Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:18]([CH3:20])[CH3:19])=[N:4][C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[NH2:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][C:5]([O:11][CH2:12][C:13]([N:31]([CH:28]2[CH2:27][CH2:26][N:25]([CH2:24][CH:21]3[CH2:23][CH2:22]3)[CH2:30][CH2:29]2)[CH3:32])=[O:15])=[N:4][C:3]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOC(=O)COc1nc(C(C)C)c(N)c(C(C)C)n1
Reactant: CNC1CCN(CC2CC2)CC1
Product: CC(C)c1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C(C)C)c1N

Procedure:
As in Example 11, a carboxylic acid derivative was synthesized from Compound 13. Then, the title compound was synthesized from the obtained carboxylic acid derivative and 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[N:12]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:17]3[N:16]=[C:15]([C:14]([F:29])([F:13])[F:30])[O:19][N:18]=3)[CH:21]=2)=[O:24])[CH2:3][CH2:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2ncccn2)CC1
Yield: 33 %

Procedure:
This compound was synthesized from 2-piperazin-1-yl-pyrimidine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (52 mg, yield 33%). 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=4.7 Hz, 2H), 8.23-8.21 (m, 2H), 7.68-7.61 (m, 2H), 6.58-6.56 (t, J=4.7 Hz, 1H), 3.97-3.85 (m, 6H), 3.53 (m, 2H). MS (ESI) m/z: Calculated for C18H16F3N6O2: 404.12. found: 405.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6]/[C:5](=[CH:7]\[C:8](O)=[O:9])/[C:4](=[O:11])[O:3]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1([CH3:12])[O:6]/[C:5](=[CH:7]\[C:8]([Cl:16])=[O:9])/[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetic acid (0.27 g, 1.6 mmol) in CH2Cl2 (3.9 mL) was added oxalyl chloride (0.13 mL, 1.6 mmol). A few drops of DMF were added, and the reaction mixture was stirred at rt for 2 h to produce a 0.4 M stock solution of (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetyl chloride (Solution A). An aliquot of Solution A (0.25 mL, 0.1 mmol) was added to each 16×100 mm Wheaton tubes that had been charged separately with CH2Cl2 (0.25 mL), DIEA (0.050 mL, 0.3 mmol) and an amine (0.1 mmol) corresponding to the R5-amide contained in the final example. The vials were capped and the reaction mixtures were agitated at 400 rpm at rt for 16 h using an INNOVA® platform shaker. After removal from the shaker, each reaction mixture was diluted with MeOH (0.25 mL), treated with polystyrene-isocyanate resin (0.091 g, 1.1 mmol/g, 0.1 mmol) and agitated at 400 rpm for 2 h. Following filtration to remove the polystyrene beads, the filtrates were collected and dried under a stream of N2 for 1 h using a ZYMARK® tabletop dryer set to 45° C. The amides thus formed were carried onto the next step without further purification. To a separate reaction vessel was added paraformaldehyde (87 mg, 2.88 mmol), MeOH (10.6 mL) and CH3NH2 (2.0 M in THF; 1.44 mL, 2.88 mmol). This mixture was heated to 60° C. for 5 min using microwave irradiation to provide Solution B. To each vial containing an amide was added a 0.5 mL aliquot of Solution B. The reaction mixtures were agitated at 400 rpm at 80° C. for 16 h on an INNOVA® platform shaker. The reaction mixtures were removed from the shaker, cooled to rt and diluted with MeOH (0.25 mL). Examples 1-12 were purified from their corresponding solutions by RP preparative HPLC using Method H. HPLC/MS data for each compound was collected using Method E, and the molecular masses were determined by MS (ES) by the formula m/z. Both the retention time and MS data for Examples 6, 7 and 9 are listed in Table 2. Note: 2.0 M CH3NH2 in MeOH may be substituted for 2.0 M CH3NH2 in THF.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[OH-].[K+].Cl.O>CO.O>[O:32]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)SC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCc2ccccc2)cc1)SC1=NS(=O)(=O)c2ccccc21
Yield: 40 %

