Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.[OH-].[Na+]>C(O)(=O)C>[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH3:22])[CH:18]=2)[NH:13]1
Reactant: COc1ccc2[nH]c(-c3ccccc3N)cc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(c1ccccc1N)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
Sodium cyanoborohydride (19.30 g) was added portionwise to a solution of 20.50 g 2-(2-aminophenyl)-5-methoxy-1H-indole in 1500 ml acetic acid at 15° C. The resulting solution was stirred at room temperature for one day. The reaction mixture was diluted and made basic by addition of 50% NaOH in ice. The mixture was extracted with ethyl acetate, and the extracts were washed with saturated NaCl solution and dried (MgSO4). Concentration yielded 20.56 g solid. Purification of a 10 g portion by HPLC yielded 2.33 g solid, m.p. 94°-98° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C)C=O>[CH2:18]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC(C)C)CCCC1=O
Temperature: 55 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
Under vigorously agitation, 13.9 g of ethyl 2-oxocyclopentane carboxylate was added to 33.4 g of fine powdery anhydrous potassium carbonate and 1.14 g of benzyl triethyl ammonium chloride. After stirring for several minutes, to the mixture was added 60 ml of N,N-dimethyl formamide and 21.9 g of iso-butyl bromide. Upon the completion of the addition, the reaction was heated to 55° C. and allowed to continue for 6 hours with stirring. The solvent was removed under reduced pressure, and solid residue was washed with diethyl ether. The washing liquor was collected and washed with water, and removing the solvent gave a crude product. The crude product was distilled under reduced pressure, and 15.3 g of colorless liquid as a distillate cut of 139-142° C./15 mmHg was colleted. Yield: 90.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:26])[N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: C1CCNCC1
Product: CC1(C)CN(CC(=O)N2CCCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 90 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and piperidine in 90% yield.
Reaction SMILES: N[C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])[CH:7]=1.N(OCCC(C)C)=O.[I:29]I>C(Cl)(Cl)Cl>[F:19][C:5]1[CH:4]=[C:3]([F:20])[C:2]([I:29])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=1[CH3:18]
Reactant: II
Reactant: COC(=O)c1ccc(-c2cc(N)c(F)cc2F)c(C)c1
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cc(I)c(F)cc2F)c(C)c1

Procedure:
methyl 5′-amino-2′,4′-difluoro-2-methylbiphenyl-4-carboxylate (500 mg, 1.80 mmol), 3-methylbutyl nitrite (317 mg, 2.71 mmol), iodine (549 mg, 2.16 mmol) and chloroform (15 ml) were refluxed in an oil bath for 5 hours then allowed to cooled to ambient overnight. Reaction crude was purified by flash chromatography (SiO2, Biotage 40+M cartridge) eluted with a EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=387.98; found=388.92 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:53][CH2:52]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:54][O:55][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:52][CH2:53]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:54][OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Crude [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 1c (4.26 g, 4.92 mmol) was dissolved in 30 mL methanol, followed by addition of acetyl chloride (52 μL, 0.74 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 1d (2.3 g, yellow grease), yield: 62.2%. 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 13H), 7.20 (m, 3H), 7.03 (m, 4H), 6.80 (d, 2H), 4.92 (m, 3H), 4.70 (m, 1H), 4.50 (m, 1H), 4.17 (m, 1H), 4.05 (m, 3H), 3.85 (m, 6H), 3.70 (m, 2H), 3.40 (m, 1H), 3.30 (m, 1H), 3.07 (s, 3H), 0.63 (m, 2H), 0.48 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[C:14](=[C:15]([NH:20][C:21]([C:23]5[N:27]6[CH:28]=[CH:29][C:30](F)=[CH:31][C:26]6=[N:25][CH:24]=5)=[O:22])[CH:16]=[CH:17][CH:18]=4)[C:13]([CH3:33])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[C:14](=[C:15]([NH:20][C:21]([C:23]5[N:27]6[CH:28]=[CH:29][C:30]([O:44][CH2:43][CH2:42][N:37]7[CH2:38][CH2:39][N:40]([CH3:41])[C@@H:35]([CH3:34])[CH2:36]7)=[CH:31][C:26]6=[N:25][CH:24]=5)=[O:22])[CH:16]=[CH:17][CH:18]=4)[C:13]([CH3:33])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: C[C@H]1CN(CCO)CCN1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 31 %

Procedure:
N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (Example 16, Step G; 0.250 g, 0.568 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.449 g, 2.84 mmol), and potassium t-butoxide (0.382 g, 3.41 mmol) were combined in t-butanol in a pressure tube. The tube was sealed and warmed to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) of the crude material followed by trituration with ether gave 102 mg (31%) of the title compound. MS (APCI), positive scan, m/z=579.1 (M+H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:19]2[CH:27]=[CH:26]C(C(O)=O)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1>ClCCl.CN(C=O)C>[N:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[C:19]2[CH:27]=[CH:26][C:1]([C:2]([Cl:4])=[O:3])=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(N2CCNCC2c2ccncc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCNCC2c2ccncc2)cc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.5 ml) was added to a stirred suspension of 4-((4-pyridyl)piperazin-1-yl)benzoic acid in dichloromethane (15 ml), followed by DMF (1 drop). The mixture was stirred for 2 hours and evaporated to dryness to give 4-[(4-pyridyl)piperazin-1-yl]benzoyl chloride which was used immediately.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[N+]=[N-].[BH4-].[Na+].[H-]>C(O)C>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=Nc1ccnc2c(F)cccc12
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccnc2c(F)cccc12
Reaction time: 2 h

