Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH3:20])[C:9]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1)([O-])=O.[N+](C1C=CC2N=C(CC3C=CC(C#N)=CC=3)N(C)C=2C=1)([O-])=O.C(Cl)Cl>CO.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH3:20])[C:9]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: Cn1c(Cc2ccc(C#N)cc2)nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: Cn1c(Cc2ccc(C#N)cc2)nc2ccc([N+](=O)[O-])cc21
Solvent: ClCCl
Solvent: CO
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(N)ccc21
Reaction time: 1 h

Procedure:
1.1 g (37.6 mmol) of 4-[(5-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 4-[(6-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile are dissolved in 30 ml methanol and 40 ml methylene chloride and after the addition of 0.2 g palladium on activated charcoal (10%) hydrogenated for 60 minutes at ambient temperature. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/methanol (30:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH2:13]([N:15]([CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=O)=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:14]>>[CH2:30]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=[C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]2=[O:12])=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:31]
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3cc(OC)ccc32)cc1C
Yield: 31 %

Procedure:
6-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 63 mg (31%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[C:5]([N+:13]([O-])=O)[C:4]=1[O:16][CH3:17]>CCO>[CH3:17][O:16][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH3:9])=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COc1cc(C)c([N+](=O)[O-])c([N+](=O)[O-])c1OC
Solvent: CCO
Product: COc1cc(C)c(N)c(N)c1OC
Reaction time: 48 h

Procedure:
3,4-Dimethoxy-6-methyl-benzene-1,2-diamine was synthesized by dissolving 11.5 g of 1,2-dimethoxy-5-methyl-3,4-dinitro-benzene in 300 mL EtOH, evacuating 3 times with N2 and adding 1.0 g of 10 wt % Pd/C. The reaction was stirred under a H2 atmosphere (balloon) for 2 days. Filtration over a pad of celite and washing with EtOH yielded after concentration in vacuo 8.8 g of 3,4-dimethoxy-6-methyl-benzene-1,2-diamine as brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)=[O:4].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:45][CH2:44][CH2:43][C@@:30]3([C:34](=[O:35])[N:33]([C@H:36]4[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[CH2:29]2)=[C:24]([F:46])[CH:23]=1>>[F:46][C:24]1[CH:23]=[C:22]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:1])[CH3:20])=[O:4])=[N:6][CH:7]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH2:45][CH2:44][CH2:43][C@@:30]2([C:34](=[O:35])[N:33]([C@H:36]3[CH2:37][CH2:38][C@@H:39]([OH:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH2:29]1
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cc1F)C2
Product: CN(C)C(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(F)c2)cn1

Procedure:
This compound was prepared by using procedures that were analogous to those described for the synthesis of Example 1, Step 8 starting from N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide and (5S)-7-(4-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC/MS m/e 495.3 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.86 (1H, d, J=1.7 Hz), 8.15 (1H, dd, J=8.1, 2.3 Hz), 7.51-7.65 (3H, m), 7.12 (1H, t, J=8.9 Hz), 4.37 (1H, d, J=3.1 Hz), 3.78 (1H, m), 3.71 (1H, m), 3.22-3.38 (3H, m), 3.06 (1H, d, J=11.7 Hz), 3.00 (3H, s), 2.97 (3H, s), 2.64-2.74 (2H, m), 2.18-2.27 (1H, m), 1.60-1.91 (8H, m), 1.39-1.51 (3H, m), 1.22-1.30 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.BrC1C=CC(C(O)[C:21](=[O:23])C)=CC=1>>[CH:21]([O:11][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:12])=[O:23]
Reactant: CC(=O)C(O)c1ccc(Br)cc1
Reactant: CC(O)C(=O)c1ccc(Br)cc1
Product: CC(OC=O)C(=O)c1ccc(Br)cc1

Procedure:
1-(4-bromophenyl)-2-hydroxypropan-1-one and 1-(4-bromophenyl)-1-hydroxypropan-2-one
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2.[C:32]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:44].Cl>>[ClH:44].[ClH:44].[CH3:32][N:29]1[CH2:30][CH2:31][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=5)=[CH:13][C:12]4=[O:27])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:28]1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCC2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc3n2C)C1
Yield: 48 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (68 mg, 0.16 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (39.6 mg, 48%) as a brown solid: mp 274-280° C.; 1H NMR (500 MHz, CD3OD) δ 9.04 (s, 1H), 8.28 (dd, J=8.7, 1.9 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.83 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.24 (dd, J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3, 1.7 Hz, 1H), 4.80-4.71 (br m, 1H), 4.44-4.35 (br m, 1H), 3.96-3.86 (br m, 1H), 3.75 (s, 3H), 3.67-3.57 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M+H]+; HPLC (Method B) 96.4% (AUC), tR=12.6 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCCc1ccccc1F
Solvent: O
Product: O=C1CCCc2c(F)cccc21
Reaction time: 1 h

