Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].O1CCCC1>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3c2c1COC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc(N)cc4)c3c2c1COC

Procedure:
15 g of 5-(4-nitrophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is hydrogenated in 450 ml of methanol: tetrahydrofuran=1:1 with 7.5 g of palladium on carbon (10%) at room temperature under hydrogen normal pressure. After filtering and concentrating, it is recrystallized from ethanol and 10.8 g (77% of theory) of 5-(4-aminophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester of a melting point of 222°-224° C. is obtained.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH:11]1([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([C:14]([CH:16]2[CH2:18][CH2:17]2)([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[OH:15])[CH2:13][CH2:12]1
Reactant: c1cscn1
Reactant: O=C(C1CC1)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1nccs1)(C1CC1)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.953 mL, 2.38 mmol) was added to a stirred, cooled −78° C. mixture of thiazole (0.169 mL, 2.383 mmol) in THF (5.0 mL) and the mixture was stirred at −78° C. for 15 min. A solution of the dicyclopropylmethanone (250 mg, 2.27 mmol) in THF (3.0 mL) was added dropwise and the mixture was stirred 30 min at −78° C. and then the temperature was allowed to reach room temperature. The reaction was quenched by addition of water and the mixture was extracted with ethyl acetate (3×). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give dicyclopropyl(1,3-thiazol-2-yl)methanol (412 mg, 2.110 mmol, 93% yield). MS APCI: [M-OH]+ m/z 179.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24]Br>CC(N(C)C)=O.C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH2:24][CH2:23][CH:22]([O:26][CH3:27])[O:21][CH3:20])[C:13]1=[O:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(CCBr)OC
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COC(CCN1CCN(CCCO[Si](C)(C)C(C)(C)C)C1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
1-[3-(tert-Butyldimethylsilanyloxy)propyl]imidazolidin-2-one (17.65 g, 68.30 mmol; prepared as described in Preparation 1) was slowly added to a suspension of NaH (8.20 g, 204.9 mmol, 3.0 eq, 40% mineral oil) in DMA (400 mL). Deprotonation was monitored with a bubbler, and bubbling was ceased after one hour of stirring at room temperature. A solution of 3-bromopropionaldehyde dimethyl acetal (25.0 g, 136.6 mmol, 2.0 eq) in DMA (100 mL) was slowly added to the reaction mixture over a period of 2 hours via an addition funnel. Following an additional hour of stirring at room temperature, the solution was concentrated in vacuo and the crude reaction mixture was taken up in DCM (200 mL) and washed with water (2×200 mL) and brine (2×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to afford the title compound (24.53 g, 68.8 mmol) as light yellow oil. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14]COC)[C:6]([CH3:13])=[C:7]([O:9]COC)[CH:8]=1.Cl.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6]([CH3:13])=[C:7]([OH:9])[CH:8]=1
Reactant: COCOc1cc(OC)cc(OCOC)c1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(O)c(C)c(O)c1
Yield: 88.3 %

Procedure:
A solution of 9 (314 mg, 1.30 mmol) in MeOH (10.8 mL) at room temperature was treated dropwise with 3 M HCl (3.46 mL, 10.3 mmol), then heated to reflux for 1 hour. Water (11 mL) was added and the solution was extracted with EtOAc (3×15 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 10 as a red amorphous solid (177 mg, 99%): 1H NMR (CDCl3, 500 MHz) 8.17 (s, 1H), 6.09 (d, J=1.6 Hz, 1H), 6.04 (s, 1H), 3.67 (d, J=9.9 Hz, 3H), 2.08 (d, J=4.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) 60.3, 157.8, 155.4, 108.4, 93.9, 93.8, 55.0, 7.0; IR (film) νmax 3445, 2924, 2853, 2359, 2332, 1653, 1636, 1456, 1080, 1022, 798, 669 cm−1; HRMS (ESI+) m/z: [2M+H]+ calcd for C8H10O3, 309.1338 found, 309.1332.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([NH2:14])[CH:3]=1.[C:15](=S)=[S:16].[OH-].[K+].C>C(O)C.O>[F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][C:5]2[N:13]=[C:15]([SH:16])[NH:14][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(-n2ccnc2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc2[nH]c(S)nc2cc1-n1ccnc1

