Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[CH2:4][N:5]1C=[CH:8][CH:7]=[C:6]1C#N.[OH-:17].[K+].[CH2:19]([OH:22])[CH2:20]O>O>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[CH2:4][N:5]1[CH:6]=[CH:7][CH:8]=[C:20]1[C:19]([OH:22])=[O:17]
Reactant: [OH-]
Reactant: OCCO
Reactant: N#Cc1cccn1Cc1cc(Cl)ccc1N
Agent: [K+]
Solvent: O
Product: Nc1ccc(Cl)cc1Cn1cccc1C(=O)O

Procedure:
A mixture of 8 g. of 1-(2-amino-5-chlorobenzyl)-2-pyrrolecarbonitrile, 8 g. of 86% potassium hydroxide and 50 ml. of ethyleneglycol is heated in an oil bath at 170° C. for 2 hours. The mixture is partly cooled and diluted with 80 ml. of water. The mixture is cooled for about 3 hours and then filtered. The filtrate is treated with acetic acid to pH 4-5 giving a precipitate which is collected and washed with water. This solid is further purified by dissolving in dilute alkali and reprecipitating with acetic acid, giving 1-(2-amino-5-chlorobenzyl)-2-pyrrolecarboxylic acid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)=O)=[CH:13][CH:12]=1.COC1C=CC(C(C(C2C=CC=CC=2)O)=O)=CC=1.[NH2:45]C(N)=O>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:45]=[C:4]([CH2:3][CH2:2][C:1]([OH:8])=[O:7])[O:6][C:19]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Reactant: O=C(O)CCC(=O)O
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(CCC(=O)O)oc2-c2ccccc2)cc1
Temperature: 0 °C
Yield: 99.4 %

Procedure:
A mixture of the crude 4-methoxybenzoin hemisuccinate (20.8 g, 0.061 mole) of Step B, urea (8.7 g, 0.146 mole) and acetic acid (60 mL) is heated at reflux under nitrogen for 5.5 hours. The mixture is cooled and poured into ice water. The liberated oil is extracted with ethyl acetate (3x). The extracts are washed with water until neutral and then extracted with saturated sodium carbonate. The combined aqueous extracts are carefully acidified in the cold with concentrated HCl and extracted with ethyl acetate. The organic extract is dried (MgSO4) and evaporated to dryness to provide a waxy yellow oil (19.6 g). Purification of the residue by flash chromatography (on silica Merck-60, eluant: dichloromethane-ethyl acetate 8:2) yields a pale yellow solid (14.3 g, 72.7%), m.p. 100°-101° C.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]([CH:25]=O)=[CH:21][CH:22]=[CH:23][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:19]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: c1ccc(-c2ccccc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: c1ccc(-c2ccccc2CN2CCN(c3ccccc3-c3ccccc3)CC2)cc1

Procedure:
148 mg of the target compound (0.37 mmol, 66.5%) was obtained using 1-(biphenyl-2-yl)piperazine (260 mg, 1.09 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH2:1]1[C:10]2C(=CC=CC=2)CCN1.[C:11]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[CH2:16][N:15]1[CH3:28])([OH:13])=[O:12]>>[C:11]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[CH2:16][N:15]1[CH3:28])([O:13][CH2:1][CH3:10])=[O:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc2c(cc1OC)CN(C)C(C(=O)O)C2
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C

Procedure:
The resulting tetrahydroisoquinoline derivative of formula 30 is then esterified with a suitable lower alkanol by standard means to produce a tetrahydroisoquinoline ester of formula 31 (step 2). For example, 3-carboxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (30) is treated with HCl in EtOH to produce 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([NH:5][C:6](=[NH:8])[NH2:7])=[NH:4].[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>CO>[NH2:10][C@@H:11]([CH2:12][CH2:13][C:14]([O-:16])=[O:15])[C:17]([O-:19])=[O:18].[CH3:1][N:2]([C:3]([NH:5][C:6](=[NH:7])[NH3+:8])=[NH:4])[CH3:9].[CH3:1][N:2]([C:3]([NH:5][C:6](=[NH:7])[NH3+:8])=[NH:4])[CH3:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CN(C)C(=N)NC(=N)N
