Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(C(N)=N)=CC=C(O[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:20]=2)C=1.[CH:24]1[C:29]([C:30]([NH2:32])=[NH:31])=[CH:28][C:27](Br)=[C:26]([O:34][CH2:35][CH2:36]COC2C=CC(C(N)=N)=CC=2Br)[CH:25]=1.C1C(C(N)=N)=CC=C(OCCCCCCOC2C=CC(C(N)=N)=CC=2)C=1>N[C@H](C(O)=O)CC(C)C>[CH:28]1[C:29]([C:30]([NH2:32])=[NH:31])=[CH:24][CH:25]=[C:26]([O:34][CH2:35][CH2:36][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH2:23])=[NH:22])=[CH:17][CH:16]=2)[CH:27]=1
Reactant: N=C(N)c1ccc(OCCCOc2ccc(C(=N)N)cc2)cc1
Reactant: N=C(N)c1ccc(OCCCOc2ccc(C(=N)N)cc2Br)c(Br)c1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N=C(N)c1ccc(OCCCCCCOc2ccc(C(=N)N)cc2)cc1
Product: N=C(N)c1ccc(OCCCCCOc2ccc(C(=N)N)cc2)cc1

Procedure:
Efflux pump inhibitory activity of propamidine, dibromopropamidine, and hexamidine was confirmed in Leu-Nap accumulation assays. The uptake of Leu-Nap (100 μg/ml) by PAM1723 (FIGS. 10A, C, and E) or PAM1626 (FIGS. 10B, D, and F) cells was studied in the presence of various concentrations of propamidine (0 μg/ml to 160 μg/ml), dibromopropamidine (0 to μg/ml to 40 μg/ml), and hexamidine (0 μg/ml to 40 μg/ml), respectively. All three compounds were capable of completely inhibiting the MexAB-OprM-mediated efflux of Leu-Nap from the strain overexpressing this pump. The rate of Leu-NAp uptake into PAM1626 and PAM1723 in the presence of 160 μg/ml propamidine, 20 μg/ml of dibromoproapmidine, and 20 μg/ml of hexamidine was the same.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1C=O)=[O:6])[CH:2]=[CH2:3].C1(CN)C2C(=CC=CC=2)C=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCc1cccc2ccccc12
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(SC(=O)OC(C)(C)C)C1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of (2S,4S)-2-formyl-4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound (1)) (3.11 grm. ) in dichloromethane(60 ml.) was added dropwise to a stirred mixture of of 1-naphthalenemethylamine (1.71 g), 4A molecular sieves(12 grms) and sodium triacetoxyborohydride(2.3 grms) in dichloromethane (200 ml) under an argon atmosphere at −20°. The mixture was stirred for a further 30 minutes at −20° C. and then allowed to warm to ambient temperature and stirred for a further 16 hours. The mixture was filtered and washed with aqueous sodium bicarbonate solution (2×200 ml),the organic phase further washed with water (200 ml), separated, dried over magnesium sulphate and purified by column chromatography, using ethyl acetate/hexane (30:70) as eluent to give (2S,4S)-2-{[naphthalen-1-ylmethyl]-amino)-methyl}-4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound(12)) as a pale yellow oil (2.09 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][N:15]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Yield: 68.4 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (500 mg, 2.48 mmol) and tert-butyl methyl[3-(methylamino)propyl]carbamate (652 mg, 3.22 mmol) were used to give the title compound (655 mg; yield, 68%) as a colorless oily substance according to the method described in Example 12a.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[NH:27][NH2:28]>C(#N)C>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[C:11]([NH:28][NH:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)nc2ccc(-n3ccnc3)cc2n1OCc1ccccc1
Reactant: CCOC(=O)NN
Solvent: CC#N
Product: CCOC(=O)NNc1nc2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-benzyloxy-2-chloro-6-(1H-imidazol-1-yl)-quinoxalin-3(4H)-one (9.4 g; ~27.6 mmol) in 500 ml acetonitrile was added ethyl carbazate (28 g; ~270 mmol). The reaction mixture was refluxed overnight. Cooling to room temperature gave the title compound (11.1 g; 99%) as a precipitate. M.p. 197°-199° C.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([NH2:22])=[O:21])=[C:9]1[CH3:23].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([NH2:22])=[O:21])=[C:9]1[CH3:23]
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1-c1ccccc1
Yield: 83 %

