Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[CH:3]/[C:4](/[CH3:18])=[CH:5]/[C@@H:6]1[C@@H:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:7]1([CH3:17])[CH3:16].Cl[CH2:20][C:21]#[CH:22].[H-].[Na+].Cl>CN(C=O)C>[CH3:16][C:7]1([CH3:17])[C@H:6](/[CH:5]=[C:4](\[CH3:18])/[CH:3]=[N:2][O:1][CH2:22][C:21]#[CH:20])[C@H:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C#CCCl
Reactant: C/C(C=NO)=C\[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.58 g of t-butyl (1R)-trans-3-[(E)-3-hydroxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate, 0.75 g of 3-chloropropyne and 10 ml of anhydrous DMF was added 88 mg of sodium hydride (60% dispersion in mineral oil), and the mixture was stirred at room temperature overnight. Then, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.46 g of t-butyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-(2-propynyloxyimino)-1-propenyl]cyclopropanecarboxylate:
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]([CH3:18])([CH3:17])[C:13](NN)=[O:14]>>[C:12]([C:13]([CH2:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4])=[O:14])([CH3:18])([CH3:17])[CH3:11]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(C)(C)C(=O)NN
Product: CC(C)(C)C(=O)CC(=O)c1ccccc1

Procedure:
The desired product is prepared as described in Example 1 using 2-hydroxyacetophenone (19.0 g, 140 mmol) and trimethylacetic hydrazide (10 g, 96 mmol). Yield: 5.0 g, 84%. m.p. 43°-45° C. 1H NMR (CDCl3), δ=1.25 (s, 9H, 3×CH3); 2.58 (s, 3H, CH3); 7.21 (d, 1H, ArH); 7.45-7.49 (m, 1H, ArH); 7.55-7.59 (m, 1H, ArH); 7.89 (d, 1H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.CC(C)([O-])C.[K+].P(Cl)(OCC)(OCC)=O.[N+:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[C-:36]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:36]=[N:35][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccn1)c1cc(Br)ccc1-2
Reaction time: 0.17 h

Procedure:
A solution of 15.8 g (0.05 mol) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 300 ml of dry tetrahydrofuran was cooled to 10° with stirring under argon. Potassium tert. butoxide 6.3 g (0.056 mol) was added and stirring was continued for 10 min. Following the addition of 14 ml of diethyl chlorophosphate the mixture was stirred for additional 20 min. A previously prepared mixture of 11.3 g ethyl isocyanoacetate, 11.3 g of potassium tert. butoxide and 300 ml of tetrahydrofuran was then poured into the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(Br)cc1Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A 100 mL round-bottom flask, was charged with 4-bromo-2-phenoxybenzaldehyde (1.00 g, 3.61 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.674 g, 3.62 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.30 g, 10.8 mmol, 3.01 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with H2O (10 mL). The resulting mixture was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92) to provide 1.20 g (74% yield) of tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 447 [M+H]+.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][N:18]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]([C:4]2[CH:5]=[CH:6][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:2][CH:3]=2)[N:18]=1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc(-c2ccccc2)cc1
Yield: 26 %

Procedure:
To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dry DCM were added pyridine (1.2 mL, 15 mmol) and anhydrous powder of copper(II) acetate (1.84 g, 10 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was refluxed for 2 days under argon. The mixture was diluted with DCM, filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated, purified with flush column to yield ethyl 3-methyl-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate (26%), Rf 0.67 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307; and its regioisomer, ethyl 5-methyl-1-(4-phenylphenyl)-1H-pyrazole-3-carboxylate (31%), Rf 0.50 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8].[CH:14]1([CH3:26])[CH2:19][CH2:18][CH:17]([CH:20]([CH3:22])[CH3:21])[CH:16]([C:23](Cl)=[O:24])[CH2:15]1>O.CCOCC>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:23]([CH:16]1[CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:19][CH:14]([CH3:26])[CH2:15]1)=[O:24])[CH3:8]
Reactant: CCOC(=O)CN
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)C1CC(C)CCC1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium bicarbonate (8.4 g., 0.1 mole) and glycine ethyl ester hydrochloride (7 g. 0.05 mole) were dissolved in water (100 ml.), and a solution of p-menth-3-oyl chloride (10 g., 0.05 mole) in ether (50 ml.) was added and the mixture stirred vigorously at room temperature for 2 hours. At the end of this time the ether layer was separated and dried (MgSO4). Removal of the solvent left an oily solid (12.3 g.). This was distilled under reduced pressure to yield N-p-menth-3-oylglycine ethyl ester, bp. 150- 2°/0.1 mm. as a colourless liquid which rapidly solidified.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21].[H-].[Na+]>C1COCC1>[Br:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]2[O:10][CH2:19][C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(O)c(N)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Br)NC(=O)CO2
Yield: 72.7 %

