Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[N:13](CC3C=CC(OC)=CC=3)[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: COc1ccc(Cn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Temperature: 80 °C
Yield: 78.5 %

Procedure:
2-[(6-Bromo-1,3-benzodioxol-5-yl)sulfanyl]-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine (999 mg, 2.05 mmol) was dissolved in TFA (8 mL) and the mixture was heated at 80° C. for 7 h. Upon completion of the reaction, the mixture was concentrated in vacuum and the residual TFA was azeotropically removed with toluene. The resulting residue was diluted with water and was adjusted to pH 7 by satd. NaHCO3. The product portion was extracted with EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuum. The residue was then triturated with EtOAc, filtered, washed with EA, and dried to afford the title compound (588 mg, 79%). Additional product (126 mg, 17%) was obtained by column (SiO2, MeOH/CH2Cl2, 0 to 10%) purification of the combined filtrates: 1H NMR (DMSO-d6) δ 7.53 (d, J=6.4 Hz, 1H), 7.39 (s, 1H), 7.16-7.08 (brs, 2H), 7.07 (s, 1H), 6.79 (d, J=6.4 Hz, 1H), 6.12 (s, 2H); LC-MS [M+H]+ 366.97.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH2:25][N:26](C)C(=O)OC(C)(C)C)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(#N)C.O1CCOCC1.O>[NH2:26][CH2:25][C:23]1[O:22][N:21]=[C:20]([C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:11])[CH:14]=2)[N:24]=1
Reactant: Cc1ccc(-c2noc(CN(C)C(=O)OC(C)(C)C)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2noc(CN)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of tert-butyl (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl(methyl)carbamate (F54) (90 mg, 0.195 mmol) in acetonitrile (1 mL) was added 4N HCl in dioxane (1 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 45 minutes. Then, the solvent was concentrated and the crude product was dried under high vacuum. The crude product N-(5-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (26) was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.46-9.44 (m, 1H), 8.74 (s, 2H), 8.63 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.86-7.80 (m, 2H), 7.59-7.54 (m, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.23-7.20 (m, 1H), 4.62 (s, 2H), 2.39 (s, 3H). MS m/z 349.4 (M+1)+.
Reaction SMILES: [Na].Cl.[Cl:3][CH2:4][C:5]1[N:9]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:8]=[N:7][CH:6]=1.[CH3:18][OH:19]>>[ClH:3].[CH3:18][O:19][CH2:4][C:5]1[N:9]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:8]=[N:7][CH:6]=1
Reactant: CO
Reactant: CC(c1ccccc1)n1cncc1CCl
Agent: Cl
Agent: [Na]
Product: COCc1cncn1C(C)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 1.38 parts of sodium in 40 parts of methanol were added 3.84 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride. Stirring was continued for one hour at reflux. The reaction mixture was evaporated. Water was added to the residue and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 4-methyl-2-pentanone. The salt was filtered off and dried, yielding 1.8 parts of 5-(methoxymethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride; mp. 166.3° C. (compound 8.37).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Na+]>CCO>[F:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][NH:8]2)=[CH:12][C:13]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C#CCCCO)c(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCCC#Cc1cc2cc[nH]c2cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 843.9 %

Procedure:
A solution of 950 mg (0.3 mmol) 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butyl ester in 20 ml EtOH was treated with 2 ml of saturated aqeous NaOH and stirred during 2 hours at 60° C. 75% of the solvent were evaporated, the resulting mixture was poured into 5 ml of water, acidified with 2M aqueous HCl, and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2 gave 550 mg (84%) of 5-(6-Fluoro-1H-indol-5-yl)-pent-4-yn-1-ol as a viscous light yellow oil, MS: 218 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](\[CH3:25])/[C:22]([OH:24])=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.O.Cl>CC(C)=O>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](\[CH3:25])/[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1.9 g of (E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 80 ml of acetone and 40 ml of water and 3 ml of concentrated hydrochloric acid was added, followed by stirring at 50° C. for 2 hours. After cooling to room temperature the reaction mixture was poured into water, and the resultant crystals were filtered and washed with hexane. 1.5 g of the titled compound was obtained as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]([C:14]([O:16]C)=[O:15])([CH:11]=[C:12]=[CH2:13])[CH2:3][CH2:4][C:5]([O:7]CC#C)=[O:6].[ClH:18]>>[ClH:18].[NH2:1][C:2]([C:14]([OH:16])=[O:15])([CH:11]=[C:12]=[CH2:13])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: C#CCOC(=O)CCC(N)(C=C=C)C(=O)OC
Agent: Cl
Product: C=C=CC(N)(CCC(=O)O)C(=O)O

