Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:7]=[C:8]([NH2:18])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](=[O:30])[NH:18][C:8]1[N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=[C:6]([C:3]2([O:2][CH3:1])[CH2:5][CH2:4]2)[CH:7]=1
Reactant: COC1(c2cc(N)n(-c3ccc(C)cc3)n2)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC1(c2cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c3ccc(C)cc3)n2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To an ice-salt cooled solution of 5-(1-methoxy-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (Preparation 11, 2.43 g, 10 mmol) and pyridine (0.9 mL, 11 mmol) in THF (30 mL), add a solution of 2,2,2-trichloroethylchloroformate (2.12 g, 10 mmol) in THF (10 mL) dropwise. Stir at −15° C. for 0.5 hour, then at 22° C. for 1 hour. Partition the reaction mixture between dichloromethane (50 mL) and saturated aq. sodium bicarbonate (50 mL). Isolate the aqueous phase and extract twice with dichloromethane (25 mL each). Dry the combined organic phases over sodium sulfate and concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give a white solid (3.73 g, 89% yield, ES+(m/z) 418.1 [M+H]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][S:10]SC>CCCCCC.O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[S:10][CH3:9]
Reactant: Fc1cccc(Cl)c1
Reactant: CSSC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1c(F)cccc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 126.7 %

Procedure:
n-Butylithium (2.5M in hexane, 129 ml) was added to a solution of 3-fluorochlorobenzene (35 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3 hours and dimethyl disulphide (60.65 g) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was evaporated to dryness and the residue was suspended in ether and washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-chloro-6-fluorothioanisole (60 g) as a crude yellow oil containing some dimethyl disulphide, NMR (CDCl3) 2.45(s,3H), 6.95(t,1H), 7.1-7.3(m,2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(Cl)CCl>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: ClCCCl
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 56.2 %

Procedure:
19.8 gm (0.062 mol) of 4-hydroxy-2-methyl-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide were reacted with 9.3 gm (0.093 mol) of 2-amino-thiazole in 500 ml of xylene analogous to Example 1 and yielded 13.5 gm (56% of theory) of 4-hydroxy-2-methyl-N-(2thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 248°-249° C (decomp.; from ethylene chloride).
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[OH:14][CH2:15][CH:16]([CH2:18][OH:19])[OH:17]>O>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:14][CH2:15][CH:16]([CH2:18][OH:19])[O:17][C:10]([CH:3]2[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]2)=[O:11])=[O:11])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: OCC(O)CO
Solvent: O
Product: CC1CCC(C(C)C)C(C(=O)OCC(CO)OC(=O)C2CC(C)CCC2C(C)C)C1

Procedure:
A mixture of p-menth-3-oyl chloride (2 g.) and glycerol (20 ml.) was heated at 100° for 4 hours. The mixture was then poured into water (600 ml.) and extracted 3 times with ether. The extracts were dried (MgSO4) and the solvent removed under reduced pressure to leave 1,2-bis-(p-menth-3-oyl)glycerol as a colourless oil (1.2 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.CC(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: COc1cccc(C(=O)O)c1
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)c1
Temperature: 4 °C
Yield: 72 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-methoxybenzoic acid (12.17 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (15.5 g; m.p. 176° C.) is dissolved in boiling 2-propanol (500 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (3×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxybenzamide (11.2 g) is produced, m.p. 178° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][CH2:21][CH2:22][OH:23])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCCO
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)NCCO

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-N-(2-hydroxy-ethyl)-3-phenyl-propionamide [JACS 1969, 91, 2684-2691.] in DMSO to provide the title compound in good yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added cyclohexanecarbonyl chloride (126 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 69%).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1cccc(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cccc(C(Cl)c2ccccc2)c1
Yield: 44 %

Procedure:
A solution of phenyl(3-(trifluoromethoxy)phenyl)methanol (300 mg, 1.12 mmol) in thionyl chloride (50 mL) was refluxed for 5 h. The solvent was removed and the residue was purified by silica gel chromatography (eluting with petroleum ether/EtOAc=100/1) to give the target compound (140 mg, 44%) as a pale yellow oil. 1H-NMR (500 MHz, DMSO-d6): δ 7.56-7.49 (m, 5H), 7.42-7.40 (m, 2H), 7.35-7.32 (m, 2H), 6.62 (m, 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([N:32]=[N+]=[N-])[CH2:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.C(O)(=O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:39])[C@H:7]([CH:36]([CH3:38])[CH3:37])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH2:32])[CH2:11][C@@H:12]([CH:29]([CH3:30])[CH3:31])[CH:13]([OH:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)N=[N+]=[N-])C(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(O)c1ccc(OC)c(CCOCOC)c1)C(C)C

