Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:17])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Mg]Cl
Reactant: CON(C)C(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-acetamide (42.1 mmol, 12.0 g) in anhydrous THF at −10° C. was added n-butyl magnesium chloride (2.0 M solution in THF, 92.6 mmol, 46.3 mL) drop-wise. After completion of addition, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched with 1.0 N HCl by adding drop-wise. The reaction mixture was poured into water, extracted with ethyl acetate, and the combined extract was washed with water followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 10% ethyl acetate in hexanes to provide 1-(4-benzyloxy-phenyl)-hexan-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([CH3:29])=[N:24][N:25]([CH2:27][CH3:28])[CH:26]=1>>[CH2:27]([N:25]1[CH:26]=[C:22]([NH:21][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[C:23]([CH3:29])=[N:24]1)[CH3:28]
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: CCn1cc(N)c(C)n1
Product: CCn1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2OC)c(C)n1

Procedure:
Using an analogous procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted with 4-amino-1-ethyl-3-methylpyrazole to give N-(1-ethyl-3-methylpyrazol-4-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.29 (t, 3H), 2.1 (s, 3H), 3.5 (s, 2H), 3.75 (s, 3H), 3.96 (q, 2H), 5.09 (s, 2H), 6.54 (m, 1H), 6.63 (d, 1H), 7.06 (d, 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 7.8 (s, 1H), 9.29 (s, 1H); Mass Spectrum: M+H+ 380; which material was hydrogenated to give N-(1-ethyl-3-methylpyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.28 (t, 3H), 2.1 (s, 3H), 3.45 (s, 2H), 3.7 (s, 3H), 3.96 (q, 2H), 6.28 (m, 1H), 6.37 (d, 1H), 6.93 (d, 1H), 7.8 (s, 1H), 9.22 (br s, 1H), 9.29 (br s, 1H); Mass Spectrum: M+H+ 290.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C(N(CC)CC)C.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH:19][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Cc1cccc([N+](=O)[O-])c1
Yield: 90.1 %

Procedure:
To a stirred solution of 3-nitrophenylacetic acid (10 g, 0.055 mol), glycine methyl ester hydrochloride (7.3 g, 0,058 mol), triethylamine (8.0 ml, 0.058 mol) and 4-dimethylaminopyridine (7.1 g, 0,058 mol) in dichloromethane (200 ml) was added, under nitrogen, 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide(11.1 g, 0.058 mol), the mixture was stirred at room temperature for 18 h then the solvent removed in vacuo. Ethyl acetate (300 ml) was added to the residue and the mixture partitioned with 1M hydrochloric acid (2×200 ml), saturated sodium bicarbonate solution (2×200 ml), water (100 ml) and brine (100 ml). The organic phase was separated then evaporated in vacuo. The residue was triturated with ether (200 ml) to afford the desired amide (12.5 g, 90%) as a white solid. mp 104°-105° C. 1H NMR (360MHz, CDCl3) δ3.71 (2H, s), 3.76 (3H, s), 4.06 (2H, d, J 5Hz), 6.06 (1H, br s), 7.53 (1H, dd, J=8 and 8Hz), 7.67 (1H, d, J =8Hz), 8.16 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][C:14]1[C:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Yield: 59.5 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (5 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (5 g) described in Preparation Example 91 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (5 g) was obtained.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.23 g, 1.36 mmol) and 4-(trifluoromethyl)benzaldehyde (0.20 mL, 1.49 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.37 g, 1.76 mmol) was slowly added and stirring continued for 30 min. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (8 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.15 g of N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 38% yield].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[N:45][CH:46]=[C:47]([O:49][CH3:50])[CH:48]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[N:44]=[N:45][CH:46]=[C:47]([O:49][CH3:50])[CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1cnnc(-c2cc(C)c(Cl)c(C)c2)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(OC)cnn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-chloro-3,5-dimethyl-phenyl)-5-methoxy-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.10 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([N:15]2[C@@H](C(C)C)COC2=O)=[O:14])=[CH:4][C:3]=1[CH3:35].C[OH:37].NO.[C-]#N.[K+]>C1COCC1.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([NH:15][OH:37])=[O:14])=[CH:4][C:3]=1[CH3:35]
Reactant: CO
Reactant: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Agent: NO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-one (100 mg, 0.20 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (4.0 mg, 0.06 mmol). The resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of 1M aqueous HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (54.2 mg) as colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:14][C:15]1[CH:16]=[C:17]([NH:24][C:25]([C:27]2([CH3:30])[CH2:29][O:28]2)=[O:26])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][C:27]([OH:28])([CH3:29])[C:25]([NH:24][C:17]2[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH3:14])[CH:16]=2)=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-acetamidophenol (2.9 g, 19 mmol) in THF (60 ml) was added dropwise to a stirred suspension of sodium hydride (0.46 g, 19 mmol, 60% dispersion in mineral oil) in THF (60 ml) and the temperature was kept below 5° C. during the addition. The mixture was stirred for 10 min and a solution of 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (3.05 g, 13 mmol) in THF (120 ml) was added. The mixture was heated to 60° C. and stirred at this temperature for 7 h, and allowed to cool to the room temperature. The solvent was evaporated and the residue was dissolved to the mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2-3 with 2 M HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate (4×150 ml). The combined organic phase was washed with 1 M Na2CO3 (5×100 ml), dried over Na2SO4 and evaporated. The oily residue was crystallised from the mixture of ethyl acetate-diethyl ether (10:1). The crude product was recrystallised from ethyl acetate. The yield was 2.5 g. 1H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J=9.6 Hz), 4.16 (1H, d, J=9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J=9.0 Hz), 7.44 (2H, d, J=9.0 Hz), 7.88 (1H, dd, J=9.0 Hz and 2.3 Hz), 7.93 (1H, d, J=2.3 Hz), 8.04 (1H, d, J=9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]2[CH:13]3[C:14]([CH3:16])([CH3:15])[C:10]([CH3:17])([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:5][CH:4]=1.[C:22]1([CH3:33])[CH:27]=[CH:26][C:25]([S:28]([O:31]C)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:22]1([CH3:33])[CH:23]=[CH:24][C:25]([S:28]([O-:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1.[O:18]=[C:9]1[C:8](=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([N+:2]([CH3:22])([CH3:1])[CH3:21])=[CH:20][CH:19]=2)[CH:13]2[C:14]([CH3:16])([CH3:15])[C:10]1([CH3:17])[CH2:11][CH2:12]2
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)c1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1
Solvent: Cc1ccccc1
Product: CC12CCC(C(=Cc3ccc([N+](C)(C)C)cc3)C1=O)C2(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
There are heated for 8 hours at reflux, in toluene and with good agitation, 283 of 4-dimethylamino benzylidene camphor (prepared in Example 1) and 186 g of methyl paratoluenesulfonate. A white solid which precipitates is then filtered and dried, yielding 417 g of product which after recrystallization in ethanol gives 362 g of white crystals, having a melting point of 305° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.Br[C:21]1[CH:30]=[CH:29]C(C(OC)=O)=[C:23](CBr)[CH:22]=1.Cl.COC(=O)C(C1C=CC=CC=1)N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH2:17][C:19]1[CH:29]=[CH:30][CH:21]=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COC(=O)C(N)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 380 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and 2-phenyl glycine methyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:7]2[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:19][CH2:18]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: COCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 80 °C
Yield: 105.1 %