Procedure:
To a solution at 15°-20° C of 4-azido-8-fluoroquinoline in 12 mL of absolute ethanol was added a portion of 0.57g (0.015 mol) of sodium borohydride. A powerful exotherm with vigorous evolution of gas was observed. The solution was cooled in ice and the remainder of the hydride was added in small portions within five minutes. The ice bath was then is removed. After about two hours, the mixture was poured into about 200 mL of ice water. The precipitate was collected and air dried overnight. Yield 1.35 g. M.P. 184°-186° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:13]3[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[CH2:11][CH2:10][C@H:9]([NH:24][C:25](=[O:27])[CH3:26])[C:8]=2[CH:28]=1)(O)=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C1C=CN=CC=1)C.ClCCl>[C:25]([NH:24][C@@H:9]1[C:8]2[CH:28]=[C:4]([C:1]([NH:44][CH2:45][CH2:46][CH2:47][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:2])[CH:5]=[CH:6][C:7]=2[C:13]2[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10]1)(=[O:27])[CH3:26]
Reactant: NCCCN1CCOCC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)O)cc1[C@@H](NC(C)=O)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)NCCCN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 30 %

Procedure:
A solution of N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (0.3 g; 0.779 mmol), (Med. Chem. Res. 1991, 142), DCCI (0.322 g; 1.55 mmol), DMAP (0.069 g; 0.389 mmol) and 4-(3-aminopropyl)morpholine (170 μl; 1.17 mmol) in dichloromethane (6 ml) was stirred under argon atmosphere overnight. After removal of the insoluble material by filtration, the residue was purified on reverse phase silica eluting with a gradient of 40–50% methanol/ammonium carbonate buffer (2 g/l, pH7). The appropriate fractions were evaporated to dryness and triturated in ether to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-N-(3-morpholinopropyl)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxamide as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:20]([CH3:21])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=1)C1C=CC=CC=1.C(O)=O>CO.[OH-].[OH-].[Pd+2]>[CH3:21][N:20]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=[C:12]1[CH2:11][CH2:10][CH2:9][OH:8]
Reactant: Cn1c(CCCOCc2ccccc2)nc2cccnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cn1c(CCCO)nc2cccnc21
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 2-[3-(benzyloxy)propyl]-3-methyl-3H-imidazo[4,5-b]pyridine (1.8 g), 20% palladium hydroxide on carbon (2.35 g, containing water (50%)), and formic acid (8.45 mL) in methanol (84.5 mL) was refluxed for 6 hr. The mixture was allowed to cool to room temperature, and the catalyst was filtered off. The obtained filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.0 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:27][C:28]1[C:32]([NH2:33])=[CH:31][O:30][N:29]=1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:33][C:32]1[C:28]([CH3:27])=[N:29][O:30][CH:31]=1)=[O:9]
Reactant: Cc1nocc1N
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 20; 150 mg, 0.35 mmol) in N,N-dimethylformamide (4 ml) was added 3-methyl-4-isoxazolamine (41.6 mg, 0.42 mmol), diisopropylethylamine (0.12 ml, 0.71 mmol), 1-hydroxy-7-azabenzotriazole (57.7 mg, 0.42 mmol) and EDC (102 mg, 0.53 mmol). The mixture was stirred for 18 hours, then the solvent removed in vacuo to give a residue. The residue was purified by column chromatography (10% 7M NH3 in methanol/dichloromethane) to yield the title compound as a solid. 178 mg.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>[Pt](=O)=O.CCO>[ClH:1].[C:2]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)C1CCNCC1
Temperature: 22 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
Place 4-tert-butylpyridine hydrochloride (50 g, 277 mmol) in a PARR reactor and add EtOH (350 mL) followed by platinum (IV) oxide (5.0 g, 22.02 mmol). Stir the mixture at 22° C. under a hydrogen atmosphere (500 psi) for 18 hours. Evacuate the excess hydrogen and filter the suspension the a Celite® pad. Concentrate the filtrate and dry the residue under vacuum (40° C., 5 mbar) to give the title compound as an off-white solid (45.1 g, 92%). 1H-NMR (d6-DMSO) δ 0.83 (s, 9H), δ 1.2-1.5 (m, 3H), δ 1.7 (d, 2H), δ 2.7-2.8 (m, 2H), δ 3.2 (d, 2H), δ 8.7-9.3 (2 bs, 2H).
Reaction SMILES: C([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([S:23]([OH:26])(=[O:25])=[O:24])=[C:15]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]=1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])CCCCCCCCCCC.C1C2C(=CC=CC=2)C=CC=1.C=CCCCCCCCCCC.OS(O)(=O)=O.O=S(=O)=O>>[CH2:39]([C:14]1[C:15]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:16]([S:23]([OH:26])(=[O:24])=[O:25])[C:17]2[C:22]([CH:13]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCc1c(CCCCCCCCCCCC)c(S(=O)(=O)O)c2ccccc2c1CCCCCCCCCCCC
Agent: C=CCCCCCCCCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: c1ccc2ccccc2c1
Product: CCCCCCCCCCCCc1cc2ccccc2c(S(=O)(=O)O)c1CCCCCCCCCCCC

