Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-3) 1.33 g (4.6 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 2.22 g (4.84 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=4:6) to obtain the title compound 2.41 g (68%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23]>CN(C)C=O>[F:23][C:22]([F:25])([F:24])[CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 42 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 6 ml of N,N-dimethylformamide, 98 mg of sodium hydride (60% in oil), and 0.43 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(3,3,3-trifluoropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (74)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].[CH3:14][C:15]1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(CC(=O)O)ccc1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C)c(OC)c1

Procedure:
To a stirred solution of 2-(3-methoxy-4-methylphenyl)acetic acid (Step A, 4.64 g, 25.7 mmol) in ethanol (100 ml) was added p-TsOH (0.7 g, 3.7 mmol) at room temperature under argon and the reaction mixture was refluxed for 12 hours or until all the starting material is consumed, concentrated, diluted in EtOAc and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 2:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15]([CH3:17])=[N:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:21][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15]([CH3:17])=[N:16][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH:19]=[CH:20][C:2]=1[NH:1][C:34]([NH:33][C:24]1[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=1[F:22])=[O:35]
Reactant: Cc1nc2nccc(Oc3ccc(N)c(F)c3)c2[nH]c1=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c2[nH]c1=O
Yield: 85 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-3-methylpyrido[3,2-b]pyrazin-2(1H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate to afford the title compound. yield=85%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:19]([CH3:20])=[N:18][C:11]3[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.Cl[C:24]([O:26][C:27]([CH3:29])=[CH2:28])=[O:25]>N1C=CC=CC=1>[F:22][C:3]1[CH:4]=[C:5]([CH3:21])[C:6]([C:8]2[C:19]([CH3:20])=[N:18][C:11]3[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:7][C:2]=1[NH:1][C:24](=[O:25])[O:26][C:27]([CH3:29])=[CH2:28]
Reactant: CNc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)nc3nc2C)c(C)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Treat a cooled solution (0° C.) of 6-(5-amino-4-fluoro-2-methylphenyl)-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine (0.85 g, 2.86 mmol) in pyridine (10 mL) dropwise with isopropenyl chloroformate (0.281 ml, 2.57 mmol) and stir the mixture for 20 min. at 0° C. Concentrate the mixture to dryness, dissolve the residue in DCM, wash with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound. Use it without purification (assuming 100% yield). MS (m/z): 382.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:14][C@@H:12]1[O:11][C:10](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (5, 290.0 g, 698.8 mmol) in anhydrous DMF (700 mL) was treated with sodium azide (NaN3, 90.84 g, 1.4 mol, 2.0 equiv) at 25° C., and the resulting mixture was subsequently warmed up to 70-75° C. for 6 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (1500 mL) and the resulting mixture was stirred at room temperature for 2 h. The solids were then collected by filtration, washed with H2O (2×500 mL), and dried in vacuo at 40° C. for 24 h to afford the crude, desired (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 248.0 g, 252.97 g theoretical, 98%) as white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1023: 1H NMR. (300 MHz, DMSO-d6) δ 3.67-3.81 (m, 31H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C10H8FIN4O2, LCMS (EI) m/e 363 (M++H).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=O>O1CCCC1>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2c[nH]c(-c3ccccc3)n2)c(Cl)c1
Temperature: 25 °C

Procedure:
A suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride and 13.7 g (0.254 mol) of sodium methylate in 170 ml of tetrahydrofuran was heated under reflux for 1 hour, and cooled to 25° C. A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-2′,4′-dichloroacetophenone in 120 ml of tetrahydrofuran was added dropwise in such a manner that the reaction temperature did not exceed 30° C. After the addition was complete, 13.7 g (0.254 mol) of sodium methylate was added, and the mixture was heated under reflux for 1 hour. Subsequently, the reaction solution was cooled to room temperature, and insolubles were filtered off. The filtrate was evaporated to dryness under reduced pressure to recover a solid. The solid was successively washed with water and toluene and then dried, to give 33.8 g (46.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile to give pale yellow purified crystals.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[F:5][C:6]([F:22])([F:21])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>C1COCC1>[CH3:3][O:20][CH2:19][C@H:16]1[CH2:15][CH2:14][C@H:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([F:21])([F:22])[F:5])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: OC[C@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h