Solvent: CO
Product: CN(C)C(=N)NC(=N)[NH3+]
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of N,N-dimethylimidodicarbonimidic diamide (1.00 g, 7.74 mmol) in methanol (40 mL) is treated with a solution of L-glutamic acid (0.570 g, 3.87 mmol) in methanol (40 mL) at RT under N2. The mixture is stirred at RT for ½ hr. The methanol is evaporated and the remaining oil is triturated with CH3CN to give a white solid. The solid is dried at RT under hi-vac for 3 hrs, then stirred in CH3CN (50 ml) at RT for 2 hrs. The solid is collected by filtration and dried under hi-vac at RT for 1 hr to give 1.3 g of bis[{[(dimethylamino)(imino)methyl]amino}-(imino)methanaminium] (2S)-2-aminopentanedioate as a white solid. 1H NMR (300 MHz, MeOD) d 1.88 (m, 1H) 2.06 (m, 2H) 2.30 (m, 2H) 3.05 (s, 12H) 4.91 (s, 14H); MS (ESI−) for C5H9NO4 m/z 146 (M−H)−. MS (ESI+) for C4H11N5 m/z 130 (M+H)+. Anal Calcd for C13H3N11O4 plus 0.75% H2O: C, 38.22; H, 7.73; N, 37.71. Found: C, 38.57; H, 7.65; N, 36.73.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.N1C=CC=[CH:11][C:10]=1[C:15]1C=CC=CN=1.BrC1C=C2C(C)(C)C3C=CC=[C:39]4[C:40](C)(C)[C:30]5[C:31]6N(C=34)C2=[C:24]([C:25](C)(C)[C:26]=6[CH:27]=[CH:28][CH:29]=5)[CH:23]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:15]1[C:6]2=[CH:7][CH:8]=[CH:1][C:4]3=[CH:3][C:2]4=[C:27]5[C:28](=[C:5]23)[C:29]2[C:30]([CH2:31][C:26]5=[CH:25][CH:24]=[CH:23]4)=[CH:40][CH:39]=[CH:11][C:10]1=2
Reactant: C1=CCCC=CCC1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: CC1(C)c2cccc3c2N2c4c1cccc4C(C)(C)c1cc(Br)cc(c12)C3(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1cc2c3c(c1)Cc1cccc4cc5cccc(c5c-3c14)C2
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Bis(1,5-cycloocatadiene)nickel(0) (0.193 g, 0.70 mmol), 1,5-cyclooctadiene (0.08 g, 0.09 mL, 0.70 mmol) and 2,2′-bipyridine (0.109 g, 0.70 mmol) were added to a flame-dried 100 mL Schlenk flask, dissolved in 9.4 mL of anhydrous N,N-dimethylformamide and stirred for 30 min at 65° C. in the absence of light. A solution of 2-bromo-4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine (0.25 g, 0.56 mmol) in 18.8 mL of anhydrous toluene at 65° C. was added slowly via a double-tipped needle and the resulting mixture was stirred for two days at 85° C. The reaction was quenched by adding 10% aqueous hydrochloric acid, extracted three times with CH2Cl2 and the organic phase was dried with MgSO4. After having removed the solvents in vacuo, the residue was subjected to column chromatography (silice, n-hexane/CH2Cl2 3:1) leading to triangulene dimer as a white crystalline solid (0.165 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]([N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=O)[C:11]([F:14])([F:13])[F:12])[C:7]#N)=[CH:4][CH:3]=1.[CH3:25]S(O)(=O)=O.[C:30](#[N:33])C=C>C1(C)C=CC=CC=1>[CH2:16]([N:9]1[C:10]([C:11]([F:14])([F:12])[F:13])=[CH:25][C:7]([C:30]#[N:33])=[C:6]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CC(c1ccc(Cl)cc1)N(Cc1ccccc1)C(=O)C(F)(F)F
Reactant: C=CC#N
Reactant: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(F)(F)F)n(Cc2ccccc2)c1-c1ccc(Cl)cc1
Yield: 40.6 %

Procedure:
A solution of N-(p-chloro-α-cyanobenzyl)-2,2,2-trifluoro-N-benzylacetamide (10.6 g, 0.03 mol) in toluene is treated with methanesulfonic acid (3.2 g, 0.033 mol) and acrylonitrile (3.9 g, 0.045 mol), heated at 100°-105° C. for 18 hours, cooled, treated with additional methanesulfonic acid (1.6 g, 0.017 mol), heated at 100°-105° C. for 22 hours, quenched with water and extracted with ethyl acetate. The organic extracts are combined and concentrated in vacuo to give a residue. The residue is purified by flash column chromatography using silica gel packed and eluted with 15% ethyl acetate in heptane to give the title product as white crystals, 4.4 g (40.6% yield), mp 103.5°-105.5° C., identified by 1H, 13C and 19F NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]#[CH:5])[CH3:2].[BH3:6].[OH:7][C:8]([C:11]([OH:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C(Cl)Cl>[CH2:4]([O:3]/[CH:1]=[CH:2]/[B:6]1[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]1)[CH3:5]