Procedure:
Prepared following the procedure for Intermediate 6 using 2-amino-4-bromo-5-methylphenol (4.73 g, 23.4 mmol), triethylamine (3.6 mL, 25.8 mmol) and chloroacetyl chloride (1.8 mL, 23.4 mmol) in THF (120 mL) followed by sodium hydride (1.9 g of a 60% suspension in oil, 49.2 mmol) to give the title compound (4.12 g, 73%) as a beige solid. δH (DMSO-d6) 2.23 (3H, s), 4.57 (2H, s), 6.97 (1H, s), 7.04 (1H, s), 10.72 (1H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH:23]([CH3:25])[CH3:24])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:12][C@H:13]([C@@H:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:32](Cl)(=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>C1COCC1>[CH3:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:1][C@@H:2]([CH:23]([CH3:25])[CH3:24])[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][C@H:6]2[C:10]([NH:12][C@H:13]([C@@H:17]([OH:22])[C:18]([F:21])([F:19])[F:20])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:4])=[O:41])=[CH:34][CH:35]=1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F)C(C)C)cc1
Temperature: -5 °C

Procedure:
Compound C was suspended in THF (350 ml) and powdered sodium carbonate (18.5 g) was added. The mixture was cooled to -5° C. and a solution of anisoyl chloride (11.9 g) in THF (50 ml) was added with stirring. The reaction mixture was stirred an additional 2 hours at 0° C. and then allowed to rise to ambient temperature. The reaction mixture was filtered and the filtrate acidified with 1M hydrochloric acid solution (20 ml) and washed with water. The aqueous layer was extracted with twice with diethyl ether and the combined organic layers washed with 50% saturated sodium bicarbonate solution, brine and dried. Solvent was removed by evaporation to give a colourless foam. The foam was triturated with diethyl ether and the resulting solid was collected by filtration and dried under vacuum at 40° C. for 3 hours to give (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[(S)-2-methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide as a white solid, m.p. 168°-170° C.; NMR (300 MHz, d6 -DMSO): 0.82-1.05 (m, 12H), 1.65-2.05 (3m, 5H), 2.05-2.25 (m, 1H), 3.60 (m, 1H), 3.82 (s, 3H+t, 1H), 3.93 (m, 1H), 4.12 (m, 1H), 4.45 (m, 2H), 6.45 (d, 1H), 6.98 (d, 2H), 7.65 (d, 1H), 7.90 (d, 2H), 8.35 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].C(N(CC)CC)C.[CH:30]([C:32]([CH3:34])=[O:33])=[CH2:31]>CC(C)=O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][CH2:30][C:32](=[O:33])[CH3:34])[CH2:20][CH2:21]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: C=CC(C)=O
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 37.1 %

