Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][C:30]2([C:43]3[C:35](=[CH:36][C:37]4[CH2:38][CH2:39][NH:40][C:41]=4[CH:42]=3)[O:34][CH2:33]2)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:40]2[C:41]3[CH:42]=[C:43]4[C:30]5([CH2:33][O:34][C:35]4=[CH:36][C:37]=3[CH2:38][CH2:39]2)[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)=[O:24])=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 2'-methoxycarbonyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D53) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D7) following a similar procedure to Example 15 as an off-white powder (66%).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[I:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[I:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(Br)cc1I
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1I

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2-aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2-iodo-4-bromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2].CN(C)C=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>[Cu]I.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:33]=[N:34][NH:35][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ncccn1)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ncccn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 5.85 %

Procedure:
A flask was charged with (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-2-pyrimidinyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 114) (45 mg, 0.147 mmol) and copper (I) iodide (2.80 mg, 0.015 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.200 mL) and the resulting mixture was treated with trimethylsilyl azide (0.078 mL, 0.588 mmol). The flask was flushed with nitrogen then the mixture was stirred at 100° C. for 1 h under microwave irradiation then cooled to room temperature. Most of the methanol was removed in vacuo and the remaining organic phase was purified by MDAP (modifier: ammonium bicarbonate) to give (2S,4R)-1-acetyl-2-methyl-N-2-pyrimidinyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinamine (3 mg, 8.59 μmol, 5.85% yield) as a colourless film.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CN(Cc2ccccc2)CC1N
Product: CC(=O)NC1CN(Cc2ccccc2)CC1C

Procedure:
3-Amino-1-benzyl-4-methylpyrrolidine (Japanese Laid-Open Patent Publication No. 22699/1980) was allowed to react with acetic anhydride to give 3-acetylamino-1-benzyl-4-methylpyrrolidine; IR 3300, 1650 cm-1. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-acetylamino-4-methylpyrrolidine as an oil.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12].Cl.CN(C)CCCN=C=NCC.[CH:31]1(/[CH:36]=[C:37](\[C:48]2[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=2)/[C:38]2[NH:39][C:40](=[O:47])[C:41]([CH:44]3[CH2:46][CH2:45]3)=[CH:42][CH:43]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O.O.C(N(CC)CC)C>[CH:31]1(/[CH:36]=[C:37](\[C:48]2[CH:56]=[CH:55][C:51]([C:52]([NH:16][CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:11][CH3:12])=[O:53])=[CH:50][CH:49]=2)/[C:38]2[NH:39][C:40](=[O:47])[C:41]([CH:44]3[CH2:45][CH2:46]3)=[CH:42][CH:43]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCN(CC)CCN
Reactant: O=C(O)c1ccc(/C(=C\C2CCCC2)c2ccc(C3CC3)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1ccc(/C(=C\C2CCCC2)c2ccc(C3CC3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
1-Hydroxybenzotriazole (39 mg), triethylamine (0.04 mL), N,N-diethylethylenediamine (0.061 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg) were sequentially added to a solution of 4-[(E)-2-cyclopentyl-1-(5-cyclopropyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]benzoic acid (50 mg) in N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=20:1) and the resulting solid was washed with diethyl ether to give the title compound as a white solid (17 mg, 26%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=O)[NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:35][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)s1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
The mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.44 mmol) and Lawesson's reagent (1.23 g, 3.0 mmol) in THF (16 ml) was heated at 80° C. for 4 hours. The solvent was removed under reduced pressure and the mixture was diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 2-[5-(4-Bromo-phenyl)-thiazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (655 mg). m/z: 410.7 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8]C(C#N)=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1.[OH-].[K+].[C:19]([O:22]CC)(=[O:21])[CH3:20]>O>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:2]1[CH:9]=[CH:8][C:20]([C:19]([OH:22])=[O:21])=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: CC1CCCCN1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cn1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of 6-chloronicotinonitrile (Maybridge SPB04745; 1.5 g; 10.8 mmol; 1 eq.) and 2-methylpiperidine (25.6 ml; 216.5 mmol; 20 eq.) was stirred at 90° C. for 24 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. To the residue (1.5 g; 7.45 mmol; 1 eq.) in water (90 mL) was added potassium hydroxide (2.09 g; 37.3 mmol; 5 eq.) and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, the precipitate was filtered off and the filtrate acidified to pH 6 with HCl 1M. The precipitate was filtered off and dried to afford the title compound as a beige solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]3[CH2:22][S@@:21](=[O:23])[CH2:20][CH2:19][C:18]=3[C:13]2=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:11]=1[Cl:32].C(N1C=CN=C1)(N1C=CN=C1)=O.O>CN(C=O)C>[Cl:32][C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:13]2[C:18]3[CH2:19][CH2:20][S@:21](=[O:23])[CH2:22][C:17]=3[S:16][C:14]2=[N:15][C:10]=1[CH2:9][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][C:4]1=[O:6]
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CC[S@](=O)C4)cc1
Reactant: O=C1CCC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CC[S@](=O)C4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of succinic anhydride (303.25 g) in DMF (3.5.L) was added (S)-2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (1134 g) and the mixture was stirred for 1 hour. To the mixture was slowly added carbonyldiimidazole (935.5 g), and stirred at room temperature for 22 hours and further at 36 to 38° C. for 5 hours. The reaction mixture was added dropwise to water (20 L). After stirring for 2.5 hours, crystals deposited were filtered off and washed with water (1277 g, 86.4%). This product was dissolved in a mixture of acetonitrile (8.7 L) and water (2.9 L) and treated with active carbon. Water (45 L) was added and crystals were filtered off. The crystals were suspended in acetone (2.9 L), stirred at 48 to 52° C. for 1 hour and cooled to room temperature. Crystals were filtered off to obtain the titled compound (997 g). Melting point 217–218.5° C. (decomp.) [α]D20−123.63 (c=0.00490, CHCl3).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:23](O)[CH3:24]>>[CH2:12]([N:13]([CH2:23][CH3:24])[CH2:14][CH2:15][CH2:7][C:1]1[CH:6]=[C:21]2[C:22](=[CH:3][CH:2]=1)[NH:17][C:19]([CH:18]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:20]2)[CH3:11]
Reactant: C1CCNCC1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 95 °C
Yield: 56 %