Procedure:
To 4-fluoro-2-(methyloxy)-1-nitrobenzene (which may be prepared according to Example 22, step A) (1 g, 5.8 mmol) in 15 mL of DMSO was added, 1-[2-(methyloxy)ethyl]piperazine (0.92 g, 6.4 mmol), and K2CO3 (2.4 g, 17.4 mmol). The mixture was heated to 80° C. overnight. The mixture was then poured into 100 mL of H2O and extracted with EtOAc, washed with a saturated NaCl solution, dried over Na2SO4, filtered and rotovapped to dryness to give 1.8 g of crude 1-[2-(methyloxy)ethyl]-4-[3-(methyloxy)-4-nitrophenyl]piperazine. MS (ESI): 296 [M+H]+. This material was dissolved in 15 mL EtOH and 1 mL DMF in a 100 mL round bottom flask. Platinum on Carbon (5% by weight) (0.2 g) was added and the flask was flushed with N2. After about 15 min, a balloon containing H2 was added and the N2 was removed. H2 was bubbled through the solution for a few minutes. The reaction mixture was let stir overnight under balloon pressure. In the morning the balloon was removed and the flask flushed with N2 to remove all H2. The solution was filtered through celite and evaporated to afford the title compound of step A (1.49 g, 5.62 mmol, 92%); MS (ESI): 266 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:33][CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole), 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of N,N-diethylethylenediamine (7.32 g, 0.063 mole) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was evaporated to a solid. The solid was triturated with water (50 ml), filtered, and the filter cake was rinsed twice with water, twice with a 5% potassium hydroxide solution and twice with water. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature. Addition of water caused a white solid to form. The solid was collected by filtration and rinsed with water to give 4.21 g (52%) of a white solid A 1.0-g sample of the solid was dried under high vacuum at room temperature to give a white solid, mp 142°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(C(C)C)C(C)C)C.[C:18]1(=[CH:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19]1>ClCCl>[C:18]1(=[CH:22][C:23]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)=[O:24])[CH2:21][CH2:20][CH2:19]1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)C=C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C=C1CCC1)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1.5 g (13.50 mmol) of 3-fluoroaniline were dissolved in 20 ml of dichloromethane and treated with 5.19 g (29.7 mmol) of N-ethyl-N-isopropylpropan-2-amine. Within 10 min 12.82 g (16.20 mmol) of 2-cyclobutylideneacetyl chloride were added at 0° C. and the solution was stirred overnight at room temperature. The mixture was poured on ice water and extracted 2× with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried with MgSO4 and evaporated in vacuo. The crude oil was treated with heptane and decanted twice, redissolved in ether-dichloromethane and treated with heptane till crystallization, yielding 2.2 g (77%) of a beige solid.
Reaction SMILES: Br[C:2]1[N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15]C)=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>CN(C=O)C.CCOC(C)=O.O.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>[CH2:26]([C:2]1[N:3]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:25]=[CH2:24]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(CC(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 79.2 %

