Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9](=[O:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C(O)(C)C>[CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@H:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
25.57 g of methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)carbamate were added portionwise at 22° C. to a suspension of 21.44 g of aluminum isopropoxide in 260 ml of isopropanol. The suspension was stirred at 50° C./400 mbar for 2 hours, hydrolyzed at 0° C. with 100 ml of 3N hydrochloric acid, subsequently concentrated to a volume of 125 ml, diluted with 125 ml of water, cooled to 0° C. and filtered. The residue was washed with water/isopropanol (4:1) and dried, there being obtained 13.01 g (89%) of isomerically-pure methyl (1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p. 162°-163.5° C. IR (KBr): 3323s, br. (NH, OH), 1689 (C=O), 1546s (amide II).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:26])([CH3:25])[C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]O)=[C:41]([Br:47])[CH:40]=1)=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:26])([CH3:25])[C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:45][C:42]2[CH:43]=[CH:44][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][NH:31][C:29]([NH:28][CH3:27])=[O:30])=[CH:40][C:41]=2[Br:47])[C:14]1=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)c(Br)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)c(Br)c1

Procedure:
Prepared from 2-t-butoxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide (Step K) and 2'-[[(methylamino)carbonyl]amino]methyl-3-bromo-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step J) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.39 (s, 12H), 1.41 (s, 3H), 1.92 (m, 1H), 2.48-2.75 (m, 6H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.70 (m, 1H), 4.92 (m, 2H), 7.08-7.35 (m, 10H) 7.42 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH3:29][NH:30][CH3:31].C(O)C>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:30]([CH3:31])[CH3:29])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CNC
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and 2.0 M dimethylamine in ethanol (4.60 ml, 9.30 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (308 mg, 78%).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]1=[O:45].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[NH:38][C:37]4=[O:45])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Reactant: O=c1[nH]c2ccccc2n1CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 72.7 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.823 g, 1.92 mmol), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.58 g, 1.92 mmol), and potassium carbonate (0.39 g, 2.88 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as a white solid (0.84 g, 73%); 1H NMR (DMSO-d6); δ 0.93-0.96 (m, 1H); 1.14-1.25 (m, 4H); 1.52 (s, 9H); 1.57-1.62 (m, 9H); 1.79 (m, 2H); 2.29-2.36 (m, 4H); 2.63 (m, 3H); 3.82 (t, J=6.8 Hz, 2H); 4.08 (s, 2H); 4.43 (s, 2H); 6.97-7.01 (m, 3H); 7.14 (d, J=6.4 Hz, 1H); 7.44-7.49 (m, 2H); 7.72 (s, 1H); 7.81 (dt, J=2.4 Hz and 6.4 Hz, 1H); 10.8 (s, 1H); MS for C35H47N5O4 m/z 602 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[C:33]([F:40])=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([Cl:31])[C:33]=3[F:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1c(Cl)cccc1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2cccc(Cl)c2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-chloro-2-fluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.42 (m, 1 H), 7.38-7.31 (m, 1 H), 7.24-7.11 (m, 3 H), 7.06-7.00 (m, 1 H), 6.94 (dd, J=4.5, 8.4 Hz, 1 H), 6.30 (dd, J=3.5, 11.5 Hz, 1 H), 5.71-5.52 (m, 3H), 4.33-4.26 (m, 2 H), 2.95-2.81 (m, 2 H), 2.76 (s, 3 H), 2.14-2.03 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=537.4 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:18]([O-])([O-:20])=[O:19].[Na+]>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2c(c1)CCN2C(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc2c(c([N+](=O)[O-])c1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Compound 2 (467 mg, 2 mmol) was added to a stirred solution of sodium nitrate (170 mg, 2 mmol) in trifluoroacetic acid (5 mL) and the mixture was stirred at rt for 4 h. The solution was poured into ice-cold water (100 mL) and extracted with EtOAc. The combined organic phases were washed with saturated aq. NaHCO3 and brine, dried and evaporated. Recrystallization (EtOAc-hexanes) afforded 16 as orange needles (395 mg, 71%), mp 136-137° C.; IR: νmax/cm−1 1740, 1670, 1530; 1H NMR: δH (90 MHz) 7.52 (br s, 1H), 7.36 (br s, 1H), 4.23 (t, J=8.3 Hz, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 3.20 (t, J=8.3 Hz, 2H) and 2.24 (s, 3H). Anal. Calcd for C13H14N2O5: C, 62.94; H, 6.27; N, 4.59. Found: C, 63.00; H, 6.16; N, 4.59.