Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>C(#N)C>[Br:19][C:12]1[C:13]([NH:15][CH2:16][C:17]#[CH:18])=[N:14][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[CH:3][CH:4]=2)=[N:10][CH:11]=1
Reactant: CCN=C=O
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Solvent: CC#N
Product: C#CCNc1nc(Nc2ccc(NC(=O)NCC)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (100 mg, 0.3 mmole, prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and ethyl isocyanate (0.5 ml) was added at room temperature. The reaction mixture was heated under reflux for 5 hours and then cooled to room temperature and stirred overnight. The solid was filtered off and dried under high vacuum to provide 47 mg of 1-[4-(5-Bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-3-ethyl-urea. ESI-MS: 390.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[CH:30][N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1>O1CCOCC1.Cl>[C:22]1([C:21]2[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=3)=[N:13][C:14]3[CH:15]=[CH:16][N:17]4[CH:30]=[N:29][N:28]=[C:18]4[C:19]=3[CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 8-[4-(1,3-dioxolan-2-yl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (4-1, 0.80 g, 2.0 mmol) in dioxane (10 mL) and 3N HCl (10 mL) was stirred at room temperature for 15 min. The mixture was concentrated at 25° C. to remove most of the dioxane. The residue was poured into ice cold water to give a brown solid which was collected via filtration and dried with toluene (×2) azeotropically the give the title compound. LRMS m/z (M+1) Calcd: 351.1. Found 351.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.CNCCNC.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Brc1ccc(-n2cccn2)cc1
Temperature: 82 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 1-bromo-4-iodobenzene (2.82 g, 9.97 mmol), 1H-pyrazole (680 mg, 9.99 mmol), CuI (380 mg, 2.00 mmol), DMEDA (430 μL, 4.00 mmol, 0.40 equiv), Cs2CO3 (6.52 g, 20.00 mmol) an CH3CN (40 mL). The resulting mixture was stirred overnight at 82° C. After cooling to ambient temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:12) as the eluent to yield the title compound as a white solid (2.1 g, 94%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[N:7]2.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH3:30][N:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:12][C:8]2[N:9]=[CH:10][C:11]3=[C:3]([CH3:2])[N:4]=[C:5]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:6]3[N:7]=2)=[CH:21][CH:22]=1)[C:27]([NH2:29])=[O:28]
Reactant: CN(C(N)=O)c1ccc(Br)cc1
Reactant: Cc1nc(-c2ccccc2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(N(C)C(N)=O)cc3)ncc12
Temperature: 160 °C
Yield: 37.5 %

Procedure:
A solution of 5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (26 mg, 0.1 mmol), N-(4-bromophenyl)-N-methylurea (27 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), 2-(di-t-butylphosphino)biphenyl (10 mg, 0.03 mmol) and sodium t-butoxide (25 mg, 0.23 mmol) in dioxane (0.80 mL) was added to a Smithcreator microwave reaction vessal. The vessal was sealed, then heated in the Smithcreator microwave at 160° C. for 20 minutes. After cooling to room temperature, the mixture was purified by silica gel chromatography, eluting with 5% MeOH/DCM to give N-methyl-N-{4-[(5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-yl)amino]phenyl}urea (14 mg, 38%) as a yellow solid. 1H NMR (DMSO-d6): δ9.59 (s, 1H), 9.20 (s, 1H), 8.39-8.46 (m, 3H), 7.34-7.71 (m, 8H), 5.94 (d, J=4.67 Hz, 1H), 2.63 (d, J=4.53 Hz, 3H), 2.52 (s, 3H). MS m/z 373 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:35]5[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=5)=[CH:3][C:4]([C:26]([F:28])([F:27])[F:29])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b), 4-trifluoromethylphenylboronic acid (152 mg, 0.8 mmol, Aldrich), Pd(PPh3)4 (46 mg, 0.04 mmol, Aldrich) and Na2CO3 (2 mL, 0.8 mmol, 0.4 M in H2O) in MeCN (4 mL) was heated at 90° C. with stirring for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 574 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][C@H:46]([CH3:48])[NH:45][CH2:44][C@H:43]5[CH3:49])=[CH:40][CH:41]=4)=[O:35])=[CH:29][C:28]=3[O:50][C:51]([F:54])([F:53])[F:52])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.[CH3:65][NH:66][C:67](Cl)=[O:68].Cl>C(Cl)Cl.CC(N(C)C)=O.O>[CH3:1][O:2][C:3](=[O:55])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][C@H:46]([CH3:48])[N:45]([C:67](=[O:68])[NH:66][CH3:65])[CH2:44][C@H:43]5[CH3:49])=[CH:40][CH:41]=4)=[O:35])=[CH:29][C:28]=3[O:50][C:51]([F:54])([F:52])[F:53])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)NC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: CNC(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)N1C[C@@H](C)N(c2ccc(C(=O)Nc3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)c(OC(F)(F)F)c3)cn2)C[C@@H]1C
Reaction time: 0.83 h

