Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Cu][C:10]#[N:11]>CN(C=O)C>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[N:11]
Reactant: O=Cc1cc(Br)cs1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1csc(C=O)c1
Yield: 71.5 %

Procedure:
49.3 g (258.05 mmol) of 4-bromothiophene-2-carbaldehyde and 27.8 g (310.41 mmol) of copper(I) cyanide were suspended in 130 ml of absolute DMF and refluxed for 8 h. The solvent was removed in a rotary evaporator at 40° C., and the residue was suspended in ethyl acetate and transferred into a Soxleth [sic] apparatus. The residue was extracted overnight, the yellow solution was dried over sodium sulfate and concentrated in a rotary evaporator, and the resulting yellow solid was recrystallized from ether to result in 25.3 g of product (80% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:14](O)[CH2:15][CH2:16][OH:17].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[O:17][CH2:16][CH2:15][CH2:14][O:7]2)[CH:8]=[C:9]([I:13])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(I)c1OC
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C2OCCCO2)cc(I)c1OC

Procedure:
3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (5.814 g,19.9 mmole), 1,3-propanediol (6.13 g, 79.6 mmole), pyridinium para-toluenesulfonate (2.0 g, 7.96 mmole) and 100 ml dry benzene were refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene was removed in vacuo and the remaining oil redissolved in diethyl ether and was washed with 10% NaHCO3 and H2O. The organic layer was washed over MgSO4, and concentrated to a white solid in vacuo. (6.823 g, 98%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:33])[CH2:16][NH:17][C:18]([CH2:20][N:21]([CH2:29][C:30](O)=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:59][O:60][C:61](=[O:67])[C@@H:62]([CH:64]([CH3:66])[CH3:65])[NH2:63]>CN(C)C=O>[CH3:59][O:60][C:61](=[O:67])[CH:62]([NH:63][C:30](=[O:31])[CH2:29][N:21]([CH2:20][C:18](=[O:19])[NH:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:33])[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH:64]([CH3:66])[CH3:65]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)[C@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(C)C
Yield: 87.1 %

Procedure:
4-Methylmorpholine (4.1 mL, 37.3 mmol) was added to a suspension of ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol), and HATU (4.61 g, 12.1 mmol) in dimethylformamide (25 mL). After 5 minutes d-valine methyl ester hydrochloride (1.56 g, 9.3 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2×100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid methyl ester (4.37 g, 8.1 mmol, 87%). C23H32BrN3O7 calculated 541.1 observed [M+1]+ 431.1; rt=2.65 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CN(C=O)C>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Temperature: 100 °C

Procedure:
A mixture of 2.00 9 (10.5 mmol) of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared as described in Example 13, 1.60 g (11.6 mmol) of anhydrous K2CO3, and 3.39 (1.26 mmol) of N-(bromopropyl)phthalimide in 43 ml of DMF is heated at 100° C. for 3 hrs under N2. The DMF is removed under vacuum and the residue taken up in 125 ml of EtOAc and 50 ml of water. The organic phase is washed with 50 ml of 5% aqueous NaOH, then with saturated NaCl, dried (MgSO4), and the solvent removed to leave a yellow solid. This solid is recrystallized from EtOAc to give 2.748 g of 6-[4-(3-phthalimidopropyloxy)phenyl]-4,5-dihydro-(2H)-pyridazinone as a white solid. Yield, 69%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a solution of 25 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5 mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 20 mL (0.15 mol) of benzenesulfonyl chloride in 50 mL of CH2Cl2 dropwise over fifteen minutes. The addition funnel was rinsed with an additional 25 mL of CH2Cl2, and the cloudy, colorless mixture was allowed to warm to room temperature with stirring overnight. The solution was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, 1× with brine, then dried (MgSO4), filtered, and concentrated to a pale yellow solid. This material was recrystallized three times from ethyl acetate/hexanes to give 38.2 g (0.142 mol, 95%) of N-(benzenesulfonyl)-Proline methyl ester (MW=269) as broad white needles (TLC vs. 2:1 hexanes/ethyl acetate, Rf=0.35). M/z=270.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:35]4[CH2:36][CH2:37][N:32]([C:38]5[CH:43]=[N:42][CH:41]=[CH:40][N:39]=5)[CH2:33][CH2:34]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1cnc(N2CCNCC2)cn1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2cnccn2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(1-piperazinyl)pyrazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.97 (M+H+); retention time=0.78 minutes.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[CH:24][S:25][C:19]=2[N:18]2[CH:26]=[N:27][C:28]([C:29]([NH2:31])=O)=[C:17]2[CH2:16]1>O1CCOCC1.N1C=CC=CC=1>[CH3:14][N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[CH:24][S:25][C:19]=2[N:18]2[CH:26]=[N:27][C:28]([C:29]#[N:31])=[C:17]2[CH2:16]1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2sccc2C1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1Cc2c(C#N)ncn2-c2sccc2C1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
8.7 ml (62.9 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 15 g (57.2 mmol) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxamide in 80 ml of dioxan and 20 ml of pyridine. The beige solution obtained was stirred at 50° for 2.5 hours and subsequently poured into 220 ml of ice-water. The resulting precipitate was filtered off. After drying at 70°/10 Torr there were obtained 12.70 g (91%) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carbonitrile as a white powder of m.p. 197°-200°.
Reaction SMILES: [NH2:1][C:2]([CH2:14][F:15])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:17]O>>[CH3:17][O:4][C:3](=[O:5])[C:2]([NH2:1])([CH2:14][F:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: CO
Reactant: NC(CF)(Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)(CF)Cc1ccc(O)cc1
Temperature: 90 °C
Yield: 70 %

