Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
(2-Nitro-phenyl)-acetic acid (2.0 g, 11.04 mmol), 4-amino-1-benzylpiperidine (2.25 mL, 10.03 mmol), 1-hydroxybenzotriazole (1.49 g, 11.04 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.3 g, 12.03 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.1 mmol) and the reaction mixture stirred at 40° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2×), 5% sodium bicarbonate, brine (2×), dried over sodium sulfate, and concentrated to afford 3.5 g (98%) of the desired product. LC/MS: tR=1.24 min, 354.30 (MH)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:34]=2)[C:29]([O:31]CC)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:35]>C(O)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:34]=2)[C:29]([NH2:35])=[O:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: N
Solvent: CCO
Product: NC(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
A solution of ethyl 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinate (0.100 g, 0.222 mmol) in ethanol (10 mL) was purged with ammonia gas at −40° C. in a sealed tube for 15 min. The tube was sealed and the reaction mixture was stirred at ambient temperature for 14 h. The sealed tube was opened at −40° C. and allowed to rise to ambient temperature. The solvent was evaporated under reduced pressure to give a residue which was purified by preparative HPLC (Condition B-58 as described in general methods) to get 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinamide (80.0 mg, 86.0%) as a white solid. LCMS Condition B-26: retention time 2.28 min, [M+1]=421.2. HPLC Condition B-6: retention time 7.62 min, purity 99.33%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.84 (d, J=4.0 Hz, 2H), 6.68 (t, J=4.0 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 7.25-7.32 (m, 1H), 7.34-7.41 (m, 5H), 7.45-7.48 (m, 2H), 7.52-7.54 (m, 2H), 7.67 (s, 1H), 7.93 (d, J=4.0 Hz, 1H), 8.32 (s, 1H), 8.95 (t, J=4.0 Hz, 1H), 9.11 (d, J=2.4 Hz, 1H), 9.46 (d, J=2.0 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:46][C:47]([F:61])([F:60])[C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:60])([F:61])[F:46])=[CH:53][CH:52]=2)[CH2:59][CH2:58]1)=[O:6]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-Iodo-5-methanesulfonyl-benzoic acid (Example C, 3.0 g, 9.2 mmol) in dimethylformamide (20 ml) were successively added TBTU (3.8 g, 11.5 mmol), N-ethyldiisopropylamine (8.0 ml, 46.0 mmol) and 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7], 2.5 g, 11.0 mmol). The reaction was then stirred at room temperature for two hours, then concentrated in vacuo and purified by column chromatography (SiO2, 50 g, CH2Cl2/MeOH/NH3=100/0/0 to 95/4.5/0.5), to give the title compound as a pale brown foam; MS (m/e): 539.1 (M+H+). TBTU=2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=3[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: NC1CC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(NC2CC2)c2[nH]c(C(F)(F)F)nc12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with cyclopropylamine to obtain the corresponding 4-(cyclopropylamino)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, m.w., 354.2.
Reaction SMILES: [OH:1][CH2:2][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:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:1][CH2:2][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)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) are added acetic anhydride (4.0 ml) and pyridine (0.5 ml), and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution is poured into ice-water and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-acetyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as colorless needles, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]CC=C)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.N1CCOCC1.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>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(N2CCC(C(=O)OCC)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of 4.74 g of 1-{4-[(allyloxy)carbonyl]phenyl}piperidine-4-carboxylic acid ethyl ester in 75 ml of THF, 2.10 ml of morpholine and 390 mg of tetrakis(triphenylphosphine)palladium were added, and the mixture was stirred at 60 for 1.5 hours. After the solvent was evaporated under reduced pressure, EtOAc was added to the residue, and the reaction solution was washed with NaHCO3 aq. three times. To the collected saturated NaHCO3 aq., conc. HCl was added, and the produced precipitate was collected by filtration and dried under reduced pressure to obtain 2.73 g of 4-[4-(Ethoxycarbonyl)piperidin-1-yl]benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1cc(OCCCCCCCCCCCC)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Methyl 3,5-dihydroxybenzoate (4.2 g, 25 mmol) was dissolved in 25 mL of dry DMF and then 13.86 g (100 mmol) of K2CO3 was added in the reaction mixture, where the above mixture was stirred at 80° C. for 1 h under a N2 atmosphere and then 1-bromododecane (12.4 g, 50 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 90° C. for 24 h under N2. At the end of the reaction, the mixture was poured onto ice, 2N—HCl and extracted with MC, H20, NaHCO3 and brine. The solvent was removed in vacuo. The crude solid was purified by column chromatograph with 10% EA and hexane to yield 75% of the product. 1H-NMR (300 MHz, CDCl3) δ 7.1 (d, 2H), 6.6 (t, 1H), 4.0 (t, 4H), 3.9 (s, OCH3), 1.7-1.8 (m, 4H), 1.4-1.6 (m, 4H), 1.1-1.3 (m, 32H), 0.9 (t, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH2:32])=[N:27]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:32][C:28]2[CH:29]=[C:30]([CH3:31])[N:26]([CH3:25])[N:27]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)nn1C
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)nn1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of tert-butyl 5-[(2,5-dichloropyrimidin-4-yl)amino]-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (1.29 g, 3.46 mmol) and 1,5-dimethylpyrazol-3-amine (0.80 g, 7.20 mmol) in 1,4-dioxane (20 mL) was added trifluoroacetic acid (2.01 g, 17.60 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a yellow solid (294.5 mg, 19%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([O-:6])=[O:5].[K+:7].O.[NH2:9][NH2:10]>>[NH:9]([CH2:3][C@H:2]([OH:1])[C:4]([O-:6])=[O:5])[NH2:10].[K+:7]
Reactant: NN
Reactant: O=C([O-])[C@@H]1CO1
Agent: [K+]
Solvent: O
Product: NNC[C@H](O)C(=O)[O-]