Procedure:
The diamine (6.7 g, 0.035 mol) (obtained in step 4 above) was dissolved in ethanol (20 mL) and added to a stirred mixture of carbon disulfide (3.0 g, 0.04 mol), potassium hydroxide (2.3 g, 0.04 mol), water (5 mL) and ethanol (15 mL). The resultant solution was refluxed for 6 h. Animal charcoal (2.0 g) was added and further refluxed for 1 h. The mixture was filtered and washed with hot water. A mixture of acetic acid and water (1:2, 15 mL) was added to the filtrate slowly with vigorous stirring to separate 6-fluoro-5-(imidazol-1-yl)-2-mercapto-1H-benzimidazole (5.0 g, 60%) as a brown solid. mp 280° C. (decomp.); IR (KBr) 3078, 1481 cm-1 ; 1H NMR (DMSO-d6) δ 2.20 (s, 1H, SH), 7.10 (s, 1H), 7.24 (d, J=6.0 Hz, 1H), 7.26 (d, J=4.1 Hz, 1H), 7.56 (s, 1H), 8.00 (s, 1H), 12.90 (brs, 1H, NH); Mass (m/z) 234 (M+.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[CH2:21]([C:23]1[NH:27][C:26]([C:28](O)=[O:29])=[N:25][C:24]=1[C:31]([F:34])([F:33])[F:32])[CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:21]([C:23]1[NH:27][C:26]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:29])=[N:25][C:24]=1[C:31]([F:33])([F:34])[F:32])[CH3:22]
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Reactant: CCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(C(F)(F)F)c(CC)[nH]3)[C@H](OC)C2)sc1C

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (40e) (44.9 mg, 0.15 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (29 mg, 0.14 mmol), WSC hydrochloride (80 mg, 0.42 mmol) and HOBT (20 mg, 0.15 mmol), to obtain 29.2 mg of the title compound as a colorless oily substance (43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O

Procedure:
A solution of N-t-Butoxycarbonyl-4-piperidone (10.0 g, 50.19 mmol) and N,N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in 1,4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8% MeOH in EtOAc) to obtain the title compound as an orange oil which crystallized on standing (7.64 g, 60%).
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1>C(O)C.C1(C)C=CC=CC=1>[Cl:1][CH2:4][CH2:3][CH2:2][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6]
Reactant: Cl
Reactant: COC(=O)C(Cc1ccc(C(=O)C2CC2)cc1)C(=O)OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OC
Temperature: 68 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Bubble hydrogen chloride gas through a solution of [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dimethyl ester (315 mg, 1.1 mmol) in ethanol (3 mL) and toluene (9 mL) for 10 minutes. Heat the solution to 68° C. After 4 hours, cool the solution to room temperature and bubble nitrogen through the solution for 1 hour. Add ethyl acetate and water to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate to give the title compound (321 mg, 91%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:32]([O:34]CC4C=CC=CC=4)=[O:33])[CH:26]=[CH:25]5)[CH:14]=[CH:15][C:16]=3[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>O1CCOCC1.[Pd]>[C:1]12([C:11]3[CH:12]=[C:13]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]5)[CH:14]=[CH:15][C:16]=3[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(OCc1ccccc1)c1ccc2cc(-c3ccc(CC(O)CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2cc(-c3ccc(CC(O)CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 5 h

Procedure:
4 g (7.32 mmol) of the ester obtained in Example 46, in solution in 100 ml of dioxane, are hydrogenated in the presence of 1.20 g of palladium on carbon (10%) under a hydrogen pressure of 7 bar, for 5 h at 50° C. After the same treatment as in Example 5, followed by a recrystallization from the ethanol/water mixture, 3 g (90%) of the expected derivative are isolated, which derivative melts at 258° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: OCCOCCCl
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Yield: 44.5 %