Procedure:
The hydrolysis of propargyl 4-amino-4-carbomethoxyhepta-5,6-dienoate was carried out by dissolving 360 mg of the diester in 10% HCl and heating the solution to 65°-70° C. for about 22 hours. When cooled, the reaction mixture was placed directly on an ion-exchange column (BioRad Ag 50×8) washed with water, and eluted with a 1.7M ammonium hydroxide solution. The ammonium hydroxide fractions were pooled and concentrated to give the free acid of the title compound which was purified further by passing an aqueous solution of the pyrrolidone through a short column of RP-18 material. Upon concentration of the eluant, a residue was obtained which was taken in a dilute HCl solution of pH 3.2. On evaporation to dryness, the title compound was obtained.
Reaction SMILES: [C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[OH-].[Na+]>C(OCC)C>[C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCC=C(c1ccccc1)C1Cc2ccccc2C1
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCN(CC)CCC=C(c1ccccc1)C1Cc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of 29.5 g. of 1-phenyl-1-(2-indanyl)-4-chloro-1-butene in 125 cc. of 95 percent (v/v) ethanolbenzene (commercial 2B ethanol) was added 100 cc. of diethylamine in one portion. The reaction mixture was shaken and heated in a sealed bomb to about 100°C for 16 hours. The reaction mixture was cooled to about 25°C. and the solvent was removed under reduced pressure to afford the product as an oily residue. The oil was dissolved in 400 cc. of diethyl ether and shaken with 5N sodium hydroxide and washed with water. The ethereal solution was dried and the solvent was removed under reduced pressure, affording 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:8][CH:9]=1
Reactant: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(NC(=O)Cc2ccccc2)nc1

