Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30]
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(F)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2cc(F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 85.4 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-5-fluoro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (93.7 mg, 0.220 mmol) was dissolved in acetonitrile (6.6 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (115 mg, 0.880 mmol), acetic acid (0.252 mL, 4.40 mmol) and sodium triacetoxyborohydride (163 mg, 0.77 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-5-fluoro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (102 mg, yield 85%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:13][CH:14]=[CH:15][CH:16]=1.N.CC(C)([O-])C.[K+].Cl[C:39]1[C:40]([N:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@H:46]2[CH3:58])=[N:41][CH:42]=[CH:43][N:44]=1>CC(O)=O.[Cl-].[Na+].O.O.[Cl-].[Na+].O.C(#N)C>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][C:12]1[C:11]([O:10][CH2:9][CH2:8][O:7][C:39]2[C:40]([N:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@H:46]3[CH3:58])=[N:41][CH:42]=[CH:43][N:44]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Reactant: CC(C)(C)OC(=O)NCCOCCOc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: N
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCCOc1cccnc1OCCOCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 40.9 %

Procedure:
tert-Butyl {2-[2-({3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}oxy)ethoxy]ethyl}carbamate (from Step 1; 0.74 g, 1.7 mmol) was suspended in 2 M HOAc (5 mL) and acetonitrile (1 mL) and heated at 50° C. for two days. The solution was neutralized with concentrated aqueous ammonia. Brine was added (3 mL) and the mixture was extracted with CHCl3 (×3). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The remaining oil was dissolved in dry DMSO (10 mL), potassium tert-butoxide (0.36 g, 3.2 mmol) was added followed by tert-butyl (3R)-4-(3-chloropyrazin-2-yl)-3-methylpiperazine-1-carboxylate (from Example 5; 0.59 g, 1.9 mmol) and the mixture was heated at 50° C. for 20 minutes. The reaction mixture was diluted with water/brine (90:10) and extracted with CHCl3 (×3). The combined organic phases were dried (MgSO4), the solvent was removed under reduced pressure and the remaining oil was chromatographed on a column of silica with hexane/EtOAc (70:30) as eluent to give 0.43 g (40%) of the title compound as a colorless oil. LC-UV purity: system (A) 100%. HRMS m/z calcd for C30H46N6O8 (M)+ 618.3377. found 618.3381. Step 3: {2-[2-({3-[2-({3-[(2R)-2-Methylpiperazin-1-yl]pyrazin-2-yl}oxy)ethoxy]pyridin-2-yl}oxy)ethoxy]ethyl}amine, bis(trifluoroacetate).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1Cl

Procedure:
Prepared according to Procedure G by stirring 2,4-dichloro-3-methyl-1,8-naphthyridine (0.4 g, 1.877 mmol), 3,5-difluorophenylboronic acid (0.445 g, 2.82 mmol), tetrakis(triphenylphosphine)palladium (0) (0.217 g, 0.188 mmol), potassium carbonate (0.519 g, 3.75 mmol), and toluene (6 mL) at 95° C. under nitrogen for 18 h. Purification by column chromatography (silica; 0-25% EtOAc in hexanes) afforded 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,8-naphthyridine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C[O-].[Na+].[Na].[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1.C>C1(C)C=CC=CC=1.CCCCCC.CS(C)=O.CO>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)C(=O)Nc1ccc(Oc2ccc(Cl)nn2)cc1
Reaction time: 1 h

Procedure:
4-Hydroxyphenyl-N,N-dimethylurea (13.5 grams; 0.075 mole) was mixed with a solution of sodium methylate (1.73 grams; 0.075 mole sodium metal in 70 milliliters (ml) of methanol) and the resulting sodium salt solution of 4-hydroxyphenyl-N,N-dimethylurea was added portionwise over a period of about one hour to a solution of 3,6-dichloropyridazine (11.2 grams; 0.075 mole) in 50 ml. of dimethylsulfoxide. During the addition and for a period of about one hour following the completion of the addition, the reaction mixture temperature was maintained between about 90° and about 95°C. Following the reaction period, the methanol was removed from the reaction mixture by evaporation and the reaction mixture extracted with methylene chloride. The methylene chloride extract was evaporated in vacuo and the waxy residue obtained dissolved in hot toluene. The resulting solution was treated with activated charcoal, cooled and hexane added thereto. The solid yellow crystalline material formed upon addition of the hexane was recovered by filtration and recrystallized from acetonitrile. As a result of these operations, the desired title compound was obtained as a white crystalline material having a melting point of 173°-174°C.
Reaction SMILES: ClC1C=CC=CC=1C1C=CC(C(=O)C)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH3:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.S(=O)(=O)(O)O.[H][H]>C1C=CC=CC=1>[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1)[CH3:31]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: CC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 7 h