Procedure:
4-Piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate (0.100 g; 10.31 mmol) was dissolved in acetone (10 ml) and treated with triethylamine (0.043 ml; 0.31 mmol) and methyl vinyl ketone (0.026 ml; 0.34 mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacuo to a yellow gum. The gum was purified by flash silica-gel chromatography with CHCl3 as eluant to yield the title compound as a colourless gum (0.050 g; 41%) which was converted to the oxalate salt.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:18][CH2:17]1)[CH3:3].[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:54])[F:53])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40](O)=[O:41]>>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:44]([N:47]2[C:51]([C:52]([F:55])([F:53])[F:54])=[N:50][N:49]=[N:48]2)=[CH:43][C:39]=1[C:40]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:17][CH2:18]2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)=[O:41]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5C(F)(F)F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 51.1 using 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].FC(F)(F)S(O[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]=1)(=O)=O>>[CH3:32][O:31][C:26]1[CH:27]=[C:28]2[C:23]([CH:22]=[C:21]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:30][CH2:29]2)=[CH:24][CH:25]=1
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Product: COc1ccc2c(c1)CCC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitro-4-trifluoromethylbenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitro-4-rifluoromethylphenyl)tin (7.4 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 7-methoxy-3-(2-nitro-4-trifluoromethylphenyl)-1,2-dihydronaphthalene (1.5 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (1.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]1[C:13](=[O:15])[O:18][C@H:16]1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCOC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 36.1 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of employing (2R,3S)-2-(heptoxycarbonylamino)-3-hydroxy-butanoic acid (0.3 g, 1.14 mmol) in dry CH2Cl2 (30 mL), Et3N (0.48 mL, 3.44 mmol) and subsequently TBTU (0.44 g, 1.37 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.10 g, 37%), as white solid.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.C(Cl)(Cl)Cl.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[F:33][C:19]([F:18])([F:32])[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(N2CCN(c3nc4cccc5c4n3CCC5)CC2)c1
Reaction time: 4 h
Yield: 50 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in 1-[3-(trifluoromethyl)phenyl]piperazine (5 ml) was stirred at 110° C., under nitrogen. After four hrs, chloroform (50 ml) was added, and the solution was stirred under reflux overnight. The reaction mixture was quenched with dilute sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by high performance liquid chromatography (silica gel; 8:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 3.0 g (50%) of product, mp 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:16]C1C=CC(N[C@H](C(O)=O)C(C)C)=CC=1>>[CH3:16][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reactant: Cc1ccc(N[C@H](C(=O)O)C(C)C)cc1
Product: CC(C)[C@@H](C(=O)O)N(C)c1ccc(Cl)cc1

Procedure:
Each of the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine and N-(4-methylphenyl)valine is methylated using the procedure of Example 2 to yield the m-phenoxybenzyl ester of N-methyl,N-(4-chlorophenyl)valine, MS m/e 423 (M+), and the m-phenoxybenzyl ester of N-methyl,N-(4-methylphenyl)valine, MS m/e 403.2 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:8]=[N:9][OH:10])=[N:6][CH:7]=1.ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C=NO)ncc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of the compound obtained in Step C (2.2 g) in dimethylformamide (24 ml) was added N-chlorosuccinimide (1.4 g) in three portions at room temperature under argon. The reaction mixture was allowed to stir overnight at room temperature then a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g, prepared as described in WO 2009/080250) in DMF (6 ml) was added followed by triethylamine (1.43 ml) in DMF (14 ml). The reaction stirred at room temperature for 1 hour then poured into ice water. A white solid precipitated, which was filtered, washed with water and dried under vacuum to give the title product (4.1 g). 1H-NMR (CDCl3, 400 MHz): 8.60 (s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.40 (s, 1H), 4.20 (d, 1H), 3.85 (d, 1H), 2.45 (s, 3H),
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[O:12])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.O>CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:6][CH:7]=1)=[O:12]
Reactant: C1CCNCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCN4CCCCC4)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
[4-(2-Chloro-ethoxy)-phenyl]-[2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-methanone (compound 189) (48 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (86 mg) and piperidine (52 mg) were then added to the solution, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform methanol to give the title compound (31 mg, yield 58%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:44][N:43]=[CH:42][CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.2 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.2 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C25H32FN5O6S, 550. found, 550.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:9]([F:14])[CH:8]=1
Reactant: Fc1cc(F)cc(Cl)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Temperature: -70 °C
Reaction time: 8 h

Procedure:
A solution of 2.5M n-BuLi in hexanes (60 ml, 0.15 mol) was added dropwise to a solution of 1-chloro-3,5-difluorobenzene (19.2 g, 0.13 mol) in THF (200 mL) cooled to −70° C. under Ar. After the addition was complete, the mixture was stirred for 1 h before a solution of chlorotrimethylsilane (21.7 g, 0.2 mol) in THF (25 mL) was added dropwise. The reaction was allowed to warm to rt with stirring overnight before cooling and quenching with H2O. The phases were separated and pentane (200 mL) was added; after washing with H2O the solution was dried over MgSO4 and carefully concentrated in vacuo to yield the title compound as a solution in THF (46 g) which was in the next step without further purification.