Procedure:
Potassium (S)-oxirane-2-carboxylate LVIII (0.63 g, 5 mmol) and hydrazine hydrate (2.57 g, 51 mmol) were heated at 95° C. for 3 days. Hydrazine and water were removed and the residue was dried at 40° C. under vacuum to produce potassium (S)-3-hydrazinyl-2-hydroxypropanoate LIX (0.75 g), which was used without purification in the next step. ESIMS found for C3H7N2O3K m/z 119 (M)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>CO>[CH3:14][O:12][C:11]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Solvent: CO
Product: COC(=O)c1c[nH]c2cc(Br)ccc12
Yield: 100 %

Procedure:
To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, about 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is re-dissolved in methanol and concentrated under reduced pressure. This process is repeated several times to give the title compound as a solid (100%). ES/MS m/e 256.0 (M+2).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Cl.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([Cl:27])[CH:19]=2)=[C:13]([Cl:28])[CH:12]=1>CN(C=O)C.S(=O)(O)[O-].[Na+].O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([Cl:27])[C:19]=2[Cl:1])=[C:13]([Cl:28])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
N-Chlorosuccinimide was (13.0 g, 99.0 mmol) added to a suspension of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid (24) (32.54 g, 89.9 mmol) in DMF (500 mL). The suspension was allowed to stir at room temperature overnight. The reaction mixture was diluted with saturated sodium bisulfite (200 mL) and water (1L) resulting in formation of a thick white precipitate which was isolated by filtration and washed with water. The solids were dissolved into THF. Two volumes of diethyl ether were added and the organic solution washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to provide an orange solid. The solid was triturated with diethyl ether to provide the desired product as an off-white solid (25) (13.34 g, 37%). MS (APCI−) m/z 393, 395, 397 (M-; Cl, Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: Brc1nccs1
Product: Clc1ccnc2cc(-c3nccs3)sc12
Yield: 46.2 %

Procedure:
This material was prepared by coupling of 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.140 g, 0.42 mmole) and 2-bromo-1,3-thiazole (0.038 ml, 0.42 mmole) with tereakis(triphenylphosphine) palladium (0.019 g) in a manner as previously described in example 39b to give a yellow solid (0.049 g, 46%). 1H NMR (300 MHz, CDCl3) δ8.59 (1H, d, J=5.1 Hz), 7.93 (1H, s), 7.89 (1H, d, J=3.4 Hz), 7.45 (1H, d, J=3.4 Hz), 7.30 (1H, d, J=5.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[S:5][C:4]=1[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:27].C(OC(=O)C)C.[ClH:49]>C(OCC)(=O)C>[ClH:49].[NH2:35][CH2:34][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][N:28]1[C:26]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8](=[O:25])[C:7]=2[C:3]=1[O:2][CH3:1])=[O:27]
Reactant: COc1c(C(=O)N2CCCCC2CNC(=O)OC(C)(C)C)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1c(C(=O)N2CCCCC2CN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 67 %

