Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH3:24])[CH3:23])[N:15]=3)[N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1O)[CH3:2].[CH2:27]1[O:29][C@H:28]1CCl.C(C1C=C([C:40]2[O:41]C(C3C=C(C)N=C(NC(C)C)N=3)=NN=2)C=C(C)C=1O)C>>[CH2:1]([C:3]1[C:8]([O:41][CH3:40])=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][CH:22]([CH3:23])[CH3:24])[N:15]=3)[N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[C@H:28]1[CH2:27][O:29]1)[CH3:2]
Reactant: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1O
Reactant: CCc1cc(-c2nnc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Product: CCc1c(OC)c(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1[C@H]1CO1

Procedure:
2-Ethyl-4-[3-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is reacted with R-epichlorohydrine in analogy to Intermediate 1 to give (S)-{4-[5-(3-ethyl-5-methyl-4-oxiranyl methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methyl-pyrimidin-2-yl}-iso-propyl-amine as a yellow oil; LC-MS: tR=1.10 min; [M+H]+=410.55.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][CH2:22][C:6]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:4]1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].Cl>C(N(CC)CC)C>[O:20]=[C:19]1[C:9]2[S:8][CH2:7][C:6]3([CH2:22][CH2:23][CH:3]([NH:2][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=4)[CH2:4][CH2:5]3)[O:11][C:10]=2[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:21]
Reactant: NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCC(NC(=O)c3cccc(C(F)(F)F)c3)CC1)O2

Procedure:
Compound 70 was synthesized using 4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione hydrochloride, 3-(trifluoromethyl)benzoyl chloride, triethylamine to neutralize the hydrochloride and conditions outlined in procedure N. M.p.=266-267° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.66 (d, J=7.8 Hz, 1H), 8.21-8.16 (m, 2H), 7.92 (d, J=7.4 Hz, 1H), 7.85 (t, J=7.1 Hz, 1H), 7.80 (t, J=7.1 Hz, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.58 (t, J=7.1 Hz, 1H), 4.08-3.94 (m, 1H), 3.06 (s, 2H), 2.20-2.10 (m, 2H), 1.94-1.72 (m, 7H), LCMS: 488 [M+H].
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:14]=C2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=C2O>ClCCCl>[Cl:11][C:6]1[C:7]2[C:20](=[CH:21][CH:22]=[C:13]([I:12])[CH:14]=2)[N:19]=[CH:18][N:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Oc1ncnc2ccc(I)cc12
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2×50 ml). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([C:22]4[CH:23]=[C:24]([NH:28][C:29]([C:31]5[N:32]([CH3:37])[N:33]=[C:34]([CH3:36])[CH:35]=5)=[O:30])[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:38])=[CH:5][CH:4]=1.Cl.[CH3:40][N:41]([CH2:43][C:44](Cl)=[O:45])[CH3:42].C(N(CC)CC)C>CN(C=O)C>[CH3:37][N:32]1[C:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:20]([C:16]2[CH:15]=[C:14]3[C:19]([C:11](=[CH:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:44](=[O:45])[CH2:43][N:41]([CH3:42])[CH3:40])=[CH:8][CH:7]=4)[C:12](=[O:38])[NH:13]3)=[CH:18][CH:17]=2)=[O:21])=[O:30])=[CH:35][C:34]([CH3:36])=[N:33]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CO)cc3)c2)n(C)n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(COC(=O)CN(C)C)cc3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
In a dry 50 mL round bottomed flask, 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-{3-[(4-hydroxymethyl-phenylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carbonyl}-phenyl)-amide (as prepared in Example 331, 0.020 mg, 0.039 mmol) was dissolved in DMF (1 mL), under Ar(g). Dimethylaminoacetyl chloride hydrochloride (9.32 mg, 0.059 mmol) was then added followed by triethylamine (0.016 mL, 0.117 mmol). The mixture was stirred at room temperature for 2 hours after which the reaction mixture was partitioned between EtOAc (˜5 mL) and brine (˜5 mL). The organic layer was extracted with brine (3×5 mL). The organic layers were combined and then concentrated in vacuo. The crude residue was then chromatographed over silica (EtOAc/MeOH gradiant was used starting from 1% MeOH up to 5% MeOH). The pure product was isolated as a yellow solid (15.5 mg, 0.026 mmol, 67%).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4C=CN=[C:24]4[CH3:28])=[CH:19][CH:18]=3)[CH:11]=2)[CH2:8][CH2:7][O:6][CH:5](C)[CH2:4]1)#[N:2].[CH3:29][C:30]1[CH:34]=C(C)N(C2C=CC(I)=CC=2)[N:31]=1.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOCC1)#N.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOC(C)C1)#N>>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:24]([CH3:28])=[CH:29][C:30]([CH3:34])=[N:31]4)=[CH:19][CH:18]=3)[CH:11]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOC(C)C3)c2)cc1
Reactant: Cc1cc(C)n(-c2ccc(I)cc2)n1
Agent: CC(C)[Si](Sc1cccc(C2(C#N)CCOCC2)c1)(C(C)C)C(C)C
Agent: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Product: Cc1cc(C)n(-c2ccc(Sc3cccc(C4(C#N)CCOCC4)c3)cc2)n1