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:38])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]=[C:24]3[C:27]3([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CC(O)C>ClCCl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2([C:24]3[C:25]4[C:20](=[CH:19][CH:18]=[C:17]([O:16][CH2:15][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:38])[CH:26]=4)[CH2:21][CH2:22][N:23]=3)[CH2:30][CH2:29][CH2:28]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CCC2)=NCC3)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (690 mg, 1.28 mmol) was dissolved in dichloro-methane. A 5 M solution of HCl in 2-propanol (5 mol) was added and the mixture was stirred for 14 h at RT. The solvent was removed and the residue (230 mg) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:6].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:12])=[O:6]
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1Cl
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ccccc2)cc1Cl
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 42B (50 mg, 0.16 mmol) in DMF (5 mL) was treated with phenethylamine (150 μL, 1.6 mmol), diisopropylethylamine (42 mL, 0.32 mmol), and EDCI (31 mg, 0.32 mmol) at room temperature. After 2 hours Bop reagent (100 mg, 0.22 mmol) was added. After 30 minutes, the reaction was concentrated and purified by chromatography (SiO2, 30% EtOAc in hexanes) to afford 42C (47 mg, 70%). HPLC retention time: 2.79 minutes (YMC S-5 Combiscreen 4.6×50 mm, 10% to 90% MeOH/H2O w/0.2% H3PO4, 4 minute gradient).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]O>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc(F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(F)c2)c1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.24 (2H, s), 5.73 (1H, d, J=2.0 Hz), 7.03-7.05 (1H, m), 7.07-7.21 (2H, m), 7.36-7.38 (1H, m), 7.40-7.42 (1H, m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=4.2 Hz). [M+H] Calc'd for C16H11FN4O, 295; Found, 295.
Reaction SMILES: [O:1]1[C@@H:7]2[C@@H:2]1[C:3]([CH3:18])([CH3:17])[O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[NH4+:26]>O1CCOCC1>[CH3:16][O:15][C:9]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]2[O:4][C:3]([CH3:18])([CH3:17])[C@H:2]([OH:1])[C@@H:7]([NH:26][CH2:2][CH2:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=3)[C:6]=2[CH:8]=1
Reactant: [NH4+]
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@@H]21
Agent: [Cl-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@H](O)[C@H]2NCCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (3R*,4S*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (2.50 g, 9.95 mmol) in 1,4-dioxane(5.0 mL), lithium perchlorate (1.06 g, 9.95 mmol) and 4-(phenylethyl)amine (1.50 mL, 11.9 mmol) were added at room temperature and the mixture was stirred at 80° C. for 1 hour. Upon the completion of the reaction, an aqeuous solution of saturated ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=6/4) and the aimed product was obtained as yellow amorphous substance (quantitative yield).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1.C1COCC1.OO.[Li+].[OH-:46]>O>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:30][C:25]([CH2:24][C@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([OH:37])=[O:46])=[CH:26][CH:27]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutanoate (1.20 g, 2.402 mmol) in a mixed solvent of THF (20 mL) and water (5 mL), a solution of aqueous H2O2 (0.960 mL, 9.61 mmol) and aqueous LiOH (4.80 ml, 4.80 mmol) is added at 0° C. during 5 minutes. After stirring for 1.5 hour, the reaction is quenched with saturated aqueous Na2SO3 (10 mL) at 0° C., and allowed to stir for 10 minutes at the same temperature. The reaction mixture is warmed up to ambient temperature while stirring for 0.5 hour. Then, saturated aqueous NaHCO3 and brine are added to the mixture. The product is extracted with ethyl acetate, washed with aqueous 1M HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 120 g of silica gel (heptane/EtOAc=75:25 to 0:100) to give (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (765 mg, 93%). HPLC retention time=1.63 minutes (condition D); MS=338.6 (m−1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 2.41 (A of ABX, Jab=16.67 Hz, Jax=4.55 Hz, 1 H) 2.52-2.67 (B of ABX, Jab=16.75 Hz, Jbx=8.45 Hz, 1 H) 2.74-2.89 (m, 1 H) 3.06-3.22 (m, 2 H) 7.22-7.29 (m, 2 H) 7.30-7.37 (m, 1 H) 7.43 (t, J=7.58 Hz, 2 H) 7.53 (d, J=8.1 Hz, 2 H) 7.57 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.Cl.[CH:22]([N:25]([CH2:29][CH2:30]Cl)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+].O>CN(C)C=O>[CH3:23][CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[CH2:29][CH2:30][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1)[CH3:24]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1)C(C)C
Reaction time: 48 h