Procedure:
To 200 gm of polyphosphoric acid heated at 80° C. was added 15.9 gm of the compound prepared in (6) above over 1 hour while stirring. The stirring was continued for another 1 hour at the same temperature. The resultant reaction mixture was poured into ice-cooled water and extracted with chloroform. The extract was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 14.1 gm of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][CH2:5][C@H:6]([CH3:18])[CH2:7][CH:8]([NH:14][C:15](=[O:17])[CH3:16])[C:9]1[S:10][C:11]([Br:19])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1cccs1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(thiophen-2-yl)butyl acetate (1.81 g, 6.70 mmol) obtained in Example 47(b) was dissolved in dimethylformamide (20 ml), and N-bromosuccinimide (1.27 g, 7.11 mmol) was added thereto in an ice bath followed by stirring under a nitrogen atmosphere for 10 minutes in an ice bath and then overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:2) to afford the title compound (2.32 g, 99% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.OO.S(=O)(=O)(O)[O-:13].[Na+].CC1C=C(C)C=C(O)C=1O>CC(C)CC(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:13]
Reactant: O=S(=O)([O-])O
Reactant: Cc1cc(C)cc(O)c1
Agent: Cc1cc(C)c(O)c(O)c1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(O)cc(C)c1O

Procedure:
In a vessel used in Example 52 were placed 100 g. (819 m. moles) of 3,5-dimethylphenol, 2.97 g. (29.7 m. moles) of 4-methyl-2-pentanone, 2.52 g. (44.5 m. moles) of 60 percent hydrogen peroxide and 0.01 g. of sodium bisulfate (NaHSO4.H2O), and the mixture was treated at 110° C. for 20 minutes in the same manner as in Example 52. As products, 2.19 g. (15.9 m. moles) of 3,5-dimethylcatechol and 1.25 g. (9.08 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 56.1 percent.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-])(O)=O.[Na+].CI>CC(N(C)C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([O:14][CH3:23])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)[C@H](CCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of (R)-2-(2-(benzyloxy)ethyl)-4-tert-butoxy-4-oxobutanoic acid (120 g, 388 mmol) in DMA (750 mL) was added NaHCO3 (65.2 g, 776 mmol) followed by MeI (36.4 mL, 582 mmol) and stirred overnight at room temperature. Additional NaHCO3 (130 g, 1.55 mol), and MeI (72.8 mL, 1.16 mol) were added and stirring was continuted for an additional 20 h. The mixture was filtered and the filtrate partitioned between MTBE (1.5 L) and H2O (1.5 L). The aqueous phase was separated and back-extracted with MTBE (1.0 L). The combined organics were washed with H2O (2×1.5 L), brine (1 L), dried over MgSO4, and filtered. The filtrate was concentrated to give a pale yellow oil containing (R)-4-tert-butyl 1-methyl 2-(2-(benzyloxy)ethyl)succinate (140 g, 379 mmol, 98% yield). Exact mass calculated for C18H26O5: 322.2, found: LCMS m/z=323.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 1.82 (m, 1 H), 1.97 (m, 1 H), 2.42 (dd, J1=16.3, J2=5.3 Hz, 1 H), 2.63 (dd, J1=16.5, J2=9.0 Hz, 1 H), 2.96 (m, 1 H), 3.50 (t, J=6.2 Hz, 2 H), 3.65 (s, 3 H), 4.48 (s, 2 H), 7.32 (m, 5 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([Br:12])[CH:6]=2.[CH2:13]([O:15][CH:16]=[CH:17][Sn](CCCC)(CCCC)CCCC)[CH3:14]>[Cl-].C([N+](CC)(CC)CC)C.[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Br:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[N:4][CH:3]=[C:2]([CH:14]=[CH:13][O:15][CH2:16][CH3:17])[CH:11]=2
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Brc1cnc2cc(Br)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Product: CCOC=Cc1cnc2cc(Br)cnc2c1

Procedure:
1,5-Naphthyridines of formula (53), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 7. 3,7-Dibromo-[1,5]naphthyridine, prepared as described by W. W. Paudler, J. Org. Chem., 33:1384 (1968), can be treated with (2-ethoxyvinyl)tributylstannane, a halide source, such as, but not limited to, tetraethylammonium chloride, and a palladium source, such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N,N-dimethylformamide with heat (about 50° C. to about 150° C.) to provide 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine. 3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with an acid, such as, but not limited to, formic acid at about 0° C. to about 60° C. in a solvent, such as, but not limited to, 1,2-dichloroethane to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively, 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as, but not limited to, tetrahydrofuran can be treated with an aqueous acid, such as, but not limited to, hydrochloric acid at about 0° C. to about 60° C. to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. (7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with an amine of formula (5) under reductive amination conditions, such as, but not limited to, sodium triacetoxyborohydride and an acid, such as, but not limited to, acetic acid in a solvent, such as, but not limited to, 1,2-dichloroethane at about 0° C. to about 50° C. to povide amines of formula (52). Amines of formula (52) can be treated with boronic acids of formula (7), a palladium source, such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0), a ligand, such as, but not limited to, tri(tert-butyl)phosphine, and a base, such as, but not limited to, potassium fluoride in a solvent, such as, but not limited to, tetrahydrofuran at about 20° C. to about 80° C. to provide 1,5-naphthyridines of formula (53).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[I-].[Na+]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][O:5][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Cl:13]
Reactant: ClCCCCCBr
Reactant: OCc1cc(Br)ccc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1ccc(Br)cc1COCCCCCCl