Procedure:
The O-alkylation procedure described for 10 (Example 5, step 2) was followed using 9 (339 mg, 1 mmol), K2CO3 (414 mg, 3 mmol), 2-[(2-chloroethyl)oxy]ethanol (0.63 mL, 6 mmol), and acetone (30 mL). The reaction mixture was refluxed for 60 h. The reaction mixture was filtered, concentrated, and purified by column chromatography to give 190 mg (45%) of the title product 24 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.16-7.13 (m, 2H), 7.11-7.07 (m, 2H), 7.0 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.59 (t, J=5.2 Hz, 2H), 4.03 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.4 Hz, 2H), 3.49-3.44 (m, 4H), 1.90 (s, 2H), 1.86 (s, 2H), 1.24 (s, 2H), 0.87 (s, 6H), 0.87 (s, 6H). LCMS (APCI): m/z 427 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][O-:24].[Na+]>C(O)CCCC>[NH2:1][C:2]1[N:10]=[C:9]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCCCC[O-]
Agent: [Na+]
Solvent: CCCCCO
Product: CCCCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 130 °C
Yield: 57 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (150 mg, 0.58 mmol) and sodium pentylate (318 mg, 2.89 mmol) were dissolved in 1-pentanol (50 ml) and then the solution was stirred under heating at 130° C. for 5 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (103 mg, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11](N)=[O:12])=[CH:7][S:8][CH:9]=1.[OH2:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11]([OH:19])=[O:12])=[CH:7][S:8][CH:9]=1
Reactant: O
Reactant: NC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
30.1 g (0.1 mole) of 4-(2,6-dichloroanilino)-3-thiophenacetamide are warmed to 100° in 135 ml of concentrated sulfuric acid and 49 ml of water for 3 hours. The mixture is poured onto ice, and the precipitate of 4-(2,6-dichloroanilino)-3-thiophenacetic acid which has formed in filtered off. The precipitate is boiled up with diisopropyl ether and dried; it then melts at 179° to 180°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13](O)=[O:14])=[CH:4][C:3]=1[O:16][CH3:17].C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([N:39]=[N+:40]=[N-:41])=[O:14])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(-c2ccsc2C(=O)O)ccc1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(-c2ccsc2C(=O)N=[N+]=[N-])ccc1Br
Reaction time: 20 h

Procedure:
A stirred solution of 3-(4-bromo-3-methoxyphenyl)thiophene-2-carboxylic acid (2.23 g, 7.13 mmol) in benzene (28.5 mL) was treated with triethylamine (1.39 ml, 9.98 mmol) and diphenylphosphoryl azide (1.96 g, 7.13 mmol). The mixture was stirred for 20 h, then the volatiles were removed ant the residue was purified by column chromatography on silica gel (eluent: toluene) to afford the title (1.63 g, 68%). LCMS (ES+) m/z 310, 312 (M+H−N2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[F:22][C:23]([F:30])([F:29])[C:24]([NH:21][CH2:20][CH2:19][NH:18][CH:15]1[CH2:16][CH2:17][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14]1)=[O:25]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2nccc(N3CCC(NCCN)C3)c2n1
Solvent: C1CCOC1
Product: COc1ccc2nccc(N3CCC(NCCNC(=O)C(F)(F)F)C3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of N1-[1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl]-ethane-1,2-diamine (1.3 g, 4.53 mmol) in THF (50 mL) at 0° C. was slowly added ethyl trifluoroacetate (1.19 mL, 4.53 mmol). The solution was stirred for 1.5 h and concentrated. The resulting solid was used without further purification (1.73 g, quantitive): LC/MS m/z 384 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[F-:13].[K+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([F:13])(=[O:11])=[O:10]
Reactant: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Br)c(S(=O)(=O)F)c1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
32 g of 2-bromo-5-methylbenzenesulfonyl chloride are dissolved in 75 ml of dioxane, and a solution of 20.6 g of KF in 20 ml of water is added. The mixture is stirred at 45° C. for 48 h, poured into 500 ml of water and stirred subsequently for 30 min, and finally the product is filtered off with suction. 24 g of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:13]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 3-(4-tert-butoxycarbonylaminophenyl)propanol (2.66 g, 10.6 mmol), methanesulfonylchloride (1.33 g, 11.6 mmol), triethylamine (1.18 g, 11.7 mmol) and ethyl acetate (10 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with hexane-ethyl acetate (3:1) to give 3-(4-tert-butoxycarbonylaminophenyl)propyl methanesulfonate as colorless crystals (2.75 g, 79%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[C:10]([NH:19][CH2:20][CH2:21][CH3:22])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([S:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]1[N:19]([CH2:20][CH2:21][CH3:22])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1)[CH3:2]
Reactant: CCCNc1ncc(C(F)(F)F)cc1NC(=O)c1ccccc1SCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCn1c(-c2ccccc2SCC)nc2cc(C(F)(F)F)cnc21
Temperature: 160 °C
Yield: 77.1 %