Procedure:
60 ml of THF are added under an N2 atmosphere to 100 mmol of NaH in the form of an oil dispersion. The mixture is mixed vigorously and heated to 45°-50° C. 120 mmol of methyl iodide are then added, and 80 mmol of trans-4-(p-trifluoromethylphenyl)cyclohexylmethyl alcohol in 20 ml of THF are subsequently added dropwise over the course of 30 minutes. The reaction mixture is then stirred for 30 minutes at the same temperature, cooled and carefully hydrolysed using aqueous THF. When the vigorous evolution of H2 is complete, customary work-up gives trans-4-methoxymethyl(p-trifluoromethylphenyl)cyclohexane.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)(=[O:19])=[O:18]
Reactant: Cn1ccnc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1ccnc1COS(C)(=O)=O

Procedure:
A solution of (1-methyl-1H-imidazol-2-yl)-methanol (Bionet Research, 66 mg, 0.59 mmol), triethylamine (0.25 mL, 0.89 mmol), and methanesulfonyl chloride (69 μL, 0.89 mmol) in 5 mL THF were processed as described in Example 1C to give the crude material which was used directly in the next reaction.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16](=[O:21])[C@H:17]([CH3:20])[CH2:18][OH:19].O>CN(C)C=O>[CH3:14][O:15][C:16](=[O:21])[C@H:17]([CH3:20])[CH2:18][O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
Imidazole (6.44 g, 42.8 mmol) and tert-butyldimethylsilyl chloride (6.05 g, 88.8 mmol) were added to a solution of (R)-3-hydroxy-2-methylpropionic acid methyl ester (5.0 g, 42.33 mmol) in dimethylformamide (50 mL), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was then dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 9.3 g (95%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 107.9 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at 55° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.24 g) as colorless amorphous.
Reaction SMILES: [N:1]#[C:2]Br.C([O-])([O-])=O.[K+].[K+].Cl.C[N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)[CH2:14][CH2:13]1.O>CS(C)=O>[C:27]1([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:2]#[N:1])[CH2:13][CH2:14]3)=[N:19]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of cyanogen bromide (5.76 g, 0.054 moles) and K2CO3 (8.82 g, 0.064 moles) in dimethylsulfoxide (110 ml) was added 3-(1-methyl-4-piperidinyl)-1-phenyl-1H-indazole (14.8 g, 0.051 moles) of Example 66 in dimethylsulfoxide (DMSO) (15 ml). The reaction was stirred at ambient temperature for 16 hours and then poured into water and extracted with ether. A precipitate formed in the ether which was collected and then the ether was concentrated to yield additional product. The crude product (11.5 g) was recrystallized three times from isopropyl alcohol which yielded 6.75 g (37%) of 4-(1-phenyl-1H-indazol-3-yl)-piperidine- 1-carbonitrile, m.p. 124°-125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][N:40]=1)[CH2:32][CH2:33][CH3:34]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:45][C:42]1[CH:41]=[N:40][C:39]([O:38][CH2:37][CH2:36][O:35][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:44][CH:43]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOCCOc1ccc(CO)cn1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CCCCOCCOc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 49.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) and 2-(2-butoxyethoxy)-5-(hydroxymethyl)pyridine (0.30 g) as starting materials, 5-benzyloxy-N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.40 g) was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:13]1[CH2:18][CH2:17][CH2:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:15]1([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:16][CH2:17][CH2:18][N:13]=[CH:14]1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: C1=NCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N2C=NCCC2)cc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a stirred solution of 2.0 g (11.76 mmol) of the 5-Flouro-3-methyl-2-nitro aniline in 10 mL of DMSO was added 1.2 g (14.11 mmol) of 1,4,5,6-Tetrahydropyrimidine, and 2.43 g (17.64 mmol) of potassium carbonate, and the mixture was heated at 100° C. for 10 hrs, cooled, diluted with water, and extracted with Ethylacetate containing 5% methanol. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent furnished the residue, which was chromatographed (20% of 2M ammonia in methanol and dichloromethane) to produce 1.85 g (67%) of the product as red solid. 1H NMR (400 MHz, CD3OD) δ 7.89 (1H,s), 6.53 (1H,d, J=2.57 Hz), 6.44 ((1H, d, J=2.1 Hz), 7.04 (1H, d, J=2.1 Hz), 3.70 (2H, t, J=6.0 Hz), 3.41 (2H, t, J=5.65 Hz, 2.43 (3H, s), 2.05 (2H, m) LCMS (M+H)+ m/z 235 (t=0.78 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:8]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 3 l-volume three-necked flask were charged 372 g of m-nitrobenzoyl chloride and 280 g of p-dimethoxybenzene, and 1.6 l of methylene chloride were added thereto to form a solution. To the solution were added dropwise 300 g of aluminum chloride over about 1 hour while stirring at room temperature. The reaction mixture slightly generated heat, and the methylene chloride began to reflux. After stirring was continued for about 2 hours, the reaction mixture was allowed to stand overnight.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][N:29]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:27]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CNc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)c3ccncc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (50 mg, 0.134 mmol) in N,N-dimethylformamide (1 mL) were added N-methylpyridin-4-amine (40 mg, 0.37 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (581 mg, 1.87 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (865 mg, 4.00 mmol) to afford the desired product (525 mg, 56%): ESI MS m/z 488 [C24H30BrN3O3+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[C:10]([N:15]2CCC(=O)[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[CH2:17][CH2:16][N:15]([C:10]2[C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: O=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium in hexanes (2.5 M, 4.93 mL, 12.3 mmol) was added dropwise over 10 min. into a suspension of 98% methyltriphenylphosphonium bromide (4.65 g, 12.8 mmol) in 40 mL of THF stirred at −70° C. After 0.5 h, a solution of 1-(3-nitro-2-pyridyl)-4-oxopiperidine (2 g, 8.5 mmol) in 16 mL of THF was added and the reaction mixture was allowed to warm up to r.t. After overnight resting, the mixture was quenched with an aqueous saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4, evaporated to dryness in vacuo. The crude product was purified by automated flash chromatography (SP1®TM-Biotage) eluting with a Petroleum Ether-EtOAc gradient from 1:0 to 9:1 yielding 1.23 g of the title compound as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.CCOC(C)=O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 297.9 %