Procedure:
Argon was bubbled into a solution of tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.68 g, 9.66 mmol) in DMF (50 mL) for 1 h. Allyltributyltin (3 mL, 9.66 mmol) was added to the reaction mixture followed by the addition of Pd(PPh3)4 (1.1 g, 10 mol %). The reaction was heated at 80° C. for 6 h and then diluted with EtOAc and H2O. The entire solution was filtered over celite and to the solute was added 20% aqueous KH2PO4. The organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide tert-butyl 2-allyl-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (2.52 g, 76%). MS (m/z) 330 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31]([N:33]2[CH:37]([C:38]3[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=3)[CH2:36][O:35][C:34]2=[O:46])=[O:30])[CH2:6][CH2:7]1
Reactant: O=C1OCC(c2cc(F)cc(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccccc1N1CCN(CCCN)CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1N1CCN(CCCNC(=O)N2C(=O)OCC2c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine (25 mg, 0.090 mmol) in 10 mL of THF, 4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester(30 mg, 0.082 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf =0.75, MeOH/EtOAc=1:3) to obtain 2-[4-(3-{[4-(3,5-difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-amino}-propyl)-piperazin-1-yl]-benzoic acid methyl ester (31 mg, 69%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M. P. 93-96° C.; [α]D =+45.3, (c=0.29, MeOH); Anal. Calcd. For C25H30N4O5F2Cl2.0.58 CH2Cl2 : C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56; N,8.91.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C.C(Cl)[Cl:23]>FC(F)(F)C(O)=O>[ClH:23].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNc1ccc2ccccc2n1
Reaction time: 1 h
Yield: 56 %

Procedure:
Tert-butyl N-[2-(2-quinolylamino)ethyl]carbamate (137 mg, 0.44 mmol) was dissolved in a mixture of DCM (6 ml) and trifluoroacetic acid (2 ml) and left standing at room temperature for one hour. The volatiles were removed under reduced pressure, the residue was dissolved in THF and evaporated to dryness under reduced pressure. The residue was dissolved in THF and the product was precipitated by the addition of HCl in dioxane (4N). The precipitate was removed by filtration, washed several times with THF and dried under reduced pressure to yield 55 mg of a solid (0.226 mmol, 56%) that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:16]=[N:15]2)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]2=[O:37])[CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl.C(=O)(O)[O-].[Na+]>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:16]=[N:15]2)[CH2:10][CH2:11][N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]3=[O:37])[CH2:27][CH2:26]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: O=CC[C@H](Cn1nnnc1-c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cl
Product: O=C1NCCCN1C1CCN(CC[C@H](Cn2nnnc2-c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.67 h
Yield: 185.8 %

Procedure:
(3S)-3-(3,4-dichlorophenyl)-4-(5-phenyltetrazol-1-yl)-butyraldehyde (0.90 g) in methanol (6 mL) and dichloromethane (2 mL) was added to a solution of 1-(piperidin-4-yl)tetrahydropyrimidin-2-one (0.458 g) and acetic acid (0.14 mL) in methanol (5 mL). After 40 minutes, sodium cyanoborohydride (0.157 g) in methanol (5 mL) was added in a single portion. After being stirred for 2 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 70:30) as eluent. The purified material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound as a white solid (0.928 g); NMR (CD3OD): 7.61-7.47 (m,3), 7.30 (m,2), 7.21 (d,1, J=8.2), 7.03 (d,1, J=2.1), 6.75 (dd,1, J=2.1, 8.3), 4.94 (dd,1, J=4.8, 14.2), 4.74 (dd,1, J=9.4, 14.2), 4.34 (m,1), 3.58 (m,2), 3.25 (m,5), 3.15-2.98 (m,3), 2.76 (m,1), 2.33-2.11 (m,4),1.90 (m,4); MS: m/z=528(M+1). Analysis for C26H31Cl2N7O·0.15 Et2O·2.50 HCl: Calculated: C, 50.65; H, 5.59; N, 15.54; Found: C, 50.58; H, 5.61; N, 15.27.