Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:17])[C:10]1=[O:32])=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:8][C@H:9]1[CH:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:32]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1[C@H](N)C(=O)N1OCC(=O)O

Procedure:
(3S-trans)-[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid. diphenylmethyl ester (4.4 g1 10.0 mmol) was dissolved in a solution of 33 ml of trifluoroacetic acid and anisole (3.3 ml; 30.0 mmol) at -10° C. The mixture was evaporated in vacuo 10 minutes later and the residue was stirred with ether, filtered off and dried over P2O5 to give colorless crystals of (3S)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid, trifluoroacetate salt (yield 2.87 g). The salt (2.87 g; 10.0 mmol) was suspended in dry acetonitrile. MSTFA (5.57 ml; 30.0 mmol) was added and stirring was continued for 30 minutes. After evaporating in vacuo the residue was dissolved in dry tetrahydrofuran and then added to a mixture of the [[[(4-methoxyphenyl)methoxy]-carbonyl]amino]benzeneacetic acid 1-hydroxybenzotriazole ester (4. g, 10.0 mmol) in 25 ml of dry tetrahydrofuran at 0° C., stirred overnight at room temperature and evaporated in vacuo. After adding ether the crude silylated product was decomposed with 1 ml methanol. After removing the solvents in vacuo the residue was stirred with ether/petroleum ether to give colorless crystals of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:30][C:31]([C@@H:33](OS(C(F)(F)F)(=O)=O)[CH3:34])=[O:32]>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C@@H:33]([C:31]([OH:32])=[O:30])[CH3:34])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COCCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Product: COCCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine (prepared as described in Example 50) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-methoxyethyl)-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.28 (d, 3H); 2.85 (t, 2H); 3.13 (s, 3H); 3.34 (m, 2H); 3.56 (q, 1H); 3.93 (m, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.57 (m, 1H); 8.41 (m, 2H); 9.70 (brs, 1H); Mass Spectrum: (M+H)+ 463.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:19]=[C:20](/[C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)=[CH:24][CH:23]=1)\[NH2:21].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.CCOC(C)=O>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:17][N:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:38][CH:39]=4)[N:19]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of the 3-(1-phenylcyclohexyl)propanoic acid (0.118 g, 0.508 mmol) and the (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Intermediate 1, 0.155 g, 0.508 mmol) in acetonitrile (5.0 mL) at room temperature was added the 1,3-diisopropylcarbodiimide (0.095 mL, 0.609 mmol). The stirring was continued at room temperature and followed by LC/MS. After 90 min., TBAF (0.609 mL, 0.609 mmol) was added to the reaction. The reaction was found to be over after 2 h. The reaction mixture was diluted with EtOAc and washed with water followed by brine. It was then concentrated and purified by preparative HPLC to give the tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate as a glassy solid. LCMS of the tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (Conditions: Start % B═O; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=220; Solvent A=10% MeOH—90% H20—0.1% TFA; Solvent B=90% MeOH—10% H2O—0.1% TFA and Column 4=Phenomenex Luna 5u C18 4.6×30 mm (2 min. grad)) (M+H)+=502.39. Retention time=1.927.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:16]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[CH3:14])=[CH:23][CH:22]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: CC(=O)Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (138 mg, 0.72 mmole) and 4-aminoacetanilide (1.50 g, 10.0 mmole) is stirred under N2 at 200° C. for 1 h. The resulting product is chromatographed over alumina (8-10% MeOH/CH2Cl2) to give 7-amino-4-(4-acetamidoanilino)pyrido[4,3-d]pyrimidine (110 mg, 52%) as a pale yellow solid. 1H NMR (DMSO) δ 9.94, 9.79 (1H, 1H, 2 brs), 9.31 (1H, s), 8.34 (1H, s), 7.69 (2H, d, J=8.9 Hz), 7.57 (2H, d, J=8.9 Hz), 6.57 (2H, brs), 6.43 (1H, s), 2.05 (3H, s).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]2[CH3:27])[CH2:3][CH2:2]1>CC(O)=O.[Fe]>[NH2:18][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]([CH3:27])[N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C2CC2)c2c(OC)c(F)c(F)c(N)c2c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 108.5 %