Procedure:
A mixture of 6-phenyl-2-oxindole (41 mg, 0.19 mmol) 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 49 mg (56%) of the title compound as an orange crystalline solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2].[CH3:39][Si](C)(C)[N-][Si](C)(C)C.[K+].CI>O1CCCC1>[C:1]([N:4]([CH3:39])[C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 60 mg (0.11 mmol) N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 2 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 40 mg (65%) of the title compound as white foam. MS m/e (%): 574 (M+Na+, 17), 552 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([O:11][CH:12]([CH2:16][O:17][CH3:18])[CH2:13][O:14][CH3:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1.C(Cl)Cl>[Br:22][CH2:20][C:19]([C:7]1[CH:8]=[C:9]([O:11][CH:12]([CH2:16][O:17][CH3:18])[CH2:13][O:14][CH3:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:21]
Reactant: COCC(COC)Oc1cc(C(C)=O)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(C(=O)CBr)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
1-[3-tert-Butyl-5-(2-methoxy-1-methoxymethylethoxy)phenyl]ethanone (O2.072; 1.64 g) was dissolved in methanol/THF (30/30 ml) and admixed while stirring with phenyltrimethylammonium tribromide (2.09 g). The mixture was stirred at RT for 1 h, then diluted with DCM and washed once with 5% sodium thiosulfate solution. The DCM phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-30% within 60 min). 890 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:11]([Li])CCC.CI>C1COCC1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([CH2:4][O:5][CH3:11])[C:2]=1[NH2:1]
Reactant: [Li]CCCC
Reactant: Nc1c(Cl)cccc1CO
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: COCc1cccc(Cl)c1N
Yield: 25.2 %