Procedure:
40 mg of 5(S)-azido-4(S),8(R,S)-dihydroxy-2(S),7(S)-diisopropyl-8-[4-methoxy -3-(2-methoxymethoxyethyl)-phenyl]-octanoic acid (N-butyl)-amide are hydrogenated in 10 ml of methanol/acetic acid (9:1) in the presence of 20 mg of 10% Pd/C at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by FC (2.4 g of silcia gel, dichloromethane/methanol =9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.17; HPLC Rt =11.44 and 12.63 minutes (diastereoisomeric mixture); FAB-MS (M+H)+ =525.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=O)[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNCC(=O)Nc2cccc(Cl)c2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 2, react N-(3-chlorophenyl)-2-[[(3,4-dimethoxyphenyl)methyl]amino]acetamide (13.6 g, 40.1 mmol) with lithium aluminum hydride (3.1 g, 81 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(F)cc2)CCc2cc(O)ccc21
Temperature: 25 °C

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-fluorobenzaldehyde 0.79 ml were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and water 300 mg was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.65 g.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].C(C1C=C(C=CC=1)OCC([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)=O)=O>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[O:11])=[CH:12][CH:13]=1)=[O:2]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Yield: 74 %

Procedure:
2-(4-Formylphenoxy)acetic acid (53) was treated in an analogous manner to Compound 49 to afford the desired product (74%) as a white solid. NMR: δ 1.461 (s, 9H), 3.38-3.64 (m, 8H), 4.802 (s, 2H), 2.06 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 9.899 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[N:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:13])[N:8]=2)[N:3]=1
Reactant: Brc1ccc2nc(Br)ccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 3-necked roundbottom flask was charged with a solution of 2,6-dibromo-1,5-naphthyridine (39 g, 135.42 mmol) in methanol (150 ml). The mixture was cooled to 0° C. and a solution of sodium methoxide (8.77 g, 162.41 mmol) in methanol (50 ml) was added dropwise. The resulting solution was allowed to react, with stirring, for three hours at 0° C. The reaction mixture was cooled to <0° C. and a solid precipitated. The mixture was filtered and the filtrated was quenched by the addition of 500 ml of ice water. The solids that formed were collected by filtration and them dissolved in ethyl acetate and dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using 1:10 ethyl acetate:petroleum ether as eluant to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([Li])[CH2:26]CC.C(I)C>C1COCC1>[CH2:25]([C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1)[CH3:26]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, ethyl iodide was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.89(s,2H), 6.07(s,1H), 3.72(d,1H), 3.34(m,1H), 2.58(q,2H), 2.16(s,3H), 2.12(s,3H), 2.09(s,6H), 1.4-1.7(m,4H), 1.25(t,3H), 0.96(t,6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C[N:22]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:22])=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 30a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol) followed by cooling in an ice bath and addition of isobutylchloroformate (0.148 mL, 1.14 mmol). The resulting mixture was allowed warm to room temperature with stirring for thirty minutes. Subsequent cooling in an ice bath was followed by addition of ammonia gas and warming to room temperature. The title compound was isolated by the addition of water and collection of the solid by vacuum filtration was used without further purification (0.289 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:36]([N:43]1[C:47](=[O:48])[C:46]2([CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[N:45]([C:54]2[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=2)[C:44]1=[O:61])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([N:43]1[C:47](=[O:48])[C:46]2([CH2:53][CH2:52][N:51]([CH2:29][CH2:28][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10]3)[CH2:50][CH2:49]2)[N:45]([C:54]2[CH:55]=[CH:56][C:57]([F:60])=[CH:58][CH:59]=2)[C:44]1=[O:61])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1N(Cc2ccccc2)C(=O)C2(CCNCC2)N1c1ccc(F)cc1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)N(Cc3ccccc3)C(=O)N4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 3-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH3:22])=[O:20])[CH:8](CC1C=CC=CC=1)[C:9](=[O:11])[OH:10])=[O:5])[CH3:2].C1(C[O:46][C:47]([C@@:49](C(Cl)=O)([CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:57])[NH2:56])[NH2:50])=O)C=CC=CC=1>C(O)(=O)C.O.[Pd]>[NH2:50][C@H:49]([C:47]([N:1]([CH2:3][C:4]([NH:6][C@H:7]([C:19]([N:21]([CH2:23][C:24]([NH:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:25])[CH3:22])=[O:20])[CH2:8][C:9](=[O:11])[OH:10])=[O:5])[CH3:2])=[O:46])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:56])[NH2:57]
Reactant: CNCC(=O)N[C@H](C(=O)N(C)CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(Cc1ccccc1)C(=O)O
Reactant: N=C(N)NCCC[C@](N)(C(=O)Cl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN(CC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)C(=O)[C@H](CC(=O)O)NC(=O)CN(C)C(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 15 h
Yield: 50.4 %