Procedure:
A mixture of 2 g of methyl 2-amino-5-(benzyloxy)benzoate, 3.1 g of 1,1-dimethylethyl 4-oxopiperidine-1-carboxylate and 3.29 g of NaBH(OAc)3 in 10 ml of AcOH is irradiated under a microwave field (Biotage Initiator Sixty) at 110° C. for 20 min. The same reaction is repeated with two other lots of 2 g of methyl 2-amino-5-(benzyloxy)benzoate. The three reaction media are combined. The combined product is taken up in AcOEt. The organic phase is washed with water, with a saturated NH4Cl solution and with a saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (30/70, 10 v/v), to give 10.2 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[C:3]=1[OH:20].[CH3:21][O:22][CH2:23]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[C:3]=1[O:20][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: COc1ccc2c(O)c(Br)c(CCC(F)(F)F)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c(Br)c(CCC(F)(F)F)cc2cc(OC)ccc12
Yield: 80 %

Procedure:
2-Bromo-6-(methyloxy)-3-(3,3,3-trifluoropropyl)-1-naphthalenol (122) (0.47 g, 1.35 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.42 g (80%) of the title compound (123) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.40-2.55 (m, 2H), 3.10-3.20 (m, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.04 (d, J=2.6 Hz, 1H), 7.16 (dd, J1=9.3 Hz, J2=2.5 Hz, 1H), 7.43 (s, 1H), 8.03 (d, J=9.3 Hz, 1H).