Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([CH:20]([CH3:22])[CH3:21])=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].[BH4-].[Na+]>>[CH:20]([C:5]1[C:4]([CH2:3][CH2:2][NH:1][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1c(CCN)cccc1Oc1ccc(C(N)=O)cn1
Reactant: CCCCC=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCNCCc1cccc(Oc2ccc(C(N)=O)cn2)c1C(C)C
Yield: 66.3 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-[3-(2-amino-ethyl)-2-isopropyl-phenoxy]-nicotinamide (299 mg, 1.00 mmol), valeraldehyde (112 mg, 1.30 mmol), and NaBH4 (57 mg, 1.50 mmol) gave the title compound (245 mg) as a colorless glass. Mass spectrum (ion spray): m/z=370 (M+1); 1HNMR (DMSO-d6): 8.59 (s, 1H), 8.22 (d, 1H), 8.00 (s, 1H), 7.44 (s, 1H), 7.10 (t, 1H), 7.01 (m, 2H), 6.80 (d, 1H), 3.24 (m, 1H), 2.76 (m, 2H), 2.63 (m, 2H), 2.50 (m, 2H), 1.38 (m, 2H), 1.25 (m, 4H), 1.16 (d, 6H), 0.84 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[C:6]=2[CH:16]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[C:6]=2[CH:16]=1
Reactant: O=S1(=O)c2ccccc2-c2ccc(F)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1cc(F)ccc1-2
Temperature: 18 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a mixture of 8.94 g of 3-fluorodibenzothiophene S,S-dioxide in 100 ml of concentrated sulfuric acid, cooled at 18° C. in a water bath, was added dropwise 3.12 g of 71% nitric acid over 3 minutes. The mixture was stirred at room temperature for one hour, then poured over 500 ml of crushed ice and the solid collected, washed with water until neutral then dried at 100° C. This solid was dissolved in 200 ml of acetonitrile, treated with charcoal, filtered through diatomaceous earth and the filtrate concentrated to 110 ml producing successive crops of crystals. The first two crops were combined and recrystallized from 100 ml of acetonitrile, giving 7.56 g of the desired product as a solid, mp 275°-279° C.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2c1C(=O)C(O)=CC2=O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1C(=O)C(O)=C([N+](=O)[O-])C2=O
Yield: 43 %

Procedure:
A solution of 3-hydroxy-5-methyl-1,4-naphthoquinone (1.9g) in chloroform (200ml) was nitrated with fuming nitric acid according to example 1(a). A yield of 1.01g (43%) of material of m.p. 148°-149° C (d) was obtained. (Found; C, 56.69; H, 3.16; N, 5,73; C11H7NO5 requires; C, 56.66; H, 3.03; N, 6.01%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: OCC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: OCC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 72.3 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), piperidin-4-ylmethanol (35 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 85:15) to furnish the title compound as white solid (51 mg, 71%), LC-MS (ESI, 3.5 min) Rt 2.49 min, m/z 261 (100%, [M+H]+); m/z (ESI) C11H15Cl2N2O requires 261.0556 found [M+H]+ 261.0558; HPLC Rt 6.68 min, 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4′-hydroxy-2′-methylacetophenone (24.88 g; 165.7 mmol)), KI (5.50 g; 33.1 mmol), K2CO3 (34.3 g; 248.5 mmol) and benzyl bromide (21.7 mL; 182.2 mmol) in acetone (200 mL) was stirred overnight at RT. Subsequently the resulting mixture was filtered and partitioned between EtOAc and 5% aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford 1-(4-benzyloxy-2-methylphenyl)-ethanone, which was used as such.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:18][C:13]1[CH:12]=[CH:11][C:16]([O:17][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Temperature: 160 °C
Yield: 51.5 %

Procedure:
A mixture of 5-bromo-1H-indole (98.0 mg, 0.500 mmol), p-cresol (108 mg, 1.00 mmol), Cu (32.0 mg, 0.500 mmol), K2CO3 (138 mg, 1.00 mL) and DMF (1.00 mL) was heated at 160° C. for 12 h. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc (4:1) to give the desired product 5-(4-methylphenoxy)-1H-indole (57.5 mg, 51.5%): ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2.[BrH:19]>OS(O)(=O)=O.CC(O)=O.O>[Br:19][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2
Reactant: Br
Reactant: Nc1cccc2ccc(C(=O)O)cc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2cccc(Br)c2c1
Temperature: 10 °C
Yield: 55 %