Procedure:
A solution of the obtained tert-butyl [(1-{[3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]quinolin-2-yl]carbonyl}piperidin-2-yl)methyl]carbamate (150 mg) and 4N hydrogen chloride ethyl acetate solution (8 mL) in ethyl acetate (15 mL) was stirred at room temperature for 18 hr. The obtained precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (133 mg, 67%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:15])[C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:15])[CH:12]=1
Reactant: O=Cc1cccn1-c1c(Cl)cncc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a solution of 2.14 g of 1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde in 10 ml of N,N-dimethylformamide was added 1.7 g of N-bromosuccinimide. The mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 2.9 g of 4-bromo-1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH2:22][CH3:23])[N+:15]=1[O-:24]>C1COCC1>[Cl:21][C:18]1[CH:17]=[C:16]([CH2:22][CH3:23])[N+:15]([O-:24])=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:19]=1[CH3:20]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCc1cc(Cl)c(C)c(Cl)[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4,6-trimethylphenol in dry THF was added NaH and stirred at room temperature for 20 minutes. A solution of 2,4-dichloro-6-ethyl-3-methyl-pyridine 1-oxide was added and the resulting mixture was heated at reflux for 1.5 hour. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give the title compound which was used directly for the next step reaction.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:2]1[NH:16][N:17]=[N:18][C:1]=1[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nn[nH]n2)CC1
Temperature: 100 °C
Yield: 51.8 %

Procedure:
A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (2.1 g), sodium azide (1.95 g) and ammonium chloride (1.6 g) in dimethylformamide was heated to 100° C. for 18 hours. The mixture was cooled and partitioned between 1N HCl and dichloromethane. The organic layer was washed with water, dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with MeOH/dichloromethane (1:99) to give tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate (1.31 g); NMR (CDCl3): 1.5 (s, 9H), 1.9 (m, 2H), 2.15 (m, 2H), 3.0 (m, 2H), 3.3 (m, 1H), 4.2 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)=[CH:20][C:19]=1[Br:37]>>[Br:37][C:19]1[CH:20]=[C:21]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]2)[CH:22]=[CH:23][C:18]=1[NH:17][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:15]
Reactant: COc1ccc(-c2ccc(C(=O)Cl)s2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)c(Br)c2)C1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Yield: 39.7 %

Procedure:
Following Step 1 from General Procedure A, 5-(4-methoxyphenyl)thiophene-2-carbonyl chloride (640 mg, 2.5 mmol) was reacted with (S)-tert-butyl 1-(4-amino-3-bromophenyl)pyrrolidin-3-ylcarbamate (800 mg, 2.2 mmol) to afford the desired product (500 mg, 39%) as a light yellow solid: ESI MS m/z 573 [C27H30BrN3O4S+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:30][O:31][CH2:32][CH2:33][O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1
Reactant: COCCBr
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), 2-bromoethyl methyl ether (0.070 mL, 0.75 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column-chromatography eluting with hexane/AcOEt (1/2) to give the title compound (89.9 mg, 79% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.45 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 7.02 (1H, dd, J=1.9, 7.9 Hz), 7.20 (1H, s), 7.34-7.45 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 8.29 (1H, s). LC-MS (ESI) m/z 457 [M+H]+. Anal. Calcd for C23H19F3N4O3.0.25H2O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.87; H, 4.09; N, 12.15.
Reaction SMILES: N#N.[CH3:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[O:13][CH3:14].N1C(C)=CC(C)=CC=1C.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>C(#N)C>[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24])=[CH:10][CH:9]=[CH:8][C:7]=2[O:13][CH3:14]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc2cc(C)[nH]c12
Agent: N#N
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: COc1cccc2c(C(=O)C(Cl)(Cl)Cl)c(C)[nH]c12
Yield: 100.5 %

Procedure:
To a 2 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-methyl-7-methoxyindole (12 g, 74 mmol), acetonitrile (125 mL) and collidine (15 mL, 113 mmol). The mixture was stirred to give a solution and was cooled with an ice water bath. Trichloroacetyl chloride (14 mL, 112 mmol) was added. The cooling bath was removed and the reaction mixture stirred at RT for 3 h. 1N HCl (500 mL) was then added over 10 minutes. The resulting slurry was stirred at RT for 30 minutes and filtered. The cake was washed with DI water (3×50 mL) and suction dried for 17 h to give 2-methyl-3-trichloroacetyl-7-methoxyindole (22.8 g, 96% yield). 1H NMR (CDCl3) δ2.79 (s, 3H), 3.96 (s, 3H), 6.71 (d, J=7.9 Hz, 1H), 7.19 (dd, J=7.9, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.92 (s, 1H).