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (25 ml). To this solution sodium hydride (60%, 625 mg, 15.6 mmol) was added and the resulting mixture was stirred for twenty minutes. To the reaction mixture 5-chloropentyl bromide was added and the resulting mixture was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. Sodium iodide (3.127 g, 20.9 mmol) was added and the resulting mixture was stirred at ambient temperature for three hours. The reaction mixture was diluted with diethyl ether and washed seven times with brine. The solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][CH:7]1[C:12]2[C:13](=[O:29])[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:15]=[C:16](S(C)(=O)=O)[O:17][C:11]=2[NH:10][CH2:9][NH:8]1.[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40]>>[C:39]([N:42]1[CH2:47][CH2:46][N:45]([C:16]2[O:17][C:11]3[NH:10][CH2:9][NH:8][CH:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=4)[C:12]=3[C:13](=[O:29])[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:15]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: Cc1ccccc1N1C=C(S(C)(=O)=O)OC2=C(C1=O)C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCN2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C2=CN(c3ccccc3C)C(=O)C3=C(NCNC3Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)O2)CC1
Yield: 68.2 %

Procedure:
In a similar manner to Example 13, 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-(methylsulfonyl)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine (Compound of Reference Example 22; 84.0 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 8-(4-acetylpiperazine-1-yl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine (62.2 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:25][CH:24]([CH3:26])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N:21]([CH3:31])[C:20]1=[O:32]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:25][CH:24]([CH3:26])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[N:21]([CH3:31])[C:20]2=[O:32])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1CC(N)C(=O)N(C)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC1CC(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (prepared from 4-methyltetralone (Aldrich) using General Procedure 6-A), the title compound was prepared as a solid having a melting point of 115-119° C. Purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[N:29]2[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=O)[CH2:36][C:37]3[N:38]=[CH:39][N:40]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:41]=3)[C:30]2=[O:62])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:72])=CC=1>C1COCC1>[Si:1]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[N:29]2[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[S:72])[CH2:36][C:37]3[N:38]=[CH:39][N:40]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:41]=3)[C:30]2=[O:62])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=O)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=S)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
A mixture of (S)-N-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidin-3-yl}-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]acetamide, as described above in Step D, (3.00 g, 3.61 mmol) and Lawesson's Reagent (728 mg, 1.80 mmol) in dry THF (45 mL), under argon, was heated to 45° C. for 90 min. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous Na2CO3 (125 mL) and CH2Cl2 (300 mL). The aqueous layer was extracted further with CH2Cl2 (150 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—40% EtOAc—1% MeOH—0.1% NH4OH to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:9](Cl)([Cl:11])[Cl:10].[OH-].[Na+].[Cl-].CC(C)CCCCCCCCCCC[NH2+]CC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[C:9]([Cl:10])[Cl:11]
Reactant: Clc1ccccc1C(c1ccccc1Cl)C(Cl)(Cl)Cl
Agent: CC(C)CCCCCCCCCCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: ClC(Cl)=C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 93 °C

Procedure:
150 g of solid 1,1-bis(chlorophenyl)-2,2,2-trichloroethane were added to 248.8 g of a 27.2% strength aqueous sodium hydroxide solution maintained at 93° C. 1.4 g of dimethyllaurylbenzylammonium chloride were added thereto. The temperature increased from 93° to 103° C. The addition of solid 1,1-bis(chlorophenyl)-2,2,2-trichloroethane was continued up to a total amount of 300 g. 1.1 g of dimethyllaurylbenzylammonium chloride were added again and the temperature was maintained between 100° and 105° C. for 14 hours, 30 min. The organic phase was separated off by phase separation and washed three times with 100 g of a 1N solution of sulfuric acid and with water (100 g). 263.7 g of 1,1-bis(chlorophenyl)-2,2-dichloroethylene were obtained (y=98.0%) with 0.09% of 1,1-bis(chlorophenyl)-2,2,2-trichloroethane.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)(C(F)(F)F)=O>[Cl:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Water (1 mL) was added in one portion to a stirred solution of benzyl [2-chloro-4-(1,4-dioxaspiro[4.5]dec-8-yl)phenyl]carbamate (2.60 g, 6.47 mmol) in TFA (20 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to 10° C. and a 2N aqueous solution of sodium hydroxide was added until the pH of the mixture was 10. Ethyl acetate (50 mL) was added and the layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to leave the title compound (2.3 g, 99%) as a solid; 1H NMR δ 1.82-1.99 (2H, m), 2.17-2.28 (2H, m), 2.45-2.57 (4H, m), 2.94-3.07 (1H, m), 5.24 (2H, s), 7.17 (1H, dd), 7.25 (1H, d), 7.32-7.5 (5H, m), 8.13 (1H, d); MS m/e (M−H)− 356.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[CH:15]=O)(=[O:9])=[O:8].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccn1
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using 3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and (5-chloro-2-methylindol-1-yl)acetic acid methyl ester.