Procedure:
A mixture that is approximately 80% didodecylated naphthalene sulfonic acid and 20% tridodecylnaphthalene sulfonic acid is prepared by the alkylation of naphthalene with dodecene followed by sulfonation of the resulting alkylate with oleum.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.I[C:21]1[CH:26]=[N:25][NH:24][C:23](=[O:27])[CH:22]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33]([C:21]2[CH:26]=[N:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1cc(I)cn[nH]1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cn[nH]1
Temperature: 100 °C
Reaction time: 22 h
Yield: 37.5 %

Procedure:
Tricyclohexyl phosphine (16.6 μL, 0.02 mmol) was added to a mixture of 5-iodopyridazin-3(2H)-one (35 mg, 0.16 mmol), 4-(trifluoromethyl)phenylboronic acid (30 mg, 0.16 mmol), potassium phosphate tribasic (117 mg, 0.55 mmol), and palladium (II) acetate (3.5 mg, 0.02 mmol) in Toluene (0.8 mL) and Water (0.3 mL). The mixture was stirred at 100° C. for 22 hours. The reaction was diluted with CH2Cl2, filtered and concentrated. The crude was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 5-(4-(trifluoromethyl)phenyl)pyridazin-3(2H)-one 18A (14.8 mg, 0.06 mmol, 39.1% yield) as a white solid. LC/MS 282 (M+H)+, tR 0.77 min (method 5).
Reaction SMILES: O.O.[Sn](Cl)Cl.[I:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]>CN(C=O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:7]([I:6])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1I
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(N)ccc1I
Temperature: 50 °C
Reaction time: 1 h

Procedure:
15.1 g (67 mmol) of tin(II) chloride dihydrate are added to a solution of 4.9 g (16.8 mmol) of the compound from Example 3A in 200 ml of DMF. The reaction mixture is stirred at 50° C. for one hour, and then the DMF is removed in vacuo. The residue is partitioned between 1 l of ethyl acetate and water, the phases are separated, and the organic phase is discarded. The aqueous phase is basified with 10% strength sodium hydroxide solution and again extracted with 500 ml of ethyl acetate. The product is dried over magnesium sulfate, filtered with suction and concentrated in vacuo. 3.95 g (90% of theory) of the title compound are obtained and are reacted without further purification in the next stage.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([CH2:55][OH:56])=[N:40][C:41]=2[Sn](CCCC)(CCCC)CCCC)[CH:38]=1>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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[N:40]=[C:39]([CH2:55][OH:56])[N:37]5[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=45)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(CO)n2cc(F)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(CO)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) and (6-Fluoro-1-tributylstannanyl-imidazo[1,5-a]pyridin-3-yl)-methanol (crude from Step 5) were dissolved in DMF (2 ml The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.010 mmol) and copper (I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3 h then cooled to room temperature, quenched with water and extracted with dichloromethane (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-3% MeOH) to afford 83 mg (71%) of 2-(6-fluoro-3-hydroxymethyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light brown solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([N+:24]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH-].[Na+].C([O-])=O.[NH4+]>C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:24][C:19]1[CH:20]=[C:21]([O:22][CH3:23])[C:15]2[O:14][C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])=[CH:17][C:16]=2[CH:18]=1
Reactant: COc1cc([N+](=O)[O-])cc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cc(N)cc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12

Procedure:
Initially, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-methoxy-5-nitro-1-benzofuran-2-carboxamide hydrochloride (120 mg, 0.31 mmol) is converted into the free base. To this end, the compound is taken up in ethyl acetate, and 30% strength aqueous sodium hydroxide solution is added. The aqueous phase is extracted repeatedly with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is removed under reduced pressure. The free base is dissolved in 3 ml of methanol. 120 mg (1.84 mmol) of ammonium formate are added, and the mixture is heated under reflux for 4 h. The reaction mixture is filtered through Celite, and the filter cake is washed with ethanol and ethyl acetate. The crude product is subjected to fine purification on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol 10:1→dichloromethane/methanol/ammonia 80:20:2). An excess of 4N HCl in dioxane is added to the free base. The solvent is then removed under reduced pressure. 25 mg (17% of theory) of the title compound are isolated.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][S:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:40][CH2:41][S:42][C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: BrCCSc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 1.25 mL of an N,N-dimethylformamide solution containing 70 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 57 mg of potassium carbonate and 0.25 mL of N,N-dimethylformamide containing 47 mg of 2-(2-bromoethylthio)thiophene were added at room temperature, and stirred at 60°C. for 3 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1], to give 91 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a yellow oil.