Reactant: B
Reactant: CC(C)(O)C(C)(C)O
Reactant: C#COCC
Solvent: ClCCl
Product: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A solution of ethoxyethyne (60% w/w in hexanes, 30 mL, 154 mmol) in DCM (230 mL) was cooled at 0° C. and pinacol borane (27 mL, 186 mmol) was added followed by Cp2Zr(H)Cl (1.96 g, 7.60 mmol). The mixture was allowed to reach room temperature and stirred for 18 hours. The reaction was filtered through a pad of neutral alumina eluting with 10% EtOAc in cyclohexane to afford the title compound (27.66 g, 91%).
Reaction SMILES: C(O[CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][O:6]1)(=O)C.[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20].[Sn](Br)(Br)(Br)Br>C(Cl)Cl>[CH2:20]([CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][O:6]1)[CH:19]=[CH2:18]
Reactant: C=CC[Si](C)(C)C
Reactant: CC(=O)OC1CC(OCc2ccccc2)CO1
Agent: Br[Sn](Br)(Br)Br
Solvent: ClCCl
Product: C=CCC1CC(OCc2ccccc2)CO1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirred solution of 4-(benzyloxy)tetrahydrofuran-2-yl acetate (3.57 g, 15.11 mmol) and allyltrimethylsilane (9.65 mL, 60.4 mmol) in CH2Cl2 (200 mL) at −78° C. was added a solution of tin(IV) bromide (7.95 g, 18.13 mmol) in CH2Cl2 (20 mL) over 15 min. After 1 h, the ice bath was removed and stirring continued at room temperature for 3 h. The CH2Cl2 was removed using a rotoevaporator and the residue taken up in 1:1 Et2O/hexane (200 mL), washed with sat. Na2CO3 (2×50 mL), water (2×50 mL) followed by brine (50 ml), then dried (Na2SO4), filtered and concentrated to give 2-allyl-4-(benzyloxy)tetrahydrofuran (3.15 g, 14.43 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ: 7.27-7.39 (5 H, m), 5.76-5.90 (1 H, m), 5.03-5.15 (2 H, m), 4.49 (1.6 H, d, J=2.3 Hz), 4.43 (0.4 H, d, J=2.3 Hz), 4.17-4.23 (1 H, m), 4.01 (0.45 H, d, J=1.8 Hz), 3.98 (0.55 H, d, J=1.8 Hz), 3.85-3.94 (1 H, m), 3.73 (1 H, dd, J=9.8, 5.3 Hz), 2.43-2.53 (1 H, m), 2.30-2.40 (1 H, m), 2.19-2.28 (1 H, m), 1.69-1.77 (1 H, m). LCMS (M+H) calcd for C14H19O2: 219.14; found: 219.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[CH:34][N:33]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[CH:36]=[CH:37][N:32]=[N:33][CH:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2ccnnc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.075 g, 0.186 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.094 g, 0.93 mmol, 5.0 eq) and BOP reagent (0.123 g, 0.278 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. the The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent, and further purified the product by prep HPLC. Yield: 0.050 g (52.00%). 1H NMR (400 MHz, CD3OD): δ 9.44 (s, 1 H), 9.15 (d, 1H), 9.11 (s, 1H), 8.02-7.94 (m, 2H), 7.86 (dd, J=2.3, 4.3 Hz, 2H), 7.73 (br s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.29 (t, J=8.9 Hz, 2H), 2.96 (s, 3H), 2.37 (s, 3H), 1.71 (s, 4H). 19F NMR (376.51 MHz, CD3OD): δ −78.16 (TFA), −113.29 LCMS: (ES+) m/z=521.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[F:21][C:22]([F:40])([F:39])[C:23]([NH:26][C:27](=O)[O:28]C1C=CC([N+]([O-])=O)=CC=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:27]([NH:26][C:23]([CH3:25])([CH3:24])[C:22]([F:40])([F:39])[F:21])=[O:28])[CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: CC(C)(NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(NC(=O)N1CCn2c(Cl)c(-c3cccc(F)c3)c(C(N)=O)c2C1)C(F)(F)F
Temperature: 65 °C

Procedure:
A suspension of 0.165 (0.56 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide, 0.197 g (0.67 mmol) of 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-ylcarbamate and 0.155 (1.12 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at 65° C. for 1 hour 30 minutes. After cooling, the mixture is poured into aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. After drying over sodium sulfate and filtering, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 24 g of silica gel, eluting with a mixture of 3% methanol in dichloromethane, to give 0.125 g of 6-chloro-7-(3-fluorophenyl)-N2-(1,1,1-trifluoro-2-methylpropan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after crystallization from 4 ml of acetonitrile, filtering off and drying under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[NH2:10].O=[C:18]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=O.C(O)(=[O:33])C>>[C:23]([O:22][C:20]1[N:8]2[N:7]=[C:6]([CH3:11])[C:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:2]=3[Cl:1])=[C:9]2[N:10]=[C:18]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:19]=1)(=[O:33])[CH3:24]
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC(=O)O
Reactant: Cc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Product: CC(=O)Oc1cc(-c2ccncc2)nc2c(Cc3cccc(Cl)c3Cl)c(C)nn12
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 4-(2,3-dichlorobenzyl)-3-methyl-1H-pyrazol-5-amine (1.21 g, 4.72 mmol), ethyl 3-oxo-3-(pyridin-4-yl)propanoate (1.004 g, 5.195 mmol) in acetic acid (50 mL) was stirred under reflux overnight. After cooled to room temperature, the mixture was concentrated. The residue was diluted with ethyl acetate (20 mL). The resulting precipitate was filtered, washed with ethyl acetate, dried in vacuo to give the titled product (1.266 g, 60%); LC/MS: MS (ES+) m/e 385 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.91 (s, 3H), 2.12 (s, 3H), 4.16 (s, 2H), 6.10 (s, 1H), 6.91 (dd, J=1.2, 7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.51 (dd, J=1.2, 7.8 Hz, 1H), 7.77 (d, J=5.7 Hz, 2H), 8.77 (d, J=5.7 Hz, 2H), 11.94 (s, 1H), 12.18 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[N:13]([CH3:23])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[CH:15]=2)[CH3:2].[Cl:26]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:26][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:21][CH3:22])=[CH:17][CH:18]=2)[N:13]([CH3:23])[C:12]=1[C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[N:3]([CH2:1][CH3:2])[CH2:24][CH3:25]
Reactant: CCN(CC)c1cc(OC)ccc1-c1cc2ccc(OC)cc2n1C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1cc(OC)ccc1-c1c(Cl)c2ccc(OC)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of diethyl[5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenyl]amine (110 mg) in tetrahydrofuran (5 ml) was added N-chlorosuccinimide (50 mg), and the solution was stirred for 1 hour at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (96 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23]4(C(O)=O)[CH:28]=[CH:27][CH:26]=[CH:25][NH:24]4)=[CH:21][C:14]=3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][CH2:39][NH2:40].CN([C:44]([O:48]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23]4([CH:35]5[CH2:36][CH2:37][NH:32][CH:33]([CH2:38][CH2:39][NH:40][CH:44]=[O:48])[CH2:34]5)[CH:28]=[CH:27][CH:26]=[CH:25][NH:24]4)=[CH:21][C:14]=3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NCCC1CCCCN1
Reactant: Cn1c(Nc2cccc(C(C)(C)C)c2)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2cccc(C(C)(C)C)c2)nc2cc(OC3(C4CCNC(CCNC=O)C4)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[3-(tert-butyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-piperidylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[3-(tert-butyl)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-piperidylethyl)-carboxamide. MS: MH+=512.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])=[O:2].[CH:12]([N:15](CC)[CH:16](C)C)(C)C.CNC.C(O)C>ClCCl.C(OCC)C>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:15]([CH3:16])[CH3:12])=[O:6])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=Cc1ccccc1C(=O)O