Procedure:
Alpha-Phenylmethoxycarbonyl-L-Arginyl(HCL)-Sarcosyl-beta-benzyl-L-Aspartyl-Sarcosyl-L-Tyrosine amide (1.0 g) was dissolved in 100 ml of 75% aqueous acetic acid and reduced with 0.5 g of 10% Pd/C at 50 p.s.i. for 15 hours. The catalyst was removed by filtration and the solution lyophilized to give 0.8 g. The material was dissolved in 7 ml water, filtered through a 3μ multipore filter, adjusted to pH 5 with NH4OH(conc.) and chromatographed in an SP-C-25 column (2.5×100 cm) with 0.20 M NH4OAc, pH 5.0, 100 ml/hr, 20 ml/tube. Tubes 71 to 78 were pooled and lyophilized to give 0.35 g of Arg-Sar-Asp-Sar-Tyr-NH2.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH2:3].C(N(CC)CC)C>ClCCl>[CH2:3]1[CH:2]2[CH2:1][CH:4]3[C:5]([CH:10]2[C:11]1=[O:13])=[CH:6][CH2:7][CH2:8][CH2:9]3
Reactant: C=CCC1CCCCC1=CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2CC3CCCC=C3C12
Yield: 83.3 %

Procedure:
A solution of 2-(2-allylcyclohexylidene)acetic acid (800 mg, 4.44 mmol) in dichloromethane (200 mL) was added Ghosez reagent (5.77 mmol, 0.795 mL) at room temperature. The solution was stirred for 45 min until the acid chloride was formed. Then N,N-dimethylaminopyridine (55 mg, 0.45 mmol) was added and the solution was heated to reflux. A solution of triethylamine (8.9 mmol, 1.25 mL) in dichloromethane (3.75 mL) was added dropwise over 30 min. The solution was refluxed for another 1 h and solvent was distilled off. Purification by flash chromatography (pentane/Et2O 95/5) gave 1,2a,4,5,6,6a,7,7a-octahydrocyclobuta[a]inden-2-one (600 mg, 83%) as a colourless liquid, with 20% of the tetrasubstituted regioisomere. 1H NMR (400 MHz, CDCl3) 5.59 (1H, brs), 3.92 (1H, brs), 3.21 (1H, dddd), 2.92 (1H, m), 2.73 (1H, m), 2.51 (1H, m), 2.04 (4H, m), 1.79 (1H, m), 1.48 (2H, m), 1.05 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:13]1(=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.4 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 14.75 g (55 mmol) of N-(3-bromopropyl)phthalimide in 80 ml of DMF was added 8.23 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture was stirred at room temperature for 6 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.32 g of the desired compound (yield: 16.4% colorless crystals).
Reaction SMILES: C(O)=O.[CH2:4]=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]3)[NH:13]2)[CH:7]=1.[OH-].[Na+]>O>[CH3:4][N:13]1[CH:12]([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)[CH:17]2[CH2:18][CH2:19][CH:14]1[CH2:15][CH2:16]2
Reactant: c1cncc(C2NC3CCC2CC3)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN1C2CCC(CC2)C1c1cccnc1
Temperature: 0 °C
Yield: 88 %

Procedure:
Formic acid (5 mL, 95-97%) and formaldehyde (0.5 mL, 37%) were added to 3-(3-pyridyl)-2-azabicylo[2.2.2]octane (XIII) (170 mg) and refluxed for 24 hours under N2. The reaction mixture was cooled to 0° C. (ice bath), basified by addition of a solution of 40% w/v NaOH in water (pH=9) and extracted with chloroform (4×10 mL). The combined extracts were dried over anhydrous K2CO3, filtered and concentrated. The resulting oil was purified by distillation under reduced pressure (116°-118° C./0.4 mm Hg) to give 160 mg (88%) of (+/-)-2-methyl-3-(3-pyridyl)-2-azabicylo[2.2.2]octane (XV). 1H NMR(CDCl3): δ 8.85 (s, 1H), 8.80-8.10 (d, 1H), 7.78-7.71 (m, 1H), 7.23-7.20 (m, 1H),4.70 (s, 1H), 3.60 (s, 1H), 2.5 (s, 3H), 2.25 (s, 1H), 2.20-1.95 (m, 2H), 1.80-1.69 (m, 3H), 1.50-1.42 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][N:10]=[C:9]2[SH:19])=[CH:4][CH:3]=1.[F:20][C:21]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:22]=1[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][N:10]=[C:9]2[S:19][CH2:23][C:22]2[C:25]([F:30])=[CH:26][CH:27]=[C:28]([F:29])[C:21]=2[F:20])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CON(C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A mixture of 1-(4-fluorophenyl)-2-mercapto-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (8) (153 mg, 0.54 mmol), 2,3,6-trifluorobenzyl bromide (71 μL, 0.54 mmol), and potassium carbonate (90 mg, 0.65 mmol) in acetone (5 mL) was heated at reflux for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-N-methoxy-N-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (9) as a white solid.