Procedure:
With ice cooling, a suspension of 2-amino-2-fluoromethyl-3-(4-hydroxyphenyl)propionic acid (10.0 g) in absolute methanol (400 ml, dried over magnesium) is saturated with HCl gas. After heating at 90° C. overnight, the solvent is removed under reduced pressure, and the residue is dried for 3 hours under the vacuum of an oil pump. After dissolving in absolute methanol (400 ml) and saturating with HCl gas, the mixture is heated at 90° C. overnight again. After evaporation of the solvent, the residue is dissolved in water and a solution of sodium carbonate is added with stirring until pH ~10. The suspension is extracted 3 times with ether; the combined ether extracts are filtered, washed carefully with water, dried (Na2SO4) and evaporated to give pure methyl-2-amino-2-fluoromethyl-3-(4-hydroxyphenyl)propionate (7.5 g, 70%) as white crystals, m.p. 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1
Temperature: 55 °C

Procedure:
To a stirred solution of 34.14 g (0.200 moles) of 4-bromoaniline in 130 ml toluene under N2, 18.00 g (0.220 moles) of diketene was added dropwise over a 10 minute period followed by 15 ml of toluene. The temperature rose to 80° C. during the addition; the solution was then refluxed 20 minutes, cooled to 55° C. and 60 ml of petroleum ether added. An immediate precipitation occurred. The tan-white crystals were filtered and washed with three 100 ml portions of 1:1 toluene/petroleum ether. The product was taken up in hot absolute ethanol and crystallisation induced by addition of toluene to the ethanolic solution. Three crops of crystals from the ethanol/toluene solvent system gave 22.90 g (43%) and had Rf 0.69 on silica TLC with ethyl acetate; mp 135.8°-137.2° C. Anal. Calcd. for C10H10BrNO2 : C, 46.90; H, 3.94; N, 5.47; Br, 31.20. Found: C, 47.13; H, 4.00; N, 5.46; Br, 31.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13](O)=[O:14])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[C:5]2[CH3:22].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][OH:14])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[C:5]2[CH3:22]
Reactant: Cc1c(-c2ccccn2)n(CCC(=O)O)c2ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(-c2ccccn2)n(CCCO)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 3-(5-chloro-3-methyl-2-pyridinyl-indol-1-yl)-propionic acid (0.344 g, 1.09 mmol) and THF (10 mL). The reaction mixture is cooled to 0° C. and LAH (1M in THF, 2.73 mL, 2.73 mmol) is added. After stirring at room temperature for 30 min, the mixture is cooled to 0° C., quenched with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford 3-(5-chloro-3-methyl-2-pyridinyl-indol-1-yl)-propan-1-ol as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.71-1.82 (m, 2H), 2.23 (s, 3H), 3.38 (t, J=6.1 Hz, 2H), 4.18-4.24 (m, 2H), 7.21 (dd, J=8.8, 2.0 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.65 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 7.98 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.65 (dd, J=2.3, 0.8 Hz, 1H), 8.67 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI) m/z 301.1108 [(M+H)+ Calcd for C17H18ClN2O: 301.1108].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2].[Br:22]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:22])=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCN2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCCN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
A mixture of the product from Example 87 (0.15 g, 0.5 mmol) and N-bromosuccinimide (0.23 g, 1 mmol) in 2 mL dimethylformamide was stirred at room temperature for 18 hours. The solution was poured onto methylene chloride/water and separated and the water layer back extracted with methylene chloride. The combined organic layers were washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (4:1 to 1:1 heptane:ethyl acetate as eluant) to give the title compound (0.15 g, 81% yield).
Reaction SMILES: Br.COC([N:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:8][C@H:7]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>C(O)(=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:7]2[CH2:8][C@@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:11][NH:6]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@H](NC(C)=O)C[C@H]1Cc1ccc(Cl)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N[C@H]1CCN[C@H](Cc2ccc(Cl)cc2)C1
Reaction time: 16 h