Procedure:
A mixture of 2-ethylsulfanyl-N-(2-propylamino-5-trifluoromethyl-pyridin-3-yl)-benzamide (710 mg), p-toluenesulfonic acid monohydrate (1.1 g), and xylene (10 ml) was stirred with heating at 160° C. for 10 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 522 mg of 2-(2-ethylsulfanylphenyl)-3-propyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 24).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:12]/[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)=[O:13]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(S(C)(=O)=O)cc1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield from 1-[4-(methylsulfonyl)phenyl]ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.96 (3H, s), 3.06 (3H, s), 3.19 (3H, s), 5.66 (1H, d, J=12 Hz), 7.83 (1H, d, J=12 Hz), 7.96-8.04 (4H, m).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][N:9]([CH:11](OC)OC)[CH3:10]>CN(C=O)C>[CH3:8][N:9]([CH3:11])/[CH:10]=[CH:1]/[C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCCCC(=O)/C=C/N(C)C
Yield: 19.3 %

Procedure:
A solution of 2-hexanone (2.0 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EtOAc=4:1-2:1) to give the title compound (0.6 g, 19%) as yellow oil.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1)=O.[N+]([O-])(O)=O.[F:19][C:20]([F:35])([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1)[CH:21]([F:23])[F:22].[OH-].[Na+]>CC(O)C>[F:19][C:20]([F:35])([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[N:34]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=3)[CH:4]=[CH:3][N:33]=2)[CH:28]=[CH:29][CH:30]=1)[CH:21]([F:22])[F:23]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)nc1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc(Cl)nc3)n2)c1
Temperature: 25 °C

Procedure:
9.22 g (43.8 mmol)of 3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is suspended in 88 ml of 2-propanol. 11 g (43.8 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate and 1.93 g (48.4 mmol) of sodium hydroxide are added and the reaction mixture is boiled under reflux for 19 h. After cooling to RT, the product is isolated by filtration, washed with 2-propanol and water and dried at 50° under HV. N[3(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-5-pyridyl)-2-pyrimidineamine is obtained; FAB-MS: 399 (M+ +H), m.p. 182°-184°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([OH:28])([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(C)(O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15 mg, 49.7%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-hydroxy-3-methylbutanoic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][OH:17])[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].O[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCO)C2=O
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-4-(2-hydroxyethyl)-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, from Example 86, Part B, (24 mg, 0.064 mmol) in 1 mL of toluene was added 3-hydroxypyridine (9 mg, 0.096 mmol), triphenylphosphine (20 mg, 0.077 mmol) and diethylazodicarboxylate (0.035 mL, 0.077 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:2 to 1:2 hexane/ethyl acetate) to afford 20 mg of the title compound which was contaminated with a small amount of triphenylphosphine oxide. LRMS (ESI): 452.3 (M+H)+.