Agent: CNC
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-formylbenzoic acid (500 mg, 3.33 mmol), N,N-diisopropylethylamine (0.58 mL, 3.3 mmol), and dimethylamine/ethanol solution (1.2 mL, 5.6 M, 6.7 mmol) in 3.3 mL of dichloromethane was added 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (1.28 g, 6.67 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain the title compound as a slightly yellow oil (113 mg, 19%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:19])=[C:8]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:9](O)=[O:10].C[N:21](C)C=O>>[Cl:5][C:6]1[C:7]([F:19])=[C:8]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:9]([NH2:21])=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 75 °C
Yield: 99 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a solution of 4.0 g (16 mmol) 3-chloro-2-fluoro-5-(trifluoromethyl) benzoic acid in 10 mL dimethylformamide. The reaction mixture was heated to 75° C. for 2 hours, cooled to room temperature and carefully added to 25 mL of ice cold ammonium hydroxide. The mixture was cooled to 0° C. and the solid product filtered, washed with water and dried to yield 3.96 g (99%) of 3-chloro-2-fluoro-5-(trifluoromethyl)benzamide.
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([CH2:11]OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([Si](C)(C)C)[CH:30]=[CH2:31].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)(O)[O-]>COC(OC)C>[CH2:11]([C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:28][CH:27]=1)[CH2:31][CH:30]=[CH2:29]
Reactant: C=CC[Si](C)(C)C
Reactant: O=P(OCc1ccc(C2CCCCC2)cc1)(c1ccccc1)c1ccccc1
Agent: COC(C)OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Product: C=CCCc1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred mixture of diphenyl-phosphinic acid 4-cyclohexyl-benzyl ester (1 g, 2.56 mmol) and 1.22 ml (7.69 mmol) of allyltrimethylsilane in 12 ml of dry dimethoxy-ethane at 0° C. was added 0.46 ml of trimethylsilyltriflate. The mixture was stirred at 0° C. for 1 h, poured into saturated bicarbonate, extracted with ethyl acetate, washed with water, dried (sodium sulfate) filtered and concentrated. The material was purified by chromatography on silica gel, eluting with ethyl acetate/heptane to provide 0.45 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N+:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](Cl)=[C:11]([C:20]([O:22]CC)=O)[CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][NH2:40].CN(C)C=O>O.COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:40][N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH3:32])[C:20](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1
Reactant: Cc1ccccc1NN
Reactant: CCOC(=O)c1c[n+](Cc2ccc(Br)cn2)c2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)cn3)cc-2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[(5-Bromopyridin-2-yl)methyl]-4-chloro-3-(ethoxycarbonyl)quinolinium salt (1.55 g, 3.51 mmol), potassium carbonate (2.63 g, 19.1 mmol, 5.4 equiv), and (2-methylphenyl)hydrazine hydrochloride (1.33 g, 8.38 mmol, 2.4 equiv) were combined in a mixture (1:1) of N,N-dimethylformamide:1,2-dimethoxyethane (25 mL) and placed into an oil bath preheated at 80° C. for 3 hours. The mixture was cooled to ambient temperature, poured into water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a yellow solid: 1H-NMR (400 MHz, CD3OD) δ 8.97 (1H, s), 8.59 (1H, s), 8.33 (1H, d, J=7.8 Hz), 8.02-8.00 (1H, m), 7.78 (1H, d, J=9.0 Hz), 7.66-7.56 (2H, m), 7.48-7.37 (5H, m), 5.85 (2H, s), 2.28 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 446.8 [(M+H)+; calculated for C23H17BrN4O: 446.3].