Procedure:
51.8 ml of 33% hydrogen bromide in acetic acid are added to (2R*,4S*)-4-acetylamino-2-(4-chloro-benzyl)-piperidine-1-carboxylic acid methyl ester (30.0 g, 92.3 mmol). After 16 hours, 200 ml of water are added to the mixture which is then washed twice with toluene. The aqueous phase is rendered basic and extracted twice with ethyl acetate. The organic phases are dried on potassium carbonate and concentrated by evaporation using a rotary evaporator. The title compound crystallises in the form of a hydrochloride from EtOH/ethyl acetate. M.p.: 288-289° C. TLC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf =0.17, FD-MS: (M+1)+ =267.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[O:22])=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1ccccc1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with benzaldehyde (56)(0.21 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.85 g (1.72 mmol, 86%) of 67 as a light yellow gum; IR (CH2Cl2) 3440, 2975, 1692, 1620, 1552, 1470, 1298, 1212, 1100 cm-1 ; 1H NMR (CDCl3, 60 MHz) δ 1.16 (t, J=6 Hz, 6H), 2.26 (s, 6H), 3.30 (s, 3H), 3.50 (t, J=5 Hz, 2H), 4.16 (t, J=5 Hz, 2H), 4.70-5.06 (m, 2H), 6.86 (bs, 1H), 7.30-8.46 (m, 10H). Anal. Calcd for C28H32N2O6 : C, 68.29; H, 6.50. Found: C, 68.16; H, 6.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]([CH3:32])[C@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C@H:25]([N:24]([CH3:32])[C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:29]([CH3:31])[CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)N(C)C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
(S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.417 mmol), (R)-2-(tert-butoxycarbonyl(methyl)amino)-3-methylbutanoic acid (116 mg, 0.501 mmol), HOBT (77 mg, 0.501 mmol), EDC (96 mg, 0.501 mmol) and triethylamine (0.116 mL, 0.834 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc) to obtain tert-butyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl(methyl)carbamate (190 mg, 0.417 mmol, 100% yield) as a white glass. MS found: (M+H)+=453.15.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]2[CH3:18])[N:5]=[C:4](O)[CH:3]=1.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:36])=O>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]2[CH3:18])[N:5]=[C:4]([Cl:36])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(N2CCc3ccccc3C2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)nc(N2CCc3ccccc3C2C)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture solution of 6-methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-hydroxypyrimidine(7.0 g, 27.4 mmol) prepared in the above Step 2, phosphorous oxychloride(30 ml) and N,N-dimethylaniline(2. 3 ml) was stirred at 90° C. for 2 hours and cooled. The reaction mixture was added to ice water and basified with sodium bicarbonate and then was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4.5 g of titled compound.
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][CH:8]([NH:25][C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])(C)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([S:5][S:6][CH2:7][CH:8]([NH:25][C:26](=[O:27])[O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:9](=[O:10])[NH:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)([CH3:3])[CH3:2]
Reactant: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)NC(CSSC(C)C)C(=O)NC1CCNCC1
Reaction time: 2 h

Procedure:
To the compound from Example 60 (7.085 g, 18.12 mmol) was added 30 ml of 4M HCl/Dioxane. The reaction was completed after 2 h at RT. The title compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[N+:27]([O-:29])=[O:28])[CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1c1ccc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of Example 12C (625 mg, 4.03 mmol) in acetonitrile (5 mL) was added 1-fluoro-4-methyl-2-nitrobenzene (1.00 g, 4.03 mmol) and potassium carbonate (1.11 g, 805 mmol). The reaction was heated in an oil bath at 60° C. overnight. The solution was concentrated onto silica gel and purified via flash chromatography (0-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.55-7.60 (m, 1H), 7.22-7.43 (m, 7H), 3.55-3.65 (m, 1H), 3.41-3.59 (m, 2H), 3.36 (s, 3H), 3.09-3.21 (m, 1H), 2.77-2.88 (m, 1H), 2.22-2.62 (m, 7H); MS (APCI+) m/z 384 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@@H:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[CH3:30][C:31]1([C:34](Cl)=O)[CH2:33][CH2:32]1>>[CH3:28][S:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][C@H:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:30]([C:31]6([CH3:34])[CH2:33][CH2:32]6)[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:29][C:14]3=[CH:15][N:16]=2)[CH2:24][CH2:23]1)(=[O:27])=[O:26]
Reactant: CC1(C(=O)Cl)CC1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(C(=N)NO)CC2)C3)CC1
Product: CC1(c2nc(N3CCC([C@H]4Cc5cc(C6=CCN(S(C)(=O)=O)CC6)ncc5O4)CC3)no2)CC1

Procedure:
The title compound is prepared from (R)—N-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (Intermediate 45; the configuration of the stereocenter is arbitrarily assigned) and 1-methyl-cyclopropanecarbonyl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.53 min; Mass spectrum (ESI+): m/z=486 [M+H]+.