Procedure:
According to the procedure of W. Adcock, et al. Aust. J. Chem. 18, 1351 (1965) and H. H. Hodgson, et al. J. Chem. Soc., 1620 (1933), to a cooled (10° C.), stirred solution of NaNO2 (1.24 g, 0.0179 mol) in H2SO4 (16.1 mL) and HOAc (14.9 mL) [prepared by adding NaNO2 to cooled (10° C.) H2SO4, heating to dissolve, recooling, and adding HOAc] was added a solution of 8-amino-2-naphthoic acid (2.80 g, 0.0150 mol) in HOAc (50 mL) over 10 minutes. The resulting solution was added slowly (over 10 minutes) to a heated (60° C.), stirred solution of CuBr (9.44 g, 0.0658 mol) in concentrated HBr (90 mL). The mixture was warmed to 90° C. for 10 minutes, cooled, diluted with H2O (200 mL) and filtered to give a green solid, 3.4 g. The crude product was combined with similarly prepared material (450 mg) and recrystallized from EtOH to give an off-white solid (2.3 g, 55%), m.p. 265°-266° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][NH:14][CH2:13]3)=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][N:14]([CH3:20])[CH2:13]3)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(C23CNCC2C3)c2ccccc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C23CC2CN(C)C3)c2ccccc12

Procedure:
A stirred solution/suspension of 1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (85 mg, 0.38 mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde (0.23 mL, 3.0 mmol), then with sodium triacetoxyborohydride (318 mg, 1.5 mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride containing 2-propanol (2×10 mL). The combined organic solution was dried (MgSO4) and concentrated in vacuo to afford 1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (76 mg, 84%, essentially pure without chromatography). This was dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with ether, collected, and dried in vacuo to afford 1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane, hydrochloride (72 mg, 82%) as a white solid. MS (M+1) 238.1. 1H NMR (CDCl3) 12.70 (br s, 1H), 8.16 (m, 1H), 8.04 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 7.26 (m, 1H), 4.20 (m, 1H), 4.06 (m, 1H), 3.50 (m, 1H), 3.14 (m, 1H), 2.90 (d, 3H, J=5 Hz), 2.68 (s, 3H), 2.40 (m, 1H), 2.13 (m, 1H), 1.22 (m, 1H). 13C NMR (CDCl3) δ 135.73, 133.21, 131.70, 126.81, 126.35, 126.33, 125.41, 124.54, 61.65, 57.62, 41.52, 30.97, 22.37, 19.75.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33](O)=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]([CH:39]=O)[CH3:38]>C1COCC1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33]([NH:8][C:14]2[CH:15]=[CH:16][C:17]([CH2:39][N:37]([CH3:36])[CH:38]3[CH2:27][CH2:26][O:25][CH2:22][CH2:21]3)=[CH:18][CH:13]=2)=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (5 ml) was dissolved 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g). Under ice-cooling, to the solution were added oxalyl (0.11 ml) and DMF (catalytic amount). The mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. In THF (25 ml) was dissolved the residue, the solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15 g) and triethylamine (0.44 ml) in THF (10 ml), under ice-cooling. The mixture was stirred at room temperature under nitrogen atmosphere and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 33) (0.26 g) as pale yellow crystals.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 90.2 %

Procedure:
4.48 g (9.5 mmoles) of Z-D-Glp-Leu-Pro-NH2 are dissolved in 200 ml of methanol, 0.9 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the amorphous residue is triturated with ether. The resulting 3.07 g of crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 2.90 g (90.5%) of D-Glp-Leu-Pro-NH2 are obtained; Rf5 =0.40, [α]D25 =-23.6° (c=1%, in acetic acid).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.[CH3:10][O:11][C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:10][O:11][C:12]([CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:7]([C:3]1[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=1)=[O:9])=[O:18]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C1CCCN1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 172.9 %

Procedure:
To a solution of niacin (0.4 g 3.50 mmol) in DCM (10 mL) were added L-proline methyl ester (0.5 g, 3.21 mmol), N-methyl morpholine (1.1 mL, 0.10.5 mmol), EDC.HCl (1.2 g, 6.4 mmol) and catalytic amount of DMAP at ice temperature (0° C.). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 h. The resulting mixture diluted with DCM (100 mL) washed with water (2×100 mL) and dried over sodium sulphate. Solvent was evaporated under reduced pressure to obtain product as yellow gummy oil (1.3 g).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1>>[O:21]([C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:2]3[S:1][CH2:6][CH2:5][S:4][CH:3]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C1=CSCCS1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)C1=CSCCS1
Yield: 78.4 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5,6-dihydro-1,4-dithiin-2-carboxylic acid (10.9 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g), and heating for 18 hours under reflux. The product obtained, after precipitation in water, washing with water and drying (18 g; m.p. approximately 240° C.), is purified by recrystallization in dimethylformamide (150 cc). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-5,6-dihydro-1,4-dithiin-2carboxamide (15 g), m.p. 245° C., is thereby obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][C:5]1[S:1][C:2]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 1,3-thiazol-2-ylcarbamate (90 g, 449.8 mmol, 1 eq.) is taken in THF (1.4 L) to which is added N-bromosuccinimide (88.06 g, 494.8 mmol, 1.1 eq.) portion wise. The reaction mixture is then stirred at RT overnight. The reaction mass is concentrated to remove THF. The crude is purified by column chromatography to get the titled produce. 1H NMR (DMSO-d6, 400 MHz): δ 11.73 (bs, 1H), 7.42 (s, 1H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorobenzyl chloroformate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a cold (0° C.) solution of 2-bromo-6-nitrotoluene (43.2 g, 0.2 mol) in con H2SO4 (600 mL) was added HNO3 (37 g, 0.24 mol) in small portions with efficient agitation while maintaining the temperature at 0-10° C. The reaction mixture was allowed to slowly warm to RT with stirring overnight then poured into crushed ice (1600 g). The solid was collected by filtration, thoroughly washed with water and dried in air. The crude material was recrystallised from EtOAc/hexanes to afford 40 g (77%) of 1-bromo-2-methyl-3,4-dinitrobenzene (154) as a pale white solid: MS (ESI) m/z=262 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH3:11]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:11][N:3]1[C:4]([N+:8]([O-:10])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1]
Reactant: COS(=O)(=O)OC
Reactant: Cc1nc(C)c([N+](=O)[O-])[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nc(C)n(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58 %

