Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23](=[O:38])[NH:24][CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)[N:27]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[N:33]1([C:28]2[N:27]=[C:26]([CH2:25][NH:24][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][NH:18]3)=[O:38])[CH:31]=[C:30]([CH3:32])[N:29]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: Cc1cc(CNC(=O)C2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)nc(-n2ccnc2)n1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cc(CNC(=O)C2CCCN2)nc(-n2ccnc2)n1
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of 2-[(2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (435 mg, 0.855 mmol) in dimethylformamide (3.2 mL) was added piperidine (800 μL, 8.09 mmol) at r.t. The solution was stirred for 20 min then concentrated under vacuum to afford 244 mg of pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide as a brown oil. [M+H]+ 287.28.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O>CCO.[Fe]>[Cl-:1].[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:6]3[CH:5]=[CH:4][N+:3]([CH3:2])=[CH:8][CH:7]=3)=[CH:11][CH:12]=2)=[O:17])=[CH:20][CH:21]=1
Reactant: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: C[n+]1ccc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)cc1
Yield: 79.8 %

Procedure:
Compound D4 (295 mg, 0.77 mmol) was dissolved in ˜5:1 EtOH:H2O (12 mL), and Fe dust (209 mg) was added. The mixture was vigorously stirred and refluxed for 4 h, and then filtered hot through a pad of Celite. The Celite was washed with boiling EtOH, and EtOH fractions were combined and evaporated to dryness. The residue was extracted into hot water, and filtered through Celite, and then evaporated to dryness. The residue was azeotroped with MeOH (3×20 mL), and then dissolved in MeOH (10 mL). Methanolic HCl (1.25 M, 5 mL) was added, and the solution stirred for 10 min. Solvent was removed under reduced pressure, and the residue was crystallized from MeOH/EtOAc to give D5 (218 mg, 80%); mp (MeOH/EtOAc); 1H NMR [(CD3)2SO] δ 11.13 (s, 1H, NH), 10.44 (s, 1H, NH), 9.88 (br, 2H, NH2), 8.36 (d, J=7.5 Hz, 2H, ArH), 8.12 (d, J=8.6 Hz, 2H, ArH), 7.86 (d, J=8.8 Hz, 2H, ArH), 7.50 (d, J=8.8 Hz, 2H, ArH), 7.32 (d, J=8.6 Hz, 2H, ArH), 7.32 (d, J=7.5 Hz, 2H, ArH), 7.30 (d, J=8.7 Hz, 2 H, ArH), 4.00 (s, 3H, N+CH3); LCMS 319+ve
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
Acetic anhydride (2.59 mL, 2.81 g, 27.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 4-aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine (7.96 g) and pyridine (3.03 mL, 2.97 g, 37.5 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, aqueous sodium hydrogen carbonate (saturated, 100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×100 mL), aqueous sodium hydrogen carbonate (saturated, 100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (50:50 increasing to 100:0) to give the title compound as an off-white solid (5.96 g, 72% from 4-cyano-4-phenylpiperidine hydrochloride), δH (250 MHz, CDCl3) 7.45-7.26 (5H, m), 5.00 (1H, br m), 3.67 (2H, m), 3.45 (2H, br m), 3.21 (2H, m), 2.08 (2H, m), 1.88 (3H, s), 1.78 (2H, m), and 1.43 (9H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22](F)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:4]=1)[CH3:2].[OH:33][C@@H:34]1[C@@H:38]([OH:39])[CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1.CC(C)([O-])C.[K+]>C1COCC1.CC(O)(C)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:33][C@@H:34]4[C@@H:38]([OH:39])[CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](O)C1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(O[C@H]5CN(C(=O)OC(C)(C)C)C[C@@H]5O)ccn34)c12
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (32 mg, 0.075 mmol; prepared as in Example 74, Step A) in THF/t-BuOH (1 mL/1 mL) was added (3S,4S)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (61 mg, 0.30 mmol) and potassium tert-butoxide (67 mg, 0.60 mmol). The reaction was heated with microwave at 100° C. for 50 minutes, and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:1) gave the crude product (42 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8]>[OH-].[Na+].CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1COc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)ccc1COc1ccc(Br)cc1

Procedure:
Methyl 5-bromo-2-(4-bromophenoxymethyl)benzoate (90 g, 0.23 mole) was refluxed in a mixture of 100 mL of 10% sodium hydroxide and 200 mL of methanol for three hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with concentrated hydrochloric acid. A solid was precipitated and collected as the acid product (80 g). mp 214°-215° C. pmr (DMSO-d6) 6: 6.76-8.01 (m, 7H, aromatic H), 5.38 (s, 2H, ArCH2O).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2C(N[C:20](=[O:21])[C:15]=12)=O)(OCC)=[O:10]>CN(C=O)C.CCOC(C)=O>[CH3:8][C:7]1[C:2]([N:1]2[C:9](=[O:10])[C:14]3=[CH:24][CH:23]=[CH:22][CH:16]=[C:15]3[C:20]2=[O:21])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccnc1N1C(=O)c2ccccc2C1=O
Temperature: 23 °C
Reaction time: 15 h

Procedure:
2-Amino-3-picoline (1.00 mL, 8.62 mmol) was dissolved in DMF (30 mL) at 23° C., and treated with solid carboethoxy-phthalimide (1.89 g, 8.64 mmol), followed by TEA (1.44 mL, 10.3 mmol). The resulting solution was stirred at 23° C. for 15 h. After 15 h, the mixture was diluted with EtOAc (50 mL), and washed with saturated NaCl (1×50 mL), H2O (1×50 mL), dried (MgSO4), and concentrated in vacuo to a yellow solid. Purification over silica gel (0 to 50% EtOAc/Hexanes) provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]1([CH2:38][O:39][C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:32]1([CH2:38][O:39][C:40]([N:22]2[CH2:21][CH2:20][CH:19]([S:18][C:10]3[N:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:24][CH2:23]2)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Fc1ccc(Cn2c(SC3CCNCC3)nc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(Sc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a stirred mixture of 10.2 parts of 1-[(4-fluorophenyl)methyl]-2-[(4-piperidinyl)thio]-1H-benzimidazole, 3.1 parts of N,N-diethylethanamine and 130 parts of dichloromethane was added dropwise a solution of 5.12 parts of (phenylmethyl)carbonochloridate in 65 parts of dichloromethane. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was washed with water. The organic layer was dried, filtered and evaporated, yielding 14.3 parts of (phenylmethyl)4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]thio]-1-piperidinecarboxylate as a residue (75).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:17]N1C(=O)CCC1=O.C(O)(C)C>O>[NH2:1][C:2]1[C:7]([Br:17])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(Oc2ccnc(N)c2Br)cc1Cl

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (1.0 g), N-bromosuccinimide (0.78 g) and isopropanol (10 ml) were stirred for 15 minutes under reflux. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=2:1, followed by 1:1, ethyl acetate) to obtain 400 mg of the target substance as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[C:10]([CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)[CH3:14])([OH:12])=[O:11]>>[C:10]([CH:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:19][CH2:20]1)[CH3:14])([OH:12])=[O:11]
Reactant: Nc1nccc(C=O)n1
Reactant: CC(C(=O)O)N1CCC(N)CC1
Product: CC(C(=O)O)N1CCC(N=Cc2ccnc(N)n2)CC1

Procedure:
2-Aminopyrimidine-4-carboxaldehyde and 1-carboxyethyl-4-aminopiperidine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][S:2][S:3]([CH3:6])(=O)=