Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.O=C1CCC(=O)N1[O:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:21](=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCCNC(=O)OC(C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 105.8 %

Procedure:
A solution of dimethyl methylphosphonate (9.308 g, 75.01 mmol) in THF (30 mL) was cooled to −78 ° C. and treated with n-butyllithium (29.5 mL of 2.5 M). The reaction mixture was stirred at −78 ° C. for 10 min, followed by addition of 6-tert-butoxycarbonylamino-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (24-1) (5.060 g, 15.41 mmol) in THF (30 mL). After 15 min the reaction was quenched with aqueous NH4Cl and allowed to warm to room temperature overnight. The water was extracted three times with ethyl acetate and the combined organics washed with brine and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound 24-2 as a pale yellow oil (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](I)=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: O=c1[nH]cnc2c(I)c(-c3ccccc3Cl)nn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=c1[nH]cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 68 °C
Yield: 144.2 %

Procedure:
A mixture of 7-(2-chlorophenyl)-8-iodo-3H-pyrazolo[1,5-a][1,3,5]-triazin-4-one (I-3A-9d; 500 mg, 1.34 mmol), 4-chlorophenylboronic acid (315 mg, 2.01 mmol), and tetrakis(triphenylphosphine)palladium (50 mg, 0.043 mmol) under an argon atmosphere in ethanol (12 ml) and 2M aqueous Na2CO3 (2.5 ml) was degassed (3×) by pulling a vacuum followed by refilling with argon gas. The mixture was heated at 68° C. for 7 hours and then cooled to room temperature. The mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), and concentrated, in vacuo, to afford a dark, viscous oil (690 mg). The product was crystallized from methanol and then collected by vacuum filtration to afford, after rinsing with methanol, intermediate I-3A-9e (218 mg, 45%) as a solid: +APcI MS (M+1) 357.0; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.54-7.41 (m, 4H), 7.34 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)#N.C[O:26]C1C=CC(N2[C@@H](C)[C@@H](COC3C=CC(C#N)=CC=3)OC2=O)=CC=1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[O:11][C:10]2=[O:24])=[CH:5][CH:4]=1)=[O:26]
Reactant: N#Cc1ccc(N2CC(COc3ccc(C=O)cc3)OC2=O)cc1
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Product: O=Cc1ccc(OCC2CN(c3ccc(C=O)cc3)C(=O)O2)cc1
Yield: 89 %

Procedure:
The same procedure of Example 16 was repeated except that 4-[3-(4-cyanophenyl)-2-oxooxazolidin-5-yl]methoxybenzaldehyde (compound 34) obtained in Example 2 was used in lieu of 4-[(4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile to give the title compound (compound 173) in a yield of 89%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(OC(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6 mmol) was added to the (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate in methylene chloride (2 mL). The reaction was stirred for 1 h., and was concentrated under reduced pressure to give a crude product, methyl (2S)-2-amino-3-(4-isopropoxyphenyl)propanoate (40 mg, 100%) as colorless oil. Analytical LCMS (M+H)+: m/z=238.0.
Reaction SMILES: O.C([O-])([O-])=O.[K+].[K+].[CH3:8][N:9]([CH2:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH2:17][N:18](C(=O)C(F)(F)F)[CH2:19][CH2:20][C:14]=2[CH:13]=1)[CH3:10]>CO>[CH3:8][N:9]([CH3:10])[CH2:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=2[CH:13]=1
Reactant: CN(C)Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
50 mL water and 8.5 g (61.51 mmol) K2CO3 were added to a solution of 4.5 g (14.98 mmol) 1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoroethanone in 50 mL MeOH and the reaction mixture was stirred for 72 h at RT. The reaction solution was evaporated down i.vac., the residue was combined with DCM, filtered to remove insoluble ingredients and evaporated down i.vac. The desired product was obtained in the form of a light-brown oil.
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([N:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>CN(C=O)C.C1COCC1>[C:41]([N:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:32](=[O:33])[CH2:31][N:10]1[C:11](=[O:15])[CH2:12][C:13](=[O:14])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]1=2)([CH3:42])([CH3:43])[CH3:44]
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: CC(C)(C)N(C(=O)CBr)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 600 mg (2.38 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 16 mL DMF is added 2.62 mL (2.62 mmol, 1.1 equiv) of 1M Sodium bis(trimethylsilyl)amide in THF at ambient temperature and stirred 0.5 h. To this solution is added 707 mg (2.62 mmol, 1.1 equiv) 2-Bromo-N-tert-butyl-N-phenyl-acetamide, prepared as in Part A, in 4 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc, washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on 40 g silica gel eluted successively with EtOAc/Hexanes (2:3, 500 mL), (1:1, 750 mL). Appropriate fractions were combined and concentrated in vacuo to give 748 mg (1.69 mmol) of N-tert-Butyl-2-(2,4-dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.45-7.21 (m, 12H), 7.08 (t, 1H), 6.90 (m, 1H), 4.30 (d, 1H, J=16.4), 3.85 (d, 1H, J=16.6), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.43 (s, 9H); TLC Rf =0.24 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[N+]=[N-].[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:16]([CH:15]1[CH2:14][N:1]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CCCCCCC
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1
Product: CCCCCCC1CN1c1ccc(C(F)(F)F)cc1