Procedure:
2,4-dimethyl-5-nitroimidazole (7.0 g, 0.05 mole) and dimethylsulfate (7.0 ml, 0.074 mole) were heated at 100° C. for 1 hour 50 minutes. After cooling to room temperature, the reaction mixture was added to about 60 ml of water. Solid sodium bicarbonate was added until the solution is basic, and the mixture was then cooled on ice. The resulting crystals were filtered off and dried to give 6.2 g. This was recrystallized from water to give 4.5 g of 1,2,4-trimethyl-5-nitroimidazole.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([C:19]([OH:21])=[O:20])[C:6]=1[C:22]([OH:24])=O)[CH2:2][CH3:3].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[C:6]2[C:22](=[O:24])[O:20][C:19](=[O:21])[C:7]=2[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:2][CH3:3]
Reactant: CCCOc1c(C(=O)O)c(C(=O)O)c(OCCC)c2ccccc12
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCOc1c2c(c(OCCC)c3ccccc13)C(=O)OC2=O
Temperature: 65 °C
Yield: 103.7 %

Procedure:
1,4-Bis(propyloxy)-2,3-naphthalenedicarboxylic acid (8.91 g, 26.8 mmol) was suspended in chloroform (80 ml) and thionyl chloride (20.5 ml, 281.4 mmol) was added dropwise whilst monitoring the temperature (no significant change). The reaction was heated at 65° C. for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The yellow/brown solid was azeotroped with chloroform (×3) to afford the title compound as a beige solid (8.74 g, 27.8 mmol).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[Na]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Brc1ncccn1
Agent: [Na]
Solvent: CCO
Product: NCCCNc1ncccn1

Procedure:
Reaction of 2-bromopyrimidine with 1,3diaminopropane in ethanol containing sodium ethoride gives 2-(3-aminopropylamino)pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.CCN(CC)CC.[Cl:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([C:30](Cl)=[O:31])[CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([C:30]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:31])[CH:25]=1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Yield: 59.8 %

Procedure:
To a stirred and cooled (0° C.) solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (7.15 g, 34.7 mmol) and Et3N (14.0 g, 138.8 mmol) in DCM (100 mL) was added 6-chloropyrimidine-4-carbonyl chloride (5.5 g, 34.7 mmol). After addition, the resulting mixture was stirred at 25° C. for 16 h, at which time LCMS showed the completion of the reaction. The solvent was evaporated and the residue purified by flash chromatography to give the (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (7.2 g, yield: 60%). LCMS (m/z): 347.0 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][O:26][C:27]3=[O:31])=[CH:3][C:4]=2[O:24][CH3:25])=[O:9])[CH2:11][CH2:12]1
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Reactant: O=C1NCCO1
Product: COc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Yield: 50 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methoxyphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (807 mg) described in Preparation Example 5 and oxazolidin-2-one (174 mg), the title compound (409 mg) was obtained.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:27]=1[O:28][CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:27]=1[O:28][CH2:29][C:30]1([NH:33][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:32][CH2:31]1
Reactant: Cc1cccc(C)c1OCC1(N)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(C)c1OCC1(NCC(O)c2ccc(O)c3c2OCC(=O)N3)CC1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 191 mg (1 mmol) 1-(2,6-dimethyl-phenoxymethyl)-cyclopropylamine. Yield: 194 mg (49%, trifluoroacetate); mass spectroscopy: [M+H]+=399.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[NH3:32]>>[O:11]=[C:9]1[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][C:2]([NH2:32])=[O:1])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10]1
Reactant: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one employing a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 2 tR=1.327 min, m/z=430.2; 1H NMR (CDCl3) 1.49 (m, 3H), 1.93 (m, 1H), 2.12-2.34 (m, 5H), 2.44 (m, 1H), 2.94 (m, 1H), 5.46 (m, 2H), 5.67 (m, 1H), 7.08 (m, 2H), 7.19-7.42 (m, 5H), 7.45 (m, 2H), 7.80 (m, 2H), 8.76 (m, 2H).