Procedure:
The procedure of Example 3 was repeated, except that the 4'-(2-chlorophenyl)acetophenone was replaced with an equal amount of 4'-(4-chlorophenyl)acetophenone, the amount of benzene employed was increased to 200 ml., and the amount of sulfuric acid was reduced to 5 drops. After 7 hours, hydrogen pressure had dropped to 35.5 psig. Evaporation of the benzene left a solid which, according to nuclear magnetic resonance analysis, contained only about 67 percent of the desired ethylbenzene. Consequently, the solid was subjected to the hydrogenation procedure again, using 200 ml. of benzene, 2 g. of catalyst, and 1 ml. of concentrated sulfuric acid. The solid obtained upon evaporation of the benzene was recrystallized from hexane, giving 1-ethyl-4-(4-chlorophenyl)benzene, mp 103° -104°. The following elemental analysis was obtained:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:13][CH2:14][CH2:15]2)[C:5]([O:10][CH3:11])=[C:6]([CH:16]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[CH:9]=1
Reactant: COc1c(C=O)cc(Br)cc1C1CCC1
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(C2CCC2)c1OC

Procedure:
5-bromo-3-cyclobutyl-2-methoxybenzaldehyde (1.15 g) was dissolved in n-hexane (5 mL) and triethyl orthoformate (0.93 mL), and Amberlyst-15 (115 mg) was added to the solution, and then the mixture was refluxed for 3 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.33 g) as a yellow oily substance.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([OH:18])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([O:18][CH3:33])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(OC)CCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Racemic ethyl 1-(biphenyl-4-ylmethyl)-5-hydroxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Example 17, 174 mg, 0.431 mmol) was dissolved in degassed N,N-dimethylformamide (2 mL), cooled to 0° C. under an atmosphere of nitrogen and treated with sodium hydride (19 mg, 0.47 mmol, 60% dispersion in mineral oil, 1.1 equiv) and then methyl iodide (0.096 mL, 1.55 mmol, 3.6 equiv). After stirring for 15 min, the mixture was warmed to ambient temperature and stirred for an additional 1 hr. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo to provide racemic ethyl 1-(biphenyl-4-ylmethyl)-5-methoxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N(CC(C)C)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and isobutyraldehyde (1.09 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added. The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.522 g, 7.50 mmol) was then added at 0° C. and the reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and crude product purified by column chromatography to afford methyl 5-bromo-3-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.52 g, 54.33%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:23]=1[NH2:24])[CH3:21]>>[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:23]=1[NH:24][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])[CH3:21]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2ccc(C)cc21
Yield: 66.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.47 g of Compound A and 0.78 g of 2,6-diethylaniline in place of aniline to obtain 1.34 g of Compound 3.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:30])[NH:23][C:24]3[C:29]\2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:30])[NH:23][C:24]3[C:29]\2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 8 from (Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone and sodium hydroxide solution in ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:9]=2[CH:10]=1
Reactant: IC1CCCC1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ice-cooled methyl 6-bromo-1H-indazole-4-carboxylate (2 g, 7.84 mmol) in 30 mL of DMF was treated with NaH (60%, 345 mg, 8.63 mmol) and the mixture was stirred for 1 hr at 0° C. Iodocyclopentane (2.31 g, 11.8 mmol) was then added and the mixture was stirred at 100° C. overnight. After cooling to RT, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated. Hexanes was added to the brown oil and it was purified using silica gel chromatography (eluent: Hex/EtOAc, gradient 0 to 25%). The less polar product was evaporated to give an orange oil, and was dried on hivac overnight. The product was confirmed to be the alkylated 1-isomer as suggested by 2D H NMR, and was collected as 807 mg (32%). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H) 8.37 (s, 1H) 7.81 (d, J=1.52 Hz, 1H) 5.26 (quin, J=7.07 Hz, 1H) 3.95 (s, 3H) 2.08-2.17 (m, 2H) 1.93-2.01 (m, 2H) 1.82-1.92 (m, 2H) 1.64-1.73 (m, 2H); LCMS (ES+): m/z=323.3/325.3
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1)[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]=[C:1]=[S:3])[CH2:23][CH2:24]1)[CH3:5]
Reactant: CCOCCn1c(CN2CCN(CCN)CC2)nc2cccnc21
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCN=C=S)CC2)nc2cccnc21
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 18 parts of carbon disulfide, 7.22 parts of N,N'-methanetetraylbis[cyclohexanamine] and 135 parts of tetrahydrofuran was added dropwise a solution of 12.9 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineethanamine in tetrahydrofuran. Upon complete addition, the temperature was allowed to reach room temperature. After stirring for 1 hour at room temperature, the mixture was evaporated, yielding 13.1 parts (100%) of 3-(2-ethoxyethyl)-2-[[4(2-isothiocyanatoethyl)-1-piperazinyl]methyl]-3H-imidazo[4,5-b]pyridine as a residue (compound 121)
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:5][CH:4]=1)N.[CH3:17][CH:18]([CH3:22])[C:19](=O)[CH3:20].CC([O-])=O.[Na+].CCOCC>CC(O)=O.C(Cl)Cl>[CH3:20][C:19]1[C:18]([CH3:22])([CH3:17])[C:4]2[C:3](=[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]3=[C:6]([S:13]([OH:16])(=[O:15])=[O:14])[CH:5]=2)[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1ccc(S(=O)(=O)O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=Nc2c(cc(S(=O)(=O)O)c3ccccc23)C1(C)C
Temperature: 110 °C
Reaction time: 3.5 h

