CC=2)=[N:13]3)[CH:11]=1.S(=O)(=O)(O)O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([C:22]4[CH:23]=[N:3][N:2]([CH3:1])[CH:28]=4)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH2:33])=[N:13]3)[CH:11]=1
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cn1cc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3cc(Br)ccc3F)CO2)cn1
Temperature: 60 °C

Procedure:
Methylhydrazine (0.0834 mL, 1.60 mmol) followed by water (2.2 mL) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C44) (0.65 g, 1.06 mmol) in ethanol (5 mL). Sulfuric acid (0.110 mL, 2.07 mmol) was then added in a drop-wise manner to the reaction mixture. The resulting solution was heated to 60° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The layers were separated and the resulting aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated to give a mixture of product and benzoylated product (0.79 g), which was taken directly to the following step. LCMS m/z 427.1 [M+H+] (product) and m/z 527.1 [M+H+] (benzoylated product).
Reaction SMILES: [NH2:1][C@@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][N:8]1[N:12]=[C:11]([CH2:13][NH:14][C:15](=[N:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:16]([CH2:24][CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=[N:9]1.[CH:44]([O:57][C:58]([C:60]1([O:63]/[N:64]=[C:65](/[C:69]2[N:70]=[C:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[S:72][CH:73]=2)\[C:66](O)=[O:67])[CH2:62][CH2:61]1)=[O:59])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[CH:44]([O:57][C:58]([C:60]1([O:63]/[N:64]=[C:65](/[C:69]2[N:70]=[C:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[S:72][CH:73]=2)\[C:66]([NH:1][C@@H:2]2[C:5](=[O:6])[NH:4][C@@H:3]2[CH2:7][N:8]2[N:12]=[C:11]([CH2:13][NH:14][C:15](=[N:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:16]([CH2:24][CH:25]3[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:28]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=[N:9]2)=[O:67])[CH2:62][CH2:61]1)=[O:59])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2N)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.4 %

Procedure:
To a solution of tert-butyl 3-((3-((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)-1,2-bis(tert-butoxycarbonyl)guanidino)methyl)azetidine-1-carboxylate (309 mg, 0.51 mmol) and (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (273 mg, 0.51 mmol) in DMF (6 mL, ratio: 1) and DCM (6 mL, ratio: 1) was added HATU (232 mg, 0.61 mmol) followed by DIPEA (0.22 mL, 1.27 mmol). After stirring at rt for 12 h, EtOAc was added to the reaction mixture and washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-heptane, 0-95%) to afford the title compound (330 mg, 58%). LCMS: Rt=1.15 min, m/z=1127.8 (M+1) Method 2m_acidic.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15].Br[CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:17][C:18]#[N:19]
Reactant: Oc1ccc2c(nnn2CC2CC2)c1Br
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCOc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-ol (25 mg, 0.093 mmol), bromoacetonitrile (34 mg, 0.28 mmol, 3 equiv) and potassium carbonate (64 mg, 0.47 mmol, 5 equiv) were combined in dimethylsulfoxide (1 mL) and placed into a preheated oil bath at 80° C. for 30 minutes. The mixture was cooled to ambient temperature, filtered and purified by preparative HPLC (20 to 95% water containing 0.5% trifluoroacetic acid: acetonitrile containing 0.5% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a light brown solid: 1H-NMR (400 MHz, CDCl3) δ 7.55 (1H, d, J=9.2 Hz), 7.41 (1H, d, J=9.0 Hz), 4.91 (2H, s), 4.53 (2H, d, J=7.1 Hz), 1.45-1.35 (1H, m), 0.71-0.66 (2H, m), 0.52-0.48 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 307.0187 [(M+H)+; calculated for C12H12BrN4O: 307.0189].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH3:20][CH:21]1[O:26][CH:25]([CH3:27])[CH2:24][N:23]([C:28](N2C=C[N+](C)=C2)=[O:29])[CH2:22]1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28]([N:23]3[CH2:24][CH:25]([CH3:27])[O:26][CH:21]([CH3:20])[CH2:22]3)=[O:29])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC1CN(C(=O)n2cc[n+](C)c2)CC(C)O1
Agent: [I-]
Product: CC1CN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC(C)O1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,6-dimethyl-morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was purified by preparative HPLC (39%, colorless oil). HPLC-MS m/z=397.1 (M+1), Rt: 4.64 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:27])[CH3:26]
Reactant: O=C1COc2cc(F)c(Br)cc2N1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(Br)cc21
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a mixture of 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 167 mmol) and K2CO3 (23.0 g, 167 mmol) in acetone (300 mL) was added ethyl 2-bromopropanoate (75.0 g, 53.8 mL, 417 mmol) drop-wise at ambient temperature and the mixture was heated at reflux overnight. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(6-bromo-7-fluoro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (43.0 g, 75%). 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.25 (q, J=7.2 Hz, 1H), 4.59 (dd, J=15.2 Hz, 2H), 4.27 (m, 2H), 1.63 (d, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1>>[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17]1
Reactant: OCC1CCC(F)(F)CC1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCC2CCC(F)(F)CC2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4,4-difluorocyclohexyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.40-1.43 (2H, m), 1.66-1.74 (2H, m), 1.84-1.88 (3H, m), 2.08-2.11 (2H, m), 3.97 (2H, d, J=6.0 Hz), 5.62 (1H, d, J=1.6 Hz), 7.33 (1H, d, J=4.8 Hz), 7.50 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.61 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H16F2N4O, 319. Found, 319.