Procedure:
1-azido-4-(trifluoromethyl)-benzene (0.392 g, 2.09 mmol), 1-octene (3.575 g, 31.9 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0029 g, 0.0021 mmol) were used in the General Catalytic Reaction described above yielding 0.212 g, 37.3%. 1H NMR (CDCl3, 499.74 MHz): δ 7.47 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 2.13 (m, 2H), 2.09 (d, J=6.0 Hz, 1H), 1.58 (m, 4H), 1.41 (m, 2H), 1.34 (m, 4H), 0.92 (t, J=6.5 Hz, 3H). 13C NMR (CDCl3, 125.66 MHz): δ 158.40, 126.27 (q, J=3.8 Hz), 124.60 (q, J=270.0 Hz), 124.19 (q, J=32.7 Hz), 120.83, 40.55, 34.23, 33.16, 31.97, 29.32, 27.71, 22.75, 14.18. 19F NMR (CDCl3, 470.2 MHz): δ −61.7. GC/MS (m/z): 271.1. DART HR MS (m/z): [M+H]+272.1609 (found). C15H21F3N, 272.1626 (calcd).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:8]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:6])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH2:1]([O:4][C:5]([N:7]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:8]([CH2:18][OH:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(CC(=O)OC)[C@@H](CCC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C=CCOC(=O)N(CC(=O)OC)[C@H](CO)CCC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 892.7 %

Procedure:
To a solution of tert-butyl (4S)-4-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}pentanoate (5.29 g, 1.2 mmol) in methanol (106 ml) was added p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol) and the mixture was stirred for 30 minutes. To the mixture was further added p-toluenesulfonic acid monohydrate (0.22 g, 1.2 mmol) and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography to give tert-butyl (4S)-4-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino]-5-hydroxypentanoate (3.7 g, 93%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[NH:13][C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl[CH2:24][C:25]([CH:27]1[O:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29][CH2:28]1)=[O:26]>CN(C)C=O>[CH3:35][O:34][C:32]([CH:30]1[O:31][CH:27]([C:25]([CH2:24][S:7][C@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:26])[CH2:28][CH2:29]1)=[O:33]
Reactant: COC(=O)C1CCC(C(=O)CCl)O1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(C(=O)CS[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Potassium carbonate (2.0 g) was added to a stirred solution of (3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-one (2.31 g) and methyl (2RS,5SR)-5-(2-chloroacetyl)tetrahydro-2-furoate (2.02 g) in dimethylformamide (30 ml). The mixture was stirred at room temperature for 1.5 h and then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed three times with water, then brine, dried over magnesium sulphate and evaporated. The title compound (2.208 g) was isolated by column chromatography of the residue (silica gel, ethyl acetate as eluent); νmax (CHCl3) 3410, 3335, 1777, 1736 and 1678 cm -1.
Reaction SMILES: [C:1]([O:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1)(=[O:16])[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)=[O:4].[C:28]([C:32]1[CH:33]=[C:34]([CH:39]=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:41]=1[OH:42])[CH2:35]N(C)C)([CH3:31])([CH3:30])[CH3:29].[NH2-].[Li+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:14][C:8]1([CH3:15])[CH2:7][CH:6]([O:5][C:3](=[O:4])[CH:2]([CH2:35][C:34]2[CH:33]=[C:32]([C:28]([CH3:29])([CH3:31])[CH3:30])[C:41]([OH:42])=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:1]([O:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[O:16])[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9]1
Reactant: CC1(C)CC(OC(=O)CC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CC(OC(=O)C(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
26 g (0.068 mole) of bis-(2,2,6,6-tetramethyl-4-piperidinyl) malonate and 17.8 g (0.068 mole) of N-(3,5-di-tert.butyl-4-hydroxybenzyl)dimethylamine are dissolved in 200 ml of toluene. After the addition of 0.5 g of lithium amide, the mixture is refluxed for 3 hours. After cooling, the mixture is neutralised with 1.5 ml of 1% acetic acid, and the organic phase repeatedly washed with water. After drying over Na2SO4, the solution is concentrated in vacuo to obtain, as oily residue, 3,5-di-tert.butyl-4-hydroxybenzyl-malonic acid-bis(2,2,6,6-tetramethyl-4-piperidinyl)ester.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:16]#[N:8])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.6 %