Procedure:
A suspension of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-5-nitro-4-oxoquinoline-3-carboxylate (200 mg, 0.523 mmol) and iron powder (175 mg, 3.14 mmol) in AcOH (5 mL) was stirred at 90° C. for 2 h. After the reaction mixture was concentrated in vacuo, the crude product was extracted with EtOAc, washed with saturated aq. NaHCO3 and brine, dried over MgSO4. The solvent was removed in vacuo and the residue was dried to yield ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxoquinoline-3-carboxylate (200 mg, quant.) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][N:16]([CH3:19])[CH:17]=O>C(N(CC)CC)C.[OH-].[Na+].[Cu]I>[CH3:10][O:9][CH2:8][CH2:7][O:6][C:5]1[C:11]([CH3:13])=[CH:12][C:2]([C:3]#[C:4][C:5]2([OH:6])[CH:11]3[CH2:13][CH2:19][N:16]([CH2:17][CH2:12]3)[CH2:15]2)=[CH:3][C:4]=1[CH3:14]
Reactant: COCCOc1c(C)cc(Br)cc1C
Reactant: CN(C)C=O
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COCCOc1c(C)cc(C#CC2(O)CN3CCC2CC3)cc1C
Temperature: 65 °C

Procedure:
1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (704 mg) and copper (I) iodide (48 mg) in dimethylformamide (DMF) (5.5 ml) and triethylamine (2.7 ml) at ambient temperature and under an atmosphere of argon. The mixture was heated at 65° C. for 14 hours, cooled to ambient temperature, diluted with 2M aqueous sodium hydroxide (20 ml) and extracted with diethyl ether (5×100 ml). The ethereal extracts were combined, washed with water (100 ml) and saturated brine (100 ml), dried (K2CO3) and evaporated. The residue was crystallised from acetonitrile to give 3-[2-(4-{2-methoxyethoxy}-3,5-dimethylphenyl)ethynyl]quinuclidin-3-ol (130 mg) as a solid, m.p. 120° C.; microanaylsis, found: C, 72.4; H, 8.2; N, 4.1%; C2OH27NO3 requires: C, 72.9; H, 8.3; N, 4.2%; NMR([CD3)2SO): 1.3(1H,m), 1.57(1H,m), 1.9(3H,m), 2.21(6H,s), 2.65(4H,m), 2.8(1H,d), 3.02(1H,d), 3.31(3H,s), 3.61(2H,m), 3.87(2H,m), 5.5(1H,br) and 7.07(2H,s); m/z 330 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1Br
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccccc1Br
Reaction time: 3 h

Procedure:
For 3 hours, 21 g (0.098 mole) of o-bromophenylacetic acid was refluxed in 100 ml of anhydrous benzene and 23.5 g (0.198 mole) of thionyl chloride. After completion of the reaction, benzene and unreacted thionyl chloride were removed by distillation under reduced pressure so that unreacted thionyl chloride was removed as completely as possible.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:4]2[N:5]([CH2:12][CH2:13][N:14]=2)[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=O.[C:23](OC(=O)CC)(=O)[CH2:24]C>N1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:3]2[C:2]3[N:1]=[C:9]([CH2:23][CH3:24])[NH:8][C:7]=3[C:6](=[O:11])[N:5]3[CH2:12][CH2:13][N:14]=[C:4]23)=[CH:17][CH:18]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: NC1=C(NC=O)C(=O)N2CCN=C2N1Cc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CCc1nc2c([nH]1)C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1