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (62.8 g, 74.1 mmol; Preparation 3) and N,N-diisopropylethylamine (20.1 mL, 115.2 mmol) in DCM (750 mL) was slowly added 1 M methylaminoformyl chloride in DMA (68.4 mL) over 10 min at 10-15° C. After 50 min, 1 M methylaminoformyl chloride in DMA (3.6 mL) was added and the reaction mixture was stirred overnight. To the reaction mixture was added water (750 mL) and 1 N HCl (40 mL). The organic layer was washed with water, dried over Na2SO4, and evaporated. Methanol (300 mL) and 2 N LiOH (10 mL) were added to the crude product and the reaction mixture was stirred for 30 min. Water (110 mL) was added slowly to the reaction mixture. Seeds of crystalline title product were added after 50 mL of water. The reaction mixture was stirred for 2 days and then methanol (60 mL) and water (24 mL) were added. After 30 min, the mixture was filtered. The solid was washed with 2:1 methanol:water (120 mL), and dried under vacuum at 35° C. overnight to provide the title compound (54 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: BrCc1cccnc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccnc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and pyridin-3-yl-methyl bromide. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>C(O)C>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:24](/[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])\[C:25]#[N:26])[CH:10]=[CH:11][C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Reactant: N#CCS(=O)(=O)c1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccc(F)cc2)ccc1O
Yield: 82.2 %

Procedure:
The reaction mixture of 178.0 mg of 3-t-butyl-4-hydroxybenzaldehyde and 219.0 mg of (4-fluorobenzenesulphonyl)acetonitrile in 2.0 mL of ethanol containing 0.01 mL piperidine was refluxed for 4 h and cooled down. To the above reaction mixture was added water and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:6) to give 295.0 mg of the titled compound.
Reaction SMILES: BrC1SC([C:7]2[NH:11][N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)=CC=1.ClC1SC(CCl)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:8]=[CH:7][NH:11][N:10]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Br)s2)[nH]n1
Agent: ClCc1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc[nH]n1
Temperature: 85 °C
Yield: 93.9 %

Procedure:
5-(5-bromothiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazole (3.23 g, 10.88 mmol), prepared in a manner similar to that described in Example 1b, was dissolved in anhydrous DMF (40 mL). To this solution was added 2-chloro-5-(chloromethyl)thiophene (2.0 g, 11.97 mmol) and K2CO3 (2.25 g, 16.32 mmol). The reaction mixture was heated at 85° C. under nitrogen atmosphere for overnight. The solvent was evaporated and the resulting residue was taken into ethyl acetate. The reaction mixture was washed with water and brine and dried over anhydrous Na2SO4. It was concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate in hexane), providing the product 5-(5-bromothiophen-2-yl)-1-(5-chlorothiophen-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole (1.39 g, 30%). 1H-NMR (CDCl3): δ 7.11 (m, 1H), 6.90 (m, 1H), 6.75 (m, 1H), 6.67 (m, 1H), 6.61 (s, 1H), 5.46 (s, 2H). The above product was coupled with an aryl boronic ester in a manner similar to that described in Example 1c, providing the title compound (161 mg, 45%). 1H-NMR (CDCl3): δ 7.63 (s, 1H), 7.50 (m, 1H), 7.40 (m, 2H), 7.32 (m, 1H), 7.12 (m, 1H), 6.74 (m, 1H), 6.69 (m, 1H), 6.66 (s, 1H), 5.54 (s, 2H), 1.66 (s, 6H). MS (ES): 511 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Li].[C:12]1(=[O:22])[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:12]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=[O:22]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccoc1
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)c1ccco1
Reaction time: 1 h
Yield: 18.5 %