Procedure:
The crude product from Step A was dissolved in a MeOH/H2O mixture (2:1, 4 ml). 0.7 g KOH was added to the solution and heated at reflux for 1.5 h. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2; ethyl acetate). The yield was 40%.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O.C(#N)C>C(OCC)(=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[CH:6][C:5]=2[I:15])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-n2nccc2C2CC2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Ic1cnn(-c2ccccc2)c1C1CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
5-cyclopropyl-1-phenyl-1H-pyrazole (200 mg, 1.09 mmol) and N-iodosuccinimide (366 mg, 1.63 mmol) were added to acetonitrile (5 ml). The reaction mixture was heated to 70° C. After 6 hours, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 5-cyclopropyl-4-iodo-1-phenyl-1H-pyrazole.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]=23)=[O:12])=[CH:4][C:3]=1[CH3:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]3[CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][CH2:18][C:17]=23)=[O:12])[CH:4]=[C:3]([CH3:25])[C:2]=1[O:1][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (200 mg, 0.561 mmol) in isopropanol (5 mL) and 3 N aq. NaOH (2 mL) is treated with epichlorohydrine (210 mg, 1.68 mmol) and the mixture is stirred at rt for 6 h before it is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by water, dried over MgSO4 and evaporated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (135 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+1]=413.26.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)=[CH:35][CH:34]=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]([C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=1)[C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(C(CCCCCBr)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1CCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
4-(3,4,5-trimethoxy-benzyl)-piperazine-2-carboxylic acid ethyl ester (2.0 g, 5.91 mmol) was dissolved in dry benzene (30 ml) followed by addition of triehylamine (0.65 g, 6.5 mmol) and resulting solution stirred for 1 hr. 1-[6,6-bis-(4-fluoro-phenyl)-hexyl bromide(2.08 g, 5.91 mmol) in dry benzene (30 ml) was added dropwise. The resulting mixture was stirred under nitrogen at room temperature overnight. The mixture was washed twice with water (30 ml) and dried over MgSO4 and evaporated. The crude product was purified by column chromatography using hexane:ethyl acetate (3:1) to give the desired product in 56% yield
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1>>[Cl:8][C:5]1[S:4][C:3]([CH2:2][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCc2ccc(Cl)s2)cc1

Procedure:
Prepared by the method of Example 2 (b) from 2-chloromethyl-5-chlorothiophene and 4-hydroxyphenyl acetone.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16](O)=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH2:8][CH2:9][CH3:10].C[N:23](C)C=O>ClCCl>[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16]([NH2:23])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH2:8][CH2:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CCCCc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (12.3 ml, 141 mmol) was added dropwise to a suspension of 5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (10 g, 46.9 mmol) in dichloromethane (100 ml) containing dimethylformamide (0.5 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 1 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in toluene (100 ml) and ammonia gas was bubbled into the solution for 2 hours. The reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (9:1, by volume) to give 5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (3.1 g) as an orange solid. 1H NMR (400 MHz, DMSO-D6): δ=7.87-7.96 (1H, brs), 7.57-7.66 (1H, brs), 2.83-2.90 (2H, t), 1.56-163 (2H, quin), 1.24-1.36 (2H, sext), 0.84-0.92 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 211. Anal. Found C, 44.66; H, 5.56; N, 25.50. C8H12N4O3.0.23 mol H2O requires C, 44.41; H, 580; N, 25.90%.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](I)[CH3:39]>CN(C)C=O>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:38][CH3:39]
Reactant: CCI
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
5-Methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) is dissolved in dimethylformamide (10 ml) and thereto are added potassium carbonate (0.5 g) and ethyl iodide (0.45 g). The mixture is stirred at room temperature overnight. After completion of the reaction, the reaction solution is poured into ice-water and the precipitated crystal is collected by filtration, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=90:1), and recrystallized from diisopropyl alcohol/petroleum ether to give 5-(N-methyl-N-ethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (50 mg) as white powder, m.p. 192-193° C.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][CH2:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:12](=[O:25])[C:11]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CI>O>[CH3:3][O:8][CH2:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:17])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:24])[C:12](=[O:25])[C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)C=O
Reactant: CC(C)(c1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Temperature: 25 °C
Yield: 67 %

Procedure:
Sodium hydride (60% in oil, 0.11 g) was suspended in diformaldahyde (2 ml), cooled with ice; then a dimethylformamide solution (6 ml) of 6-hydroxymethyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 53, 0.8 g) was added slowly thereto. After stirring the mixture, methyl iodide (0.71 g) was added, and the mixture was stirred again at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was rinsed with saturated saline solution, and dried with magnesium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography to afford the captioned compound (0.56 g, yield 67%).
Reaction SMILES: CO/[N:3]=[CH:4]/[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([F:12])[C:6]=1F.O.[NH2:15]N>C1COCC1>[Br:11][C:9]1[CH:10]=[C:5]2[C:6](=[C:7]([F:12])[CH:8]=1)[NH:15][N:3]=[CH:4]2
Reactant: CO/N=C/c1cc(Br)cc(F)c1F
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(Br)cc2cn[nH]c12
Temperature: 90 °C