Procedure:
A mixture of 25.00 g. (0.078 mol) of the product of Procedure 2 and 50 ml. dry pyridine in 50 ml. (0.388 mol) of propionic anhydride was heated at reflux for 3 hr. Upon cooling, a white solid precipitated. CH3CN was added, and the white solid filtered and air-dried to give crystals, mp 278.0°-279.0° (corr.). The material may be recrystallized from DMF-i-PrOH.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])ccc1-c1cccc(C#N)c1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
A solution of 2-bromo-5-nitrotoluene (8.82 gm, 40.83 mmol) in 1,2-dimethoxyethane (150 mL) was added to a solution of tetrakis(triphenylphosphine)palladium(0) (2.35 gm, 2.04 mmol) in 1,2-dimethoxyethane (100 mL) under nitrogen at room temperature. A solution of 3-cyanophenylboronic acid (J. Med.Chem., 1997, 40, 4208)(9.0 gm, 61.25 mmol) in ethanol (45 mL) was added and stirred for 10 mins. Finally, 2M aqueous sodium carbonate (234 mL) was added and the mixture was heated under reflux for 18 h. After being cooled, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water, dried (Na2SO4), concentrated under reduced pressure and triturated with diethyl ether to give 1-(3-cyanophenyl)-2-methyl-4-nitrobenzene (8.48 gm, 87%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([NH:23][NH2:24])=[O:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl.[C:31](=N)(OCC)[CH3:32]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:20]([C:21]5[O:22][C:31]([CH3:32])=[N:24][N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=N
Reactant: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1nnc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)o1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid hydrazide (Starting material 8a-2) (58 mg, 0.15 mmol) and ethyl acetimidate hydrochloride (74 mg, 0.6 mmol) in pyridine (0.6 mL) was heated to 100° C. for 2 h. The mixture was cooled to 23° C., diluted with H2O (30 mL) and stirred for 20 min. The precipitate was collected by filtration, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (28 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2cc(CC)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nn2cc(CC)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 24 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-ethyl-3H-imidazo[1,2-b][1,2,4]triazole (from Steps B and C) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 24% yield of the title compound as a light tan solid, mp>100° C. (gradual); homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([OH:13])[CH:3]=1.[CH2:14]([S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17])[CH3:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:13][C:22]2[CH:23]=[CH:24][C:19]([S:16]([CH2:14][CH3:15])(=[O:18])=[O:17])=[CH:20][C:21]=2[Cl:26])[CH:3]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step ii) and the product from example 4 step i).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[NH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[NH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C(=O)O)c1C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 23,9 g (0.1 mol) of diethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate in 300 ml of hot ethanol was added a solution of 14 g (0.25 mol) of potassium hydroxide in 350 ml of water. The solution was boiled and the ethanol was allowed to evaporate. After 1.5 hours, the volume was reduced by 350 ml then cooled, filtered, and acidified with 2 N hydrochloric acid. A precipitate formed which was collected, washed with water, and dried to give 19 g of 3,5-dimethyl-4-ethoxycarbonyl-1H-pyrrolecarboxylic acid. This acid was disolved in quinoline, 5 g of powdered copper was added, and the mixture heated to 200° C. during which time carbon dioxide was released. The residue was distilled (0.1 mm/120°-140° C.) and the distillate recrystallized (ethyl ether/pentane) to give the title compound, m.p. 74°-76° C.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:33])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC([N:41](C(OC(C)(C)C)=O)[C@H:42]([C:48](O)=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>CC(N(C)C)=O>[NH2:41][C@H:42]([C:48]([NH:30][C:29]1[CH:31]=[CH:32][N:25]([C@@H:23]2[O:24][C@H:20]([CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:21]([OH:33])[CH2:22]2)[C:26](=[O:27])[N:28]=1)=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)[C@@H](N)CCCCN)nc2=O)C[C@@H]1O
Temperature: 4 °C
Reaction time: 90 h