Procedure:
The titled compound was prepared according to the procedure described in example 29E for the preparation of (2SR,4RS)-4-cyano-2-methyl-4-[3-[4-(2 -methylimidazol-1-yl) phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran using 4-(3,5-dimethylpyrazol-1-yl)phenyl iodide and 4-cyano-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran in place of 4-(2-methylimidazol-1-yl)phenyl iodide and (2SR,4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran, respectively.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19]=2[N:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:15])[C:17]2[C:18]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CN[C@@H]1CCCN(Cc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@@H]4CCCN(Cc5ccccc5)C4)ncnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of (R)-1-benzyl-N-methylpiperidin-3-amine (800 mg, 3.9 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 3.9 mmol) in DMF (10 mL), DIEA (2.02 mL, 15.6 mmol) was added and the reaction mixture was stirred at 60° C. overnight. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 mL) and was washed with water (3×40 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (750 mg, 40%). 1H-NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.38 (d, 0.1=4.0 Hz, 1H), 7.28 (m, 7H), 6.53 (d, J=3.6 Hz, 1H), 3.59 (d, J=13.2 Hz, 1H), 3.46 (d, J=13.2 Hz, 1H), 3.13 (s, 3H), 2.89 (m, 2H), 2.37 (s, 3H), 2.09 (t, J=10.8 Hz, 1H), 1.96 (dt, J=1.2, 10.8 Hz, 1H), 1.83 (m, 2H), 1.65 (m, 3H). LC-MS: m/z [M+1]=476.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10](O)[C:4]=2[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C1CCCc2ccc(Br)cc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)ccc2CCC1
Yield: 80.9 %

Procedure:
To a solution of methyl 3-bromo-5-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate from step A3 (230 mg, 0.769 mmol) in toluene (3 mL) was added p-toluenesulfonic acid monohydrate (29.2 mg, 0.154 mmol). The mixture was heated at reflux for 4 h. The solvent was removed in vacuo, and the residue was purified using silica gel column chromatography (hexanes-10% EtOAc) to give methyl 2-bromo-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (175 mg, 0.622 mmol, 81% yield). 1H NMR (500 MHz, chloroform-d) δ 7.61 (s, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.32 (dd, J=8.1, 2.0 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 3.83 (s, 3H), 2.79-2.72 (m, 2H), 2.63 (t, J=6.6 Hz, 2H), 2.09-2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[CH2:22]1[O:31][C:30]2[C:24](=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[O:23]1>>[ClH:1].[ClH:1].[CH2:22]1[O:31][C:30]2[C:24](=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=3[O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:5]=[CH:4][N:3]=2)[O:23]1
Reactant: Nc1cccc2c1OCO2
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4c3OCO4)ncnc2c1
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 2,3-methylenedioxyaniline (J. Med. Chem., 1979, 22, 1354) to give the title compound, a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 2.0–2.1 (m, 2H), 2.15–2.3 (m, 4H), 2.31 (s, 3H), 2.85 (m, 2H), 3.91 (s, 3H), 6.01 (s, 2H), 6.5 (d, 1H), 6.68 (d, 1H), 6.82 (d, 1H), 6.91 (m, 1H), 8.0 (d, 1H), 8.6 (s, 1H), 9.72 (s, 1H); Mass Spectrum: M+H+ 409.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2].[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([CH:60]([CH3:62])[CH3:61])[CH:54]=1)[C:46]([OH:48])=[O:47]>CO.C(Cl)Cl>[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:54]=[C:55]([CH:60]([CH3:61])[CH3:62])[C:56]([OH:59])=[C:57]([Br:1])[CH:58]=1)[C:46]([OH:48])=[O:47]
Reactant: Cc1c(C(=O)O)cc(Cl)c(Oc2ccc(O)c(C(C)C)c2)c1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)O)cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c1Cl
Yield: 32.7 %