Procedure:
A mixture of (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g, 78.6 mmol), hydrazine hydrate (80 mL), and dry THF (80 mL), was heated at 90° C. for 84 h. Work-up: the organic solvent was evaporated. The resulting mixture was diluted with EtOAc (400 mL), washed with water (150 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether) to give 5-bromo-7-fluoro-1H-indazole as a white solid (9.3 g). 1H NMR (300 MHz, CDCl3): δ 13.83 (br, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.45 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:10]>>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9](=[O:10])[CH2:6][C:2]#[N:1])=[CH:12]1)[CH3:21]
Reactant: CCn1cc(C(=O)OC)c2ccccc21
Reactant: Nc1cc[nH]n1
Product: CCn1cc(C(=O)CC#N)c2ccccc21
Yield: 91 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1bis) from 1-ethyl-1H-indole-3-carboxylic acid methyl ester (860.0 mg, 4.2 mmol, 1.0 eq). 820.0 mg of the title product (yield 91%) were obtained and used directly for the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[CH:26]=[N:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][N:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1cnc(C)cn1
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g. 0.87 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.5 g, 8.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.25 g, 2.1 mmol) was added and stirred for further 5 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch) then further purified through preparative TLC to provide the desired compound as yellow solid (0.05 g, 16% yield). 8-Isopropyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.143 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.018 g, 0.143 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.02 g, 32% yield).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:4][C:5](=[O:8])[O:6][CH3:7]>C(#N)C.CN(C1C=CN=CC=1)C>[C:19]([O:18][C:16]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([CH2:3][CH2:4][C:5]([O:6][CH3:7])=[O:8])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COC(=O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
13.4 g of Boc-Glu(OMe)-OtBu (˜39.6 mmol) are dissolved in 30 mL of acetonitrile and treated with 986 mg of DMAP (7.91 mmol, 0.2 eq). Under nitrogen atmosphere a solution of 17.6 g of di-tert-butylbicarbonate (77.1 mmol, 2 eq) in 100 mL of acetonitrile is added. After stirring overnight, the solvent is removed in vacuo and the obtained crude product is purified by chromatography on silica gel (column: 31*6.0 cm, petroleum ether/ethyl acetate 9:1)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH2:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:22][CH:21]2[C:23](O)=[O:24])=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:12][C:23]([CH:21]3[CH2:22][CH:20]3[C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)=[O:24])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(N)c1ccc2c(c1)CCO2
Reactant: O=C(O)C1CC1c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1CC1c1ccc(Cl)cc1)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 1-(2,3-dihydro-benzofuran-5-yl)-ethylamine (0.1 mmol), 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.2 mmol), and triethylamine (0.4 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography eluting with 50% hexanes in ethyl acetate to give the title compound (23 mg) as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][C:16]([OH:18])=[O:17])[N:13]=[N:12][N:11]=3)=[CH:9][C:2]1=2.S(=O)(=O)(O)O.[CH2:24](O)[CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][O:17][C:16](=[O:18])[CH2:15][N:14]1[C:10]([C:8]2[CH:7]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][C:2]=3[CH:9]=2)=[N:11][N:12]=[N:13]1
Reactant: O=C(O)Cn1nnnc1-c1ccc2ccsc2c1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc2ccsc2c1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 85.5 %

Procedure:
To a solution of 400 mg (1.54 mM) of [5-(6-benzo[b]thienyl)tetrazol-1-yl] acetic acid in 3 ml of ethylene glycol was added 0.3 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=50/1) for separation and purification, to give 400 mg (yield 85.5%) of [5-(6-benzo[b]thienyl)tetrazol-1-yl]acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:23])([OH:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc2cccc(C)c2c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc2ccc(C(C)(C)O)c(OCc3ccccc3)c12
Temperature: -78 °C
Reaction time: 72 h

Procedure:
4.8 g of 1'-benzyloxy-8'-methyl-2'-acetonaphthone was dissolved in 200 ml of tetrahydrofuran and cooled down to -78° C. At the temperature, 28 ml of a tetrahydrofuran solution of 1M methylmagnesium bromide was added, followed by returning to room temperature. It was agitated at room temperature for 72 hours and was further reacted at 80° C. for 2 hours. The reaction solution was cooled down to 0° C., to which a saturated ammonium chloride aqueous solution was added portion by portion, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtained 1.8 g of the captioned compound as a brown oily substance.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[N+]=[N-]>C1COCC1.CO.[Pd]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[C:5]([CH2:4][NH2:1])=[CH:14]2
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-methoxyphenyl)-quinoline (210.7 mg, 615 mmol) in THF 5 mL and MeOH 12 mL was added palladium, 10 wt. % on activated carbon (0.329 mmol) and placed under a medium balloon containing H2. The reaction was complete after 2 h, it was filtered (Celite™) and solvents removed.