Procedure:
4-(Di-tert-butoxycarbonylaminomethyl)benzonitrile (2 g, 6.0 mmoles) (prepared as described in Preparative Example 247, Step A above) was dissolved in TFA (4 mL) and the solution was stirred at 25° C. for 0.25 h. The reaction mixture was diluted with dichloromethane and extracted with 1N sodium hydroxide. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (15×5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(aminomethyl)benzonitrile (108 mg, 68%): FABMS: m/z 133.1 (MH+); HRFABMS: m/z133.0764 (MH+). Calcd. for C8H9N2: m/z 133.0766; δH (CDCl3) 2.04 (2H, s, —CH2NH2), 3.89 (2H, s, —CH2NH2), 7.40 (2H, d, Ar—H) and 7.59 ppm (2H, d, Ar—H); δC (CDCl3) CH2, 45.7; CH, 127.8, 127.8, 132.4, 132.4; C, 110.6, 118.9, 148.0.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:10][OH:11])[CH2:4][CH3:5])[CH3:2].[Cl:22][C:23]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27](Cl)=[O:28]>C1C=CC=CC=1.CCOCC>[Cl:22][C:23]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27]([O:11][CH2:10][C:9]1[C:12]([CH3:18])=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8]=1[N+:19]([O-:21])=[O:20])=[O:28]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(=O)COc2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
3-[(1-Ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl alcohol (2.0 g; 0.007 mol) and 2,4-dichlorophenoxyacetyl chloride (used in excess over theory) are dissolved in benzene, and the solution stirred at 60° C. until tlc (silica gel-benzene) indicates the reaction to be complete. The reaction mixture is then cooled down, diluted with ether, and washed with dilute sodium bicarbonate solution until the washings became alkaline. The organic layer is then separated, dried over magnesium sulfate, and evaporated to afford a liquid residue, which solidifies gradually (3.3 g; 94%). Recrystallization of this solid from methanol affords 1.4 g of title product, melting point 103°-106° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.11 g, 0.40 mmol) and 3-fluoro-5-piperidin-1-ylbenzoic acid (0.10 g, 0.40 mmol) according to conditions described in general procedures E and F. A light pink solid is produced (67 mg). Mp: 150-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.60 (bs, 6H), 2.49-2.57 (m, 4H), 2.89 (bs, 2H), 3.30 (bs, 4H), 3.61 (bs, 4H), 4.32 (bs, 2H), 3.96 (d, J=12.6 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.15 (d, J=9.3 Hz, 1H), 7.40-7.45 (m, 2H), 7.54-7.57 (m, 2H), 7.83-7.87 (m, 1H), 8.23 (s, 1H), 10.24 (s, 1H); MS 478 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:4]1[N:3]([CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[N:1][CH:6]=[CH:5]1
Reactant: O=c1ccnc[nH]1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1cnccc1=O
Temperature: 105 °C