Procedure:
A suspension of benzyltrimethylamonium tribromide (2.2 g, 5.63 mmol) and CaCO3 (0.28 g, 2.82 mmol) was stirred for 2 hr at 20° C. in a 1:1 MeOH/CH2Cl2 solution (10 mL) containing 3,5-dichloro-2-methyl-4-(4-hydroxy-3-isopropylphenoxy)-benzoic acid (1.0 g, 2.82 mmol). Once HPLC analysis indicated that conversion to the desired monobrominated phenol was optimal, the reaction was quenched by addition of 15 mL of 1N HCl. After removal of the organic solvents under vacuum using a rotary evaporator, the aqueous suspension was extracted twice with EtOAc. After drying the combined EtOAc layers over MgSO4, the salts were filtered prior to removal of the EtOAc under vacuum. The resulting residue after purification by gradient elution from a reverse phase C18 column employing MeOH/H2O containing 0.1% TFA yielded 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoic acid (400 mg).
Reaction SMILES: [N+](C1C=C(N[N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])C=CC=1)([O-])=O.[N+:17]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])([O-:19])=[O:18].C(#N)CC#N.O.[NH2:33][NH2:34]>>[N+:17]([C:20]1[CH:21]=[C:22]([NH:23][N:11]=[C:12]2[C:13]([NH2:14])=[N:34][N:33]=[C:15]2[NH2:16])[CH:24]=[CH:25][CH:26]=1)([O-:19])=[O:18]
Reactant: N#CC(C#N)=NNc1cccc([N+](=O)[O-])c1
Reactant: NN
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc([N+](=O)[O-])c1

Procedure:
4-[(3-Nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 2-[(3-nitrophenyl)hydrazono]malononitrile (0.107 g, 0.5 mmol) which was derived from 3-nitroaniline (0.133 g, 1.0 mmol) and malononitrile (1.5 mmol) in a manner similar to that described in Example 2, and hydrazine hydrate. The resulting solid (0.088 g) was isolated by filtration, a portion (0.060 g) of which was purified by flash chromatography to yield 0.024 g (28%) of the title compound as an orange solid; MS (m/z, ES+): 248.0 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:23]1([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCOC(=O)[C@](C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)Oc1ccccc1

Procedure:
(S)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester, shown below, from Example 1, Step C, and toluene-4-sulfonic acid 2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (S)-3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (41%). 1H NMR (300 MHz, CDCl3): δ 7.96 (m, 2H), 7.41 (m, 3H), 7.19 (t, 2H), 7.12 (d, 2H), 6.93 (t, 1H), 6.82 (m, 4H), 4.20 (q, 2H), 4.18 (t, 2H), 3.23 (d, 1H), 3.06 (d, 1H), 2.95 (t, 2H), 2.37 (s, 3H), 1.33 (s, 3H). MS [EI+] 486 (M+H)+, [EI−] 484 (M−H)+.
Reaction SMILES: Cl[C:2](=[O:13])[CH2:3][C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(OCC)(=O)C.O.ClCCl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2](=[O:13])[CH2:3][C:4]2([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:17][CH:16]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)C1(CC(=O)Cl)CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 150 mL flask was added dichloromethane (70 mL), methyl 1-(2-chloro-2-oxoethyl)cyclopentanecarboxylate] (3.50 g, 16.8 mmol) [prepared as described by Bajaj, et al., J. Indian Chem. Soc. 52:1076-78, 1975] and bromobenzene (2.77 g, 17.6 mmol), and the reaction mixture cooled to 0° C. before aluminum trichloride (4.77 g, 35.7 mmol) was slowly added. The mixture was stirred for 1 h at 0° C., then for 12 h at rt. The reaction mixture was slowly poured into 50 mL chilled (0° C.) 1 N aqueous hydrochloric acid solution. Water (50 mL) was added, followed by ethyl acetate (100 mL), and the mixture stirred for 30 minutes. The layers were separated and the aqueous layer extracted with additional ethyl acetate (100 mL). The combined organic layer was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown oil which was purified by flash chromatography (10:1/hexane:ethyl acetate) to afford methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentane carboxylate as a yellow, crystalline solid (1.62 g, 30%). LC-MS ret. time 3.45 min, m/z 324.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.50-1.83 (overlapping signals, 6H), 2.22-2.33 (m, 2H), 3.37 (s, 2H), 3.66 (s, 3H), 7.59 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][N:27]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CNCC(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Temperature: 25 °C