Procedure:
3.4 g of furan was dissolved in 30 ml of tetrahydrofuran, and the solution was added dropwise to 34 ml of normal butyllithium (1.6M, hexane solution) at -40° C. After stirring the resultant solution at 0° C. for 4 hours, the lithium reagent was added dropwise to a solution of 7.4 g of phthalic anhydride in 100 ml of tetrahydrofuran at -70° C. After stirring the solution at the same temperature for 1 hour, the reaction solution was poured into 0.5-N hydrochloric acid, and extracted with chloroform. By purification by column chromatography (eluent: chloroform, methanol), 2.0 g of o-(2-furoyl) benzoic acid was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CO)cn4c3-c3ccccc3)cc2)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C=O)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {1-[4-(6-hydroxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg) and triethylamine (0.125 mL) in DCM (1.9 mL) at 0° C. was treated with a solution of pyridine-sulfur trioxide complex (142 mg, 0.894 mmol) in DMSO (0.021 mL). The reaction mixture was warmed to rt and stirred for 2 hours. The mixture was partitioned between ethyl acetate and water and the organic phase washed with water, dried and concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43]C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:41][N:42]([CH3:43])[CH2:2][CH2:9][CH2:8][N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCCN(C)C)c4)cc23)CC1
Yield: 31.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting [3-(dimethylamino)propyl]methylamine (116 mg, 1.0 mmol) for N-methylethanamine to afford 21.0 mg of the title compound (31.8%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2(C(OC(C)(C)C)=O)[S:22][C:13]34[CH:21]=[CH:20][CH:19]=[CH:18][C:14]3=[N:15][CH2:16][CH2:17][CH:12]4[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:30]>C(OCC)(=O)C>[ClH:30].[CH:1]1([NH:7][C:8]([CH:10]2[S:22][C:13]34[CH:21]=[CH:20][CH:19]=[CH:18][C:14]3=[N:15][CH2:16][CH2:17][CH:12]4[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1(C(=O)NC2CCCCC2)CC2CCN=C3C=CC=CC32S1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)C1CC2CCN=C3C=CC=CC32S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
g of N-cyclohexyl-2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-carboamide was added to 30 ml of ethyl acetate. A mixture of 5N hydrochloric acid and 13.3 ml of ethyl acetate was further added thereto and stirred for 2 hours at 50° C. to form a precipitate. The precipitate was separated by filtration and washed with 30 ml of ether to obtain 6.37 g of N-cyclohexyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-carboamide.hydrochloride (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22](O)=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1>>[CH:33]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([N:37]4[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]4)=[O:23])[C:16]=3[N:15]=2)=[O:36])[CH2:28][CH2:29]1)([CH3:35])[CH3:34]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: OC1CCNCC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCC(O)CC4)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(4-hydroxy-piperidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 670 mg (1.10 mmol) 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 124.0 mg (1.21 mmol) piperidin-4-ol. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C@H:13]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:14]([NH:16][CH2:17][CH:18]([OH:28])[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:15])C1C=CC=CC=1>C(O)C.[Pd]>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH:18]([OH:28])[CH2:17][NH:16][C:14](=[O:15])[C@@H:13]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11][NH2:10])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCN)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
25 mg (0.048 mmol) of benzyl[(3S)-3-[(tert-butoxycarbonyl)amino]-4-({3-[(tert-butoxycarbonyl)amino]-2-hydroxypropyl}amino)-4-oxobutyl]carbamate (Example 154A) are dissolved in 10 ml of ethanol. 10 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr, and the filtrate is concentrated on a rotary evaporator in vacuo. The crude product is reacted without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:3]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)[CH3:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[N:3]=[C:2]([S:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:5]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2nc(Cl)cc(NCCCN3CCOCC3)n2)cc1
Reactant: CCc1ccc(S)cc1
Product: CCc1ccc(Sc2cc(NCCCN3CCOCC3)nc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
Similarly, 4-chloro-2-(4-chlorophenyl)-6-[3-(morpholino)propylamino]-pyrimidine is reacted with p-ethylthiophenol to produce 2-(4-chlorophenyl)-4-(4-ethylphenylthio)-6-[3-(morpholino)propylamino]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(E)-2-ethoxycarbonylvinyl]pyrrolidine (29 g, 50 mmol) in ethanol (500 ml) was added 10% palladium-carbon catalyst (5 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 h. To the mixture was added an additional 10% palladium-carbon catalyst (2 g), and the mixture was stirred for 1.5 h under the same condition. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-ethoxycarbonyl)ethylpyrrolidine (15.62 g, yield: 78%).