Procedure:
A 2.64 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 60 ml of dimethylformamide by warming on a steam bath and then cooled. A 2.0 g portion of diisopropylaminoethyl chloride hydrochloride was added and dissolved with stirring. A 20 ml portion of 5N sodium hydroxide was added dropwise over 5 minutes, then 5 ml of water was added and the mixture was stirred for 20hours. The mixture was then heated on a steam bath for 30 minutes, allowed to stand 48 hours and then evaporated. The residual gum was purified by flash dry column chromatography on silica gel eluting fractions 1-3 with methanol and fractions 4-6 with 1% methanol in chloroform. Fractions 4-6 were combined and evaporated, giving 500 mg of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([CH3:7])[CH3:6].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][CH2:2][N:13]=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(CCCCl)C1OCCO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CCCN=[N+]=[N-])C1OCCO1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of 0.74 g (3.8 mmol) of 2-(4-chloro-1,1-dimethylbutyl)-1,3-dioxolane and 0.50 g (7.7 mmol) of sodium azide in 5 mL of DMSO was heated to 100° C. with stirring. After 18 hours the solution was cooled to RT, diluted with water, and the mixture extracted with ether (3×). The combined ether extracts were washed with water (3×), dried over MgSO4, and concentrated in vacuo to afford 0.69 g (90%) of the desired compound as a light yellow liquid.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([C:17]3[CH:22]=[CH:21][N+:20]([CH3:23])=[CH:19][CH:18]=3)[C:7]=2[CH:24]=1.[BH4-].[Na+]>CO.O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH:18]=3)[C:7]=2[CH:24]=1
Reactant: C[n+]1ccc(C2=Cc3ccccc3Oc3ccc(Br)cc32)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC=C(C2=Cc3ccccc3Oc3ccc(Br)cc32)CC1
Temperature: 25 °C
Yield: 99 %

Procedure:
A stirred suspension of 4-(8-bromodibenz[b,f]oxepin-10-yl)-1-methylpyridinium iodide (2.7 g) in methanol (50 ml) was treated with sodium borohydride (1.04 g) and 15 ml of water. The mixture was stirred at ambient temperature for thirty minutes and then was diluted with 175 ml of water. The resulting solid was filtered off, washed with water and then was dissolved in dichloromethane (100 ml). The organic solution was washed with water, then was dried (potassium carbonate) and evaporated in vacuo. A solution of the residual solid in ethyl acetate (75 ml) was treated with a solution of maleic acid (0.64 g) in ethanol (5 ml). The crystalline product was recovered in two crops to give a total yield of 2.0 g of 4-(8-bromodibenz[b,f]oxepin-10-yl)-1,2,3,6-tetrahydro-1-methylpyridine, (Z)-2-butenedioate (1:1) salt, mp 186°-188°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[O:20][N:19]=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Product: COc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[4-(methyloxy)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 399 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[CH3:29][C:30]1[C:35]([C:36](O)=[O:37])=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:36](=[O:37])[C:35]3[C:30]([CH3:29])=[CH:31][CH:32]=[N:33][CH:34]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: Cc1ccncc1C(=O)O
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Product: Cc1ccncc1C(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)C

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with 4-methyl-nicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 516. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.3 (s, 1H)) 8.6 (s, 1H) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (m, 3H) 6.9 (d, 1H) 5.6 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.0 (d, 1H) 2.9 (m, 2H) 2.7 (s, 3H) 1.2 (d, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1Cl)[CH3:23]>C(Cl)Cl.[Cu]>[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:3]1)[CH3:23]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C[C@@H]1Cc1ccccc1
Agent: [Cu]
Solvent: ClCCl
Product: CCOCCn1c(N[C@@H]2CCN(C(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)nc2ccccc21
Yield: 72.8 %

Procedure:
(±)-1,1-dimethylethyl trans-4-amino-2-(phenylmethyl)-1-piperidinecarboxylate (5 g), 1-(2-ethoxyethyl)-2-chloro-1H-benzimidazole (4.5 g) and copper (1.28 g) were stirred at 150° C. for 4 hours. The mixture was taken up in CH2Cl2 and filtered. The filtrate was washed with water/NH3. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 98/2). The pure fractions were collected and the solvent evaporated, yielding 6 g (73.7%) of (±)-1,1-dimethylethyl trans-4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]-2-(phenylmethyl)-1-piperidine-carboxylate (interm. 6).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH3:25])[NH2:21]>>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(N)cc1F
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1F
Yield: 22.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 3-fluoro-4-methylaniline (0.07 mL, 0.65 mmol) to provide 246 (31 mg, 20% yield) as a brown solid. LC-MS (M+H (parent)=321, obsd.=321).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4cccc(Cl)c4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 3-chlorophenyl boronic acid according to the procedure of Example 2, m.p. 170-171° C.