Procedure:
To a 20 mL scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30.0 μL 0.176 mmol). Following 4, hours of stirring at room temperature, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.98-1.20 (m, 2 H), 1.38-1.55 (m, 2 H), 1.70-1.93 (m, 5 H), 2.20-2.33 (m, 2 H), 2.78-2.88 (m, 1H), 3.01-3.10 (m, 3 H), 3.64 (s, 3 H), 4.08 (s, 2 H), 7.03-7.19 (m, 1 H), 7.28-7.41 (m, 2 H), 7.66-7.76 (m, 2 H), 13.80-14.09 (m, 1H); MS (ESI) m/z 438 [M+H]f;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][C@@H:4]2[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]2)=[O:21])[CH2:25][CH2:26]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Reactant: CN1CCO[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@@H](COC(=O)N2CCN(c3ccc(F)cc3F)CC2)C1
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
(R)-(4-Methylmorpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 330 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and the solvents were removed in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-(2,4-difluorophenyl)-piperazine-1-carboxylate (87 mg, 32%) as a colourless gum.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][CH2:30][C:29]2[CH:38]=[CH:39][CH:40]=[CH:41][C:28]1=2>C(C(C)=O)C.C(OCC)(=O)C>[CH:38]1[C:29]2[CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:27](=[CH:26][CH2:25][CH2:24][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:2][CH2:3]3)[C:28]=2[CH:41]=[CH:40][CH:39]=1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C

Procedure:
The above benzonitrile (4.89 g, 26 mmol) was dissolved in methyl ethyl ketone (100 ml), and potassium carbonate (21.7 g, 157 mmol), potassium iodide (3.45 g, 52 mmol), and 5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (8.18 g, 26 mmol), were added. The resulting mixture was stirred at reflux temperature for 18 h. After cooling to room temperature, ethyl acetate (200 ml) was added and the mixture was washed with water (2×150 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting first with a mixture of ethyl acetate and heptane (1:4), and then with a mixture of ethyl acetate and heptane (1:2). This afforded 5.60 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:11][N:10]=1.OO.[OH-].[Na+].C(OCC)(=[O:33])C.C(OCC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N+:11]([O-:33])[N:10]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[n+]([O-])c(-n3cncn3)c2c1
Reaction time: 48 h
Yield: 41 %

Procedure:
Under N2 at 0° C. a solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-4-[1,2,4]triazol-1-yl-phthalazine (5.1 g, 13.2 mmoles), prepared as described in example 51, in trifluoroacetic acid (25 ml), was dropwise added with H2O2 (1.35 ml, 13.5 mmoles). The temperature was left to rise to the room value and, after 48 hours, the pH was adjusted with NaOH. After further 24 hours under stirring, the mixture was dried, taken up in CH2Cl2. The organic phase was washed with water, anhydrified and dried to give a foam which was flash chromatographed (eluent: ethyl acetate/ethyl ether 6:4, then 8:2) to give 2.2 g of the title compound (yield: 41%). m.p.: 218-220° C. (dec.).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C.CCCCCC>C1C=CC=CC=1.CO>[CH3:18][O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of N-carbobenzyloxy-L-serine (4.0 g, 16.7 mmol) in benzene (200 ml) and methanol (50 ml) was added a solution of 2M trimethylsilyldiazomethane in hexane (10.9 ml, 21.7 mmol) in an ice bath, and the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:3) as the eluant to afford N-carbobenzyloxy-L-serine methyl ester (4.40 g, yield 100%) as a colorless oil.