Procedure:
A solution of N-(5-nitropyridin-2-yl)-2-phenylacetamide (4.35 g, 16.9 mmol) in EtOH (75 mL) and EtOAc (75 mL) is stirred at rt and ammonium formate (4.27 g) and 10% Pd/C (500 mg) are added. The mixture is heated at reflux for 30 min, cooled, filtered through celite and evaporated to afford the title compound as an off-white solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][C:8]2[CH:34]=[CH:33][C:11]3[N:12]([C:15]4[CH:24]=[CH:23][C:22]5[C:17](=[C:18](OS(C(F)(F)F)(=O)=O)[CH:19]=[CH:20][CH:21]=5)[N:16]=4)[CH:13]=[N:14][C:10]=3[CH:9]=2)[CH2:5][O:4][CH2:3]1.[C:35]([O:39][C:40](=[O:48])[NH:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].ClC(Cl)C>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].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.C1(C)C=CC=CC=1>[C:35]([O:39][C:40](=[O:48])[NH:41][CH:42]1[CH2:47][CH2:46][N:45]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[C:15]([N:12]2[C:11]4[CH:33]=[CH:34][C:8]([O:7][CH2:6][C:2]5([CH3:1])[CH2:3][O:4][CH2:5]5)=[CH:9][C:10]=4[N:14]=[CH:13]2)[CH:24]=[CH:23]3)[CH2:44][CH2:43]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(OS(=O)(=O)C(F)(F)F)c3n2)COC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3n2)COC1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
BINAP (379 mg, 608 μmol, 0.06 equivalents), tris(dibenzylideneacetone)dipalladium (186 mg, 203 μmol, 0.02 equivalents) and toluene (35 mL, 7 volumes) were added to a 100 mL round bottom flask. The solution was deoxygenated and stirred at 20–25° C. for ˜30 minutes. Next, trifluoro-methanesulfonic acid 2-[5-(3-methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester (5 g, 10.1 mmol, 1 equivalent), piperidin-4-yl-carbamic acid tert-butyl ester (4.06 g, 20.3 mmol, 2.0 equivalents), and cesium carbonate (4.62 g, 14.2 mmol, 1.3 equivalents) were charged. The reaction was again deoxygenated and then heated to 85° C. for 24–32 hours. At reaction completion, the reaction was cooled to 30° C. and dichloroethane (5 volumes) and Celite (0.5 wt. equivalent) were added. The slurry was filtered through a pad of Celite and rinsed with dichloroethane (5 volumes). The mother liquor was then concentrated to low volume and ethyl acetate (75 mL, 15 volumes) was charged. The thin slurry was granulated at 20–25° C. for 8–15 h and then filtered. The mother liquor was collected and washed with a 2.5% NaH2PO4 solution (3×9 volumes). The organics were again concentrated to low volume and acetonitrile (25 mL, 5 volumes) was charged. The slurry was granulated for 10–20 hours, and then the solids were filtered and dried under vacuum at 40° C. with a slight nitrogen bleed to yield 4.33 g (1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. (79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([NH:17][S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)Nc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
A solution of N-(4-Bromophenyl)-2-amino-5-bromobenzamide (8.64 g, 23.3 mmol), 4-chlorobenzenesulfonyl chloride (4.98 g, 23.6 mmol), and 7.37 g (93.2 mmol) in 300 ml of CH2Cl2 was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The solution was washed twice with 10% HCl, water, 5% NaHCO3, water, and dried over MgSO4. Concentration and recrystallization from 10% EtOAc in hexane gave product which had satisfactory NMR, MS, and elemental analysis.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:31])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[S:8][C:7]=2[CH:40]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:31])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:8][C:7]=2[CH:40]=1
Reactant: CCCCCCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CCCCCCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)CC1
Yield: 41.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-hexylpiperidin-4-oxy]benzoyl)benzo[b]thiophene (375 mg, 0.941 mmol), ethane thiol (3.36 mmol), and aluminum chloride (538 mg, 4.04 mmol) were converted to 209 mg (42%) of the title compound by the procedure of Example 16. MS(FD) 529(M+). EA calculated for C32H35NO4S: C, 72.56; H, 6.66; N, 2.64. Found: C, 72.33; H, 6.89; N, 2.52.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:43])[CH:24]([NH:35]C(OC(C)(C)C)=O)[CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)[N:16]=[C:15]([NH2:44])[N:14]=2)[C:10]([CH3:45])=[CH:9][C:8]=1[CH3:46])([CH3:4])([CH3:3])[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[C:1]([O:5][C:6](=[O:47])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:43])[CH:24]([NH2:35])[CH2:25][CH2:26][NH2:27])[N:16]=[C:15]([NH2:44])[N:14]=2)[C:10]([CH3:45])=[CH:9][C:8]=1[CH3:46])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)c(-c2cc(SCCNC(=O)C(CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)nc(N)n2)cc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(-c2cc(SCCNC(=O)C(N)CCN)nc(N)n2)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-{2-Amino-6-[2-(2,4-bis-tert-butoxycarbonylaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid tert-butyl ester obtained in Step 2 above was dissolved in dichloromethane (37 ml). After the solution was cooled to 0° C., trifluoroacetic acid (13 ml) was added thereto. The reaction solution was gradually warmed to room temperature, and then stirred at room temperature for six hours. After the solvent was distilled off under reduced pressure, dichloromethane (10 ml) was added to the residue and again concentrated under reduced pressure. The resulting residue was suspended in ethyl acetate (60 ml). After the suspension was stirred at room temperature for two hours, the insoluble material was collected by filtration. The obtained solid was dried under reduced pressure to yield 5-{2-amino-6-[2-(2,4-diaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid tert-butyl ester tri(trifluoroacetate) (3.6 g) as a white solid material.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>>[O:1]([CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CSCCCOc2ccccc2)S1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCC1(CCC(=O)O)OCC(CSCCCOc2ccccc2)S1