Procedure:
To pyrimidin-4(3H)-one (0.608 g, 6.33 mmol) was added 5 N sodium hydroxide solution (2.5 mL) followed by chloroacetic acid (0.598 g, 6.33 mmol). The reaction mixture was heated at 105° C. for 2 h. After cooled down to ambient temperature, it was neutralized with 2 N hydrochloric acid (3.2 mL) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.43 (s, 1H), 7.94 (d, J=6.7 Hz, 1H), 6.43 (d, J=6.6 Hz, 1H), 4.63 (s, 2H). LC/MS 155.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: Nc1nc(NCCC2CC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1nc(NCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(2-cyclopropylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (4.17 g) in chloroform (46.0 ml) at 0° C., was added N-bromosuccinimide (2.58 g) to give a dark green suspension. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was taken up in dichloromethane (100 ml) and washed with water (1×100 ml). The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give a green gum (5.50 g, 80% pure).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:22]([C@H:24]([NH:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:35]=1[O:50][CH2:51][CH2:52][NH2:53])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1.O(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([C@H:24]([NH:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:35]=1[O:50][CH2:51][CH2:52][NH:53][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C(O)Cc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)Cc2ccncc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
0.41 g (2.4 mmol) of 4-pyridylacetic acid hydrochloride were suspended in 80 ml of CH2Cl2; the suspension was cooled to 0° C. and 0.33 ml (2.4 mmol) of TEA, 0.64 g (4.7 mmol) of HOBT and 1.0 g (2.4 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were added. 0.58 g (2.8 mmol) of DCC, dissolved in 10 ml of CH2Cl2, were added dropwise and the reaction mixture was stirred at 0° C. for 1 h and at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 20% citric acid, sat. sol. NaCl and brine, dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of CH2Cl2/MeOH 95:5 containing 0.5% NH4OH (28%), to yield, after trituration with i-Pr2O, 0.85 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([F:31])=[CH:24][C:23]=2[O:32][CH3:33])[N:9](CC2C=CC(OC)=CC=2)[C:8]1=[O:43]>C(O)(C(F)(F)F)=O>[F:51][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=1)[CH2:6][N:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=2[C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([F:31])=[CH:24][C:23]=2[O:32][CH3:33])[NH:9][C:8]1=[O:43]
Reactant: COc1ccc(CN2C(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C1CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)N1
Reaction time: 0.02 h

Procedure:
A solution of 15 mg of 1-[3,5-bis(trifluoromethyl)benzyl]4-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one in 0.5 mL of TFA was stirred overnight at r.t. The reaction mixture was concentrated and then purified by reverse-phase HPLC [Waters XTerra C8 19×25 mm column, eluting at 20 mL/min with 90% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 5.15 min, hold for 1.45 min, then back to 90% water over 0.5 min] to provide the title compound. Mass spectrum (ESI) 623.4 (M+1).
Reaction SMILES: [BrH:1].[Br:2][CH:3]1[CH2:18][CH2:17][C:6]2[N:7]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:8]3[S:9][C:5]=2[C:4]1=O.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)C>[BrH:2].[BrH:1].[NH2:23][C:21]1[S:22][C:3]2[CH2:18][CH2:17][C:6]3[N:7]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=[C:8]4[S:9][C:5]=3[C:4]=2[N:20]=1
Reactant: O=C1c2sc3nc4ccccc4n3c2CCC1Br
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CCc1c-2sc2nc3ccccc3n12
Yield: 61 %

Procedure:
2-Bromo-1,3-cyclohexadione prepared in Example 1, Route 1 (A) was reacted with 2-mercaptobenzimidazole in the same manner as that of Example 1, Route 1 (B) to give 1,2-dihydrobenzimidazo[2,1-b]benzothiazole-4(3H)-one (Compound (IIb) of Reaction Scheme II), which was subjected to bromination in the same manner as that of Example 1, Route 1 (C) to give 3-bromo-1,2-dihydrobenzimidazo[2,1-b] benzothiazole-4(3H)-one hydrobromide. The hydrobromide (1.45 g) and thiourea (0.15 g) were placed into ethanol (50 ml), and the mixture was heated to reflux for 2 hours, cooled, and the filtered to give the titled compound (61%).