Procedure:
A solution of sodium 4-aminonaphthalene-1-sulfonate (2.45 g, 10 mmol) in H2O (15 mL) was added a solution of NaNO2 (0.70 g, 10 mmol) in H2O (2 mL) at 10-15° C. The solution was then added to a cold solution of conc. H2SO4 (0.54 g, 5.5 mmol) in 0.5 mL of H2O. The temperature was maintained below 10° C. and the mixture was stirred for 1.5 h after the addition was complete. The mixture was then added dropwise to a cold solution of SnCl2 (3.8 g, 17 mmol) in 2.5 mL of conc. HCl and 1.5 ml of H2O. The reaction temperature was kept below 10° C. and allowed to sit onemoght. It was filtered and washed thoroughly with H2O. The cake was removed twice from the Buchner funnel and suspended in H2O and filtered. The solid obtained was dried under vacuum to give 1.4 g of 4-hydrazinylnaphthalene-1-sulfonic acid (59%). The material was used directly for next step. A solution of 4-hydrazinylnaphthalene-1-sulfonic acid (0.7 g, 2.9 mmol) in 3 ml of HOAc was added 3-methylbutan-2-one (0.5 ml, 1.5 eq), NaOAc (0.47 g, 2.0 eq.). The mixture was stirred at 110° C. for 3.5 h. After cooling and addition of ether, the precipitate was filtered to give 700 mg. The solid was dissolved in DCM and purified by flash chromatography on SiO2 using 10% MeOH in DCM to give 273 mg of product. The mother liquor was concentrated and was also purified by flash chromatography on silica gel to give additional 372 mg of product. The overall yield was 77%. 1H NMR (DMSO) δppm: 8.8 (dd, 1H), 8.4 (dd, 1H), 8.0 (s, 1H), 7.5 (m, 2H), 3.1 (s, 5H), 2.3 (s, 4H), 1.3 (s, 6H). LC-MS: 288.2 [M−H].
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: [Cl-]
Solvent: O
Solvent: COC(C)(C)C
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether was treated within 10 minutes with 9.7 g of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred for a further 1 hour. The mixture was then treated dropwise within 15 minutes at -10° C. with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 1 hour at 0° C. The reaction mixture was subsequently poured into 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The resulting, viscous oil was dissolved in 20 ml of ethyl acetate and the clear solution was diluted with 300 ml of petroleum ether and left to stand for 10 minutes at -20° C. The precipitated triphenylphosphine oxide was subsequently filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as colourless crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.32.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C@@H:7]([CH3:21])[CH2:6][C@H:5]2[N:22]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:23](=[O:26])[CH2:24][CH3:25].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([N:22]([C@H:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([N:86]4[CH2:91][CH2:90][O:89][CH2:88][CH2:87]4)[CH:3]=3)[N:8]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C@@H:7]([CH3:21])[CH2:6]2)[C:23](=[O:26])[CH2:24][CH3:25])=[CH:32][CH:31]=1
Reactant: C1COCCN1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N3CCOCC3)cc21
Temperature: 90 °C

Procedure:
(±)-Cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide was dissolved in toluene, followed by Pd2(dba)3, BINAP, sodium tert-butoxide, and morpholine. The reaction mixture was heated to 90° C. for 24 hours. The reaction mixture was cooled to room temperature and filtered through Celite® and concentrated. Crude mixture was purified by flash chromatography on silica gel using a gradient elution of hexane-ethylacetate (10–50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][C:10]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([F:1])[CH:7]=1)=[O:12]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1F
Yield: 87.9 %

Procedure:
A mixture of 26 grams (206 millimoles) of ortho-fluoroanisole and 19.4 grams (247 millimoles) of acetyl chloride was dissolved in 200 milliliters of methylene chloride, and then 33.0 grams (247 millimoles) of anhydrous aluminum chloride was gradually added thereto while cooling with ice and stirring. The resulting mixture was further stirred for 1.5 hours while cooling with ice. The reaction mixture was added to 1,200 milliliters of 5% hydrochloric acid, which was then allowed to separate into aqueous and organic layers. The organic layer thus obtained was washed with a 5% aqueous solution of sodium carbonate and dried over anhydrous sodium sulfate and, thereafter, the methylene chloride was distilled away under reduced pressure, and the residue was recrystallized from ethanol. Thus, as a product, 30.4 grams (181 millimoles) of 3-fluoro-4-methoxyacetophenone was obtained (yield, 88%).