Procedure:
The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 6 (2.44 g, 0.0052 mol) and aqueous lithium hydroxide solution (2 M, 9 ml). The product, 1.86 g (82%), was obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[NH2:24][C:25]1[CH:30]=[C:29]([OH:31])[C:28]([CH3:32])=[CH:27][CH:26]=1.Cl.N1C=CC=CC=1>C(OC(O)C)C>[OH:31][C:29]1[CH:30]=[C:25]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]=3)[N:5]=[CH:4][C:3]=2[C:22]#[N:23])[CH:26]=[CH:27][C:28]=1[CH3:32]
Reactant: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1Cl
Reactant: Cc1ccc(N)cc1O
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(Nc2c(C#N)cnc3ccc(OCCCN4CCOCC4)nc23)cc1O

Procedure:
A mixture of 4-chloro-6-(3-morpholin-4-yl-propoxy)-[1.5]naphthyridine-3-carbonitrile (400 mg, 1.202 mmol), 5-amino cresol (222 mg, 1.8 mmol) and pyridine HCl salt (208 mg, 1.8 mmol) in ethoxyethanol (20 ml) was heated at reflux for 6 hrs under argon. After cooling, the solvent was removed by rotary evaporation. The residue was dissolved in ethyl acetate and treated with sat NaHCO3. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed (sat NaHCO3 aq sol, brine), dried (Na2SO4), and concentrated. The residue was triturated with CH2Cl2, and ether and hexane were added to form a solid. The yellow solid was collected (200 mg, 40%) and dried. mass spectrum (electrospray, m/e): 420 (M+H); IR cm-1: 3322, 2226, 1628.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:12]2[N:8]([C:9]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]1([CH3:35])[CH3:34])(=O)C.[OH-].[K+].O.Cl>CO>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:12]3[N:8]([CH2:7][C:6]([CH3:34])([CH3:35])[CH:5]3[O:4][CH3:1])[C:9]=2[CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: CC(=O)OC1c2c(-c3ccccc3)c(-c3ccc(Cl)cc3)c(CC(=O)OC(C)(C)C)n2CC1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1c2c(-c3ccccc3)c(-c3ccc(Cl)cc3)c(CC(=O)O)n2CC1(C)C

Procedure:
tert-Butyl 1-acetoxy-6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-ylacetate (example 9c, 1.00 g, 2.0 mmol) is dissolved in 10 ml of MeOH. 0.5 g of KOH is added and the mixture is heated under reflux until the intermediately formed precipitate has dissolved. It is then allowed to cool and is stirred into 600 ml of water. The cloudy solution is brought to pH 3 using conc. HCl. It is extracted three times using 100 ml of diethyl ether each time. The ether extracts are washed twice with water and dried over Na2SO4, filtered and concentrated in a rotary evaporator. A mixture of 6-(4-chlorophenyl)-2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-ylacetic acid and 2-[6-(4-chlorophenyl)-2,3-dihydro-1-methoxy-2,2-dimethyl -7-phenyl-1H-pyrrolizin-5-yl]acetic acid is obtained (cf. example 16).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>O>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:5]([NH:4][CH2:3][CH2:2][NH:1][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NCCN)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: O
Product: COc1ccc(NCCNc2ccc([N+](=O)[O-])cc2)cc1
Yield: 278.4 %

Procedure:
A mixture containing 0.1 mole (223 g) of N- β-aminoethyl paraanisidine and 0.447 mole (70.6 g) of parachloronitrobenzene is heated for 5 hours at 120°. After cooling the reaction mixture is poured into a liter of water and drying yields a crude product. This product after recrystallization in chlorobenzene, produces 80 g of N- [(4-methoxy) phenyl] - N'[4-nitro phenyl] ethylene diamine, which melts at 150°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1([CH2:39][NH2:40])[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1>>[F:1][C:2]1[C:3]([C:22]([NH:40][CH2:39][C:32]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CN1CCC(CN)(c2ccccc2F)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5F)CCN(C)CC4)c3F)s2)c1

Procedure:
The compound was prepared following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and (4-(2-fluorophenyl)-1-methylpiperidin-4-yl)methanamine (amine intermediate “Z”) were reacted to give the title compound. LC/MS (M+H)+: 567. Ret. time: 1.45 min. (Condition G); analytical HPLC Ret. time: 5.83 min (Condition H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1F
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(3,4-Difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.104) (0.25 g, 0.67 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.28 g, 0.81 mmol) according to the general procedure VI. Obtained as light yellow solid (0.29 g), which was subsequently deprotected.