Procedure:
14 grams of 5′-O-palmitoyl-deoxycytidine is dissolved in 100 ml dimethylacetamide, 1 molar equivalent of di-tert-butoxycarbonyl-lysine is added, and the mixture is cooled in an ice bath. 1.2 molar equivalents (7.4 g) of dicyclohexylcarbodiimide are added and the mixture is stirred at 4° C. for 90 hours. The precipitate (dicyclohexylurea) is removed by filtration. 100 ml of water is added to the filtrate, followed by 1 liter of ethyl acetate. N4-(di-N-tert-butoxycarbonyl-lysyl)-5′-O-palmitoyl-deoxycytidine is separated from unreacted reagents by chromatography over silica gel. The t-butoxycarbonyl protecting groups are removed by the standard methods of treatment with an acid, such as trifluoroacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][NH:16][CH2:15][CH2:13][OH:14])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: NCCO
Reactant: Clc1ccc(CCCBr)cc1Cl
Product: OCCNCCCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-(3-Bromopropyl)-1,2-dichlorobenzene (Chem Abs No. 29648-26-8, 1.30 g) was added to ethanolamine (2.8 ml) and the mixture stirred at 60° C. under nitrogen for 2 h. The mixture was concentrated under vacuum at 80° C. and the residue was partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The phases were separated, the aqueous layer was re-extracted with ethyl acetate (100 ml) and the combined organic extracts were washed with water (2×100 ml) and brine then dried (Na2SO4). The solution was concentrated under vacuum to give the title compound as a pale yellow liquid (1.10 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(CCCCNCc1cc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of indole-2-carboxaldehyde (prepared as described for COMPOUND 65) (31 mg, 0.21 mmol) and N1-(1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine (see COMPOUND 17) (51 mg, 0.15 mmol) in MeOH (1.8 mL) was stirred at room temperature under nitrogen for 23 hours. NaBH4 (14 mg, 0.37 mmol) was added, and the reaction stirred for a further 15 minutes before the solvent was evaporated under reduced pressure. The residue was dissolved into CH2Cl2 (25 mL) and was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. The yellow residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 19:1:0.1) giving COMPOUND 31 as a white solid (37 mg, 0.077 mmol, 53%). 1H NMR (CDCl3) δ 1.35-1.49 (m, 4H), 1.60-1.76 (m, 1H), 1.81-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.11-2.22 (m, 1H), 2.45 (t, 2H, J=6.5 Hz), 2.50-2.60 (m, 1H), 2.66-2.76 (m, 2H), 2.76-2.90 (m, 1H), 3.83 (s, 2H), 3.93-4.10 (m, 3H), 6.27 (s, 1H), 7.02-7.16 (m, 3H), 7.16-7.24 (m, 2H), 7.32 (d, 1H, J=7.8 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.55-7.62 (m, 2H), 8.56 (d, 1H, J=3.6 Hz), 9.01 (br. s, 1H). 13C NMR (CDCl3) δ 21.6, 23.8, 26.2, 27.5, 29.6, 47.2, 48.9, 49.8, 50.8, 62.3, 100.6, 111.2, 119.8, 120.4, 121.7, 122.0, 122.6, 128.8, 135.1, 136.5, 137.8, 147.1, 156.9, 157.8. ES-MS m/z 479 (M+H). Anal. Calcd. for C30H34N6.0.5CH2Cl2.0.2C4H10O: C, 70.15; H, 6.96; N, 15.68. Found: C, 70.16; H, 6.97; N, 15.73.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][C@@H:9]([CH3:11])[O:10][C:6]=2[C:5]([NH2:12])=[CH:4][C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:11][C@@H:9]1[CH2:8][C:7]2[C:2]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)=[C:3]([CH3:13])[CH:4]=[C:5]([NH2:12])[C:6]=2[O:10]1
Reactant: Cc1cc(N)c2c(c1Br)C[C@@H](C)O2
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)c2c(c1-c1ccncc1)C[C@@H](C)O2
Temperature: 135 °C
Reaction time: 1 h

Procedure:
The mixture of (R)-4-bromo-2,5-dimethyl-2,3-dihydrobenzofuran-7-amine (3g) (1.0 g, 4.3 mmol), pyridin-4-ylboronic acid (1.08 g, 8.77 mmol), Cs2CO3 (3.56 g, 10.9 mmol), Pd(PPh3)4 (0.506 g, 0.438 mmol) and water (9 mL) in DMF (44 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (150 mL, washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (3h) as a solid. MS-ESI (m/z): 241 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.O>[CH2:16]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:3]1[C:2]([F:1])([F:12])[F:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
8.6 g of 2-trifluoromethyl-(1H)-indole and 100 ml of tetrahydrofuran were mixed together under an inert atmosphere and cooled to 0° C. Over 15 minutes, about 2.4 g of a suspension of sodium hydride at 50% in oil was added in small fractions and 6.5 ml of benzyl bromide in solution in 10 ml of tetrahydrofuran were introduced over 5 minutes. The mixture was stirred for 42 hours at ambient temperature and then was poured into water saturated with monosodium phosphate. The mixture was extracted with ethyl ether, and the extracts were dried and concentrated to dryness by distillation under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (9/1) to obtain 12.54 g of 1-benzyl-2-trifluoromethyl-(1H)-indole melting at approx. 20° C.