Procedure:
A solution of 4.00 g (25.4 mmol) of 2-amino-3-chlorobenzyl alcohol in 30 ml of dry THF was cooled to -78° C., treated with 16.7 ml (26.7 mmol) of 1.60M n-butyllithium in hexane, warmed to 0°-5° C., treated with 3.61 g (25.4 mmol) of methyl iodide and heated at reflux for 5.5 hours. The solvent was removed by evaporation at reduced pressure. The residue was partitioned between 175 ml of ether and water, and the organic phase was separated and dried (MgSO4). The solvent was removed by evaporation at reduced pressure, and the residue was purified by HPLC eluting with ETOAc (5:95, v/v) to afford 1.1 g of the desired product as a pale brown oil. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[P:6]1[CH3:16])[CH2:2][CH2:3][CH3:4].[CH3:17][I:18]>>[I-:18].[CH2:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[P+:6]1([CH3:17])[CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC)p(C)c1=O
Reactant: CI
Product: CCCCN1C(=O)N(CCCC)[P+](C)(C)C1=O
Product: [I-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 820 mg (3.3 mmol) of 1,4-dibutyl-2-methyl-1,4,2-diazaphospholidine-3,5-dione (cf. Ex. 3) with 6.27 g (44 mmol) of methyl iodide (from Aldrich) was heated at reflux (bath temperature: to 80° C.) while stirring with a magnetic stirrer bar for 24 h. The yellow mixture, whose viscosity had risen noticeably, was analysed by NMR spectroscopy without further workup:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.FC(F)(F)C(O[C:38]1[C:43]([F:44])=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48])=O.Cl>C(Cl)Cl>[F:44][C:43]1[C:38]([O:12][C:11]([C:8]2[N:9]=[N:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:7]=2)=[O:13])=[C:39]([F:48])[C:40]([F:47])=[C:41]([F:46])[C:42]=1[F:45]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CCCCc1nnc(C(=O)O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of the carboxylic acid (24.4 mmol, 8.6 g) in DCM (100 mL) was added pyridine (81 mmol , 6.4 g) followed pentafluorophenyl trifluoroacetate (40.52 mmol, 11.3 g) drop-wise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 8 h. The reaction was added to 1N HCl (100 mL), and the product was extracted with ethyl acetate. The crude product was purified using a mixture of hexanes in ethyl acetate on a 330 g silica gel ISCO column to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (9.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1>C(O)(=O)C.O1CCCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][OH:28])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCOC5CCCCO5)ccc24)CCC3)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
Heat a solution of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[2-(tetrahydropyran-2-yloxy)ethoxy]quinoline (421 mg, 0.92 mmol) in acetic acid:tetrahydrofuran:water (4:2:1) (20 mL). Remove the solvent in vacuo and recover the residue with chloroform:isopropyl (3:1). Wash the organic layer with saturated sodium bicarbonate and dry over sodium sulfate. Concentrate in vacuo. The residue will be pure enough for the next step in the scheme (425 mg, 100%). MS ES+ m/e 373.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=[CH:10][CH3:11])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O>CN(C=O)C.O>[CH2:14]([O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH:9]=[CH:10][CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC=Cc1ccc(Br)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC=Cc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-2-(propenyl)-phenol (mixture of E- and Z-isomer ca. 85:15) (1.10 g, 4.99 mmol, 1.0 eq.) in DMF (15 mL) was slowly added to sodium hydride 60% dispersion in mineral oil (261 mg, 6.52 mmol, 1.3 eq.) at 0° C. under N2. Upon completion of the addition, the mixture was allowed to warm to r.t. Benzyl bromide (0.61 mL, 4.99 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. AcOEt was added and the reaction was stirred at r.t. for 30 min. Water was added to the mixture. The layers were separated and the org. phase was washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield 2-benzyloxy-4-bromo-1-(propenyl)-benzene as a pale yellow oil as an unseparable mixture of E- and Z-isomers (ca. 9/1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([F:16])[CH:5]=1.[CH:17](OCC)=[O:18].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:17]=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([F:16])[CH:5]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1F
Reaction time: 0.5 h

Procedure:
Then, 3.6 g of sodium hydride (60% in oil) was suspended in 120 ml of tetrahydrofuran, and the mixture was cooled to 5° C., to which a solution of 17.8 g of ethyl 4-chloro-2-fluorophenylacetate in 120 nm of tetrahydrofliran was slowly added dropwise. The mixture was stirred for 30 minutes with a gradual temperature increase to room temperature, to which 20 ml of ethyl formate was added at room temperature, followed by stirring for 3 hours. Then, the reaction mixture was cooled with ice, to which diluted aqueous hydrochloric acid was added. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 19.1 g of ethyl 2-(4-chloro-2-fluorophenyl)-2-formylacetate.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[CH2:9][O:10][C:11]1[CH:16]=CC(Br)=C[C:12]=1C.CN([CH:26]=[O:27])C>C1COCC1>[CH3:5][C:4]1[CH:16]=[C:11]([O:10][CH2:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[CH3:6])[CH:12]=[CH:2][C:3]=1[CH:26]=[O:27]
Reactant: Cc1ccccc1COc1ccc(Br)cc1C
Reactant: CN(C)C=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2C)ccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A 2.5M solution of n-BuLi (2.1 mL, 5.26 mmol) in THF was added dropwise to a −78° C. solution of 31.2 (1.46 g, 5.01 mmol) in THF (25 mL). The reaction was stirred at −78° C. for 15 minutes and then DMF (3.3 mL) was added. Cooling was removed after 5 minutes and the reaction was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted 1 additional time with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified via radial chromatography (5% ethyl acetate in hexanes0 to yield 269 mg (22%) of 2-Methyl-4-(2-methyl-benzyloxy)-benzaldehyde (31.3). LC/MSD m/e: 241.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[NH4+].I[CH3:26]>C(O)C>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:21][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Sc1nc2cnc3ccccc3c2n1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyl-1H-imidazo[4,5-c]quinoline-2-thiol (4.15 g, 14.2 mmol), deionized water (35 mL), ethanol (35 mL), and aqueous ammonium hydroxide (3.2 mL) were combined, and iodomethane (1.06 mL, 17.0 mmol) was added. The reaction was stirred at room temperature for one hour, and a precipitate formed. The precipitate was collected by filtration, washed with diethyl ether (5×100 mL), and dried under vacuum to provide 1-benzyl-2-(methylthio)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-Bromo-3-pyridinamine (200 mg) was dissolved in pyridine (5 ml), cooled to 0° C. and stirred for 10 min. Methanesulfonyl chloride (0.05 ml) was added dropwise and the reaction continued stirring for 1 hr. 2M HCl (aq) (5 ml) was added and the reaction was extracted with DCM, passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DCM and adsorbed onto fluorosil and purified by column chromatography on silica, eluting with 50% ether/cyclohexane then 0-10% MeOH/DCM to give the title compound (96 mg).