Procedure:
A solution of 369 mg (0.96 mmol) of 1-([1,1′-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide and 4 mL of 1M BBr3/methylene chloride in 20 mL of methylene chloride was stirred for 6 hours. The mixture was concentrated at reduced pressure, the residue dissolved in ethyl acetate, washed with water, brine and dried (MgSO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel and eluted with EtOAc to give 295 mg (85% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-5-hydroxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Li]CCCC.C(O[B:42]1[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]1)(C)C>C1COCC1>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([N:7]([C:20]2[CH:25]=[CH:24][C:23]([B:42]3[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]3)=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
N-(biphenyl-4-yl)-N-(4-bromophenyl)biphenyl-4-amine (56 g, 0.117 mol) was introduced into a 2 L RBF, and dissolved in THF (600 ml). Then, the temperature was maintained at −78° C. for about 30 minutes. Then, n-BuLi (1.6M in Hex) (90 ml, 0.141 mol) was slowly added thereto. After 1 hour, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26.2 g, 0.141 mol) was added thereto, followed by heat-stirring at room temperature for 12 hours. After the reaction was completed, the resultant solution was sufficiently washed with distilled water and Brain, and purified through column chromatography to obtain N-(biphenyl-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)biphenyl-4-amine (white solid, 20 g, yield 33%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:21]([C:17]1[O:16][CH:20]=[CH:19][CH:18]=1)=[O:22]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccco1
Product: CN(C)CCN(C(=O)c1ccco1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and furan-2-carbonyl chloride
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])=[O:19]
Reactant: O=C(NNC(=O)C(F)(F)F)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)C(F)(F)F)[C@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 87.3 %

Procedure:
To a solution of (2R,5R)-6-(benzyloxy)-7-oxo-N′-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 185 (0.224 g, 0.58 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite and the filtrate was evaporated to give (2R,5R)-6-hydroxy-7-oxo-N′-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 186 (0.15 g, 88%) as a colorless foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH2:19][OH:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([N:21](S(C3SC(Cl)=CC=3)(=O)=O)[S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48].[OH-].[Na+]>ClCCl.CO>[Cl:30][C:27]1[S:26][C:25]([S:22]([NH:21][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][OH:20])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:47](=[O:49])[CH3:48])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(CO)cccc32)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(hydroxymethyl)-1H-indazol-3-yl]-5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-2-thiophenesulfonamide (for a preparation see Intermediate 72) (53 mg, 0.082 mmol) was suspended in dichloromethane (0.5 mL) and triethylamine (0.115 mL, 0.823 mmol). Acetic anhydride (0.008 mL, 0.09 mmol) was added to the suspension and it stirred for 1 h. LCMS showed starting material remaining so dichloromethane (0.3 mL) and acetic anhydride (3.88 μL, 0.041 mmol) were added to the solution and stirred for 2 h. LCMS showed only a small amount of starting material remaining so the reaction mixture was concentrated in vacuo to leave an off-white residue, which was dissolved in methanol (3 mL) and treated with NaOH (1.546 mL, 3.09 mmol). The reaction was stirred at room temperature for 1 h and then was concentrated in vacuo, and acidified with 5% citric acid. The solution was extracted with ethyl acetate and the organic layer was washed twice with water (25 mL) and once with brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo. The yellow residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (17 mg, 43%) as a colourless glassy solid. LCMS (System A) RT=0.91 min, ES+ve m/z 505/507 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([F:37])[CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:10][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]5)[CH2:24]4)[O:8][C:5]3=[CH:6][N:7]=2)=[C:30]([F:37])[CH:29]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: N#Cc1ccc(B(O)O)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(C#N)cc4F)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-cyano-2-fluoro-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=1.16 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].[Cl-].[NH4+]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47]([C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)([OH:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(Nc1ccc(Oc2ccc(Br)cc2)cc1)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: Cc1cc(Cl)ccc1B(O)O
Product: Cc1cc(Cl)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4-chloro-2-methylphenylboronic acid (CAS RN 209919-30-2). Off-white solid (27%). MS (ESI): m/z=472.8 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]#[C:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]1(=[C:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC#CC1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)=C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 73.1 %

Procedure:
To a suspension of 3-cyclopentylprop-2-ynenitrile (0.4 g, 0.003 mol) in ACN (10 mL) was added 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.53 g, 1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This mixture was stirred at room temperature for 50 minutes. The reaction mixture was partitioned between ethyl acetate and dilute HCl. The aqueous portion was separated and extracted with ethyl acetate. The combined organic extracts were washed with dilute HCl and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (540 mg, 74%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]2[N:60]3[CH2:61][CH2:62][NH:63][CH2:64][C@@H:59]3[CH2:58][CH2:57]2)=[C:52]([CH3:65])[C:51]=1[CH3:66]>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]2[N:60]3[CH2:61][CH2:62][N:63]([C:7]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[O:9])[CH2:64][C@@H:59]3[CH2:58][CH2:57]2)=[C:52]([CH3:65])[C:51]=1[CH3:66]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: COc1ccc([C@H]2CC[C@H]3CNCCN32)c(C)c1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2CC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c(C)c1C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6-Trifluoromethyl nicotinic acid (18.1 mg, 0.12 mmol), BOP (66.3 mg, 0.15 mmol), and Et3N (34.8 μL, 0.25 mmol) are added to a solution of (6R,8aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrrolo[1,2-a]pyrazine (52.2 mg, 0.2 mmol) in anhydrous DMA (0.1 mL). The reaction mixture is stirred at 50° C. for 16 h, diluted with toluene, evaporated to dryness and the residue purified by filtration through an SCX cartridge, eluting with EtOAc-MeOH-NEt3 (10-1-1) to produce an oil (LC/MS: 434).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Br:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[C:5]([Cl:20])=[CH:4][C:3]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]([Cl:33])=[CH:30][CH2:31]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Br:15])=[CH:13][C:12]([C:16]([F:17])([F:19])[F:18])=[CH:11][N:10]=2)[C:5]([Cl:20])=[CH:4][C:3]=1[O:21][CH2:31][CH:30]=[C:29]([Cl:33])[Cl:28]
Reactant: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Br)cc1Cl
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2cc(Cl)c(OCC=C(Cl)Cl)cc2Cl)c(Br)c1
Temperature: 0 °C
Yield: 82.8 %

Procedure:
To a mixture of 0.77 g of 2,5-dichloro-4-(3-bromo-5-trifluoromethyl-2-pyridyloxy)phenol, 0.29 g of potassium carbonate and 20 ml of N,N-dimethylformamide, a solution prepared by dissolving 0.31 g of 1,1,3-trichloropropene in 5 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 10 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of ethyl acetate. Then, the ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.81 g of 2,5-dichloro-4-(3-bromo-5-trifluoromethyl-2-pyridyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 83%; m.p., 95.4° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([OH:13])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[CH3:15][OH:16]>>[ClH:14].[CH3:15][O:16][N:2]=[CH:1][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([OH:13])=[CH:5][CH:4]=1
Reactant: CO
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: Cl
Product: CON=Cc1ccc(O)c(C(=O)OC)c1

Procedure:
In 450 ml of anhydrous methanol, was suspended 44.0 g of methyl 5-cyanosalicylate. While being cooled in ice and stirred, the suspension was saturated with dried gaseous hydrogen chloride. The suspension was further stirred for 2 days at room temperature, then the resulting solution was concentrated to about 200 ml at a low temperature under reduced pressure, and admixed with ethyl acetate to precipitate colorless crystals. The crystals were collected by filtration and dried to obtain 41.0 g of methyl 5-methoxyiminomethylsalicylate hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:21]=[O:22])[C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:24]O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:24][O:18][C:17]=2[C:16]2[C:11]([OH:10])=[C:12]([C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[CH:21]=[O:22])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1c(O)c(Cl)cc2c(=O)c(-c3ccc(Br)cc3)coc12
Agent: Cl
Solvent: CCO
Product: O=Cc1c(O)c(Cl)cc(-c2oncc2-c2ccc(Br)cc2)c1O
Yield: 59.7 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-6-chloro-7-hydroxy-4-oxo-4H-chromene-8-carbaldehyde 53.5 mg, 0.14 mmol) in EtOH (6 ml), hydroxylamine hydrochloride (100 mg, 1.4 mmol) was added. The resulting mixture was heated at reflux for 16 hours. EtOH was evaporated and EtOAc (20 ml) was added. The organic layer was washed with sat. NaHCO3 and dried. Solids (33 mg) were obtained when the resulting oil was triturated with ether. 1H NMR (d6-DMSO) δ=9.83 (1H, s); 8.70 (1H, s); 8.21 (1H, s); 7.78 (2H, d) and 7.68 (2H, s). LCMS: (M+1)+=394.1 (RT=8.60 min.)
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=[O:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].S(Cl)(Cl)=O>>[CH3:2][C:1]1[O:20][C:11]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CCc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1CCc1ccccc1

Procedure:
1 g. of ethyl 2-acetamido-3-oxo-5-phenylvalerate is dissolved in 4 ml. of thionyl chloride, and the solution heated for 15 minutes. The reaction mixture is then evaporated under vacuum to obtain a residue which is then washed with 10 ml. of 5% aqueous sodium bicarbonate solution, then extracted twice with 25 ml. of methylene chloride. The combined extracts are then evaporated under vacuum to obtain ethyl 2-methyl-5-phenethyl-4-oxazolecarboxylate as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[H][H]>C(O)C.[Pd].[C]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1
Reactant: [H][H]
Reactant: Cn1ncc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1ncc2c(N)cccc21
Temperature: 25 °C

Procedure:
1-Methyl-4-nitro-1H-indazole (6.1 g; 35.4 mmol) and 10% Pd/carbon (500 mg) were combined in ethanol and hydrogenated in a Parr apparatus at 60 PSI hydrogen at 50° C. for 1 hour. The mixture was allowed to cool to ambient temperature, filtered through Celite, and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-d6) δ 8.02 (s, 1H), 7.02 (t, 1H), 6.62 (d, 1H), 6.14 (d, 1H), 5.75 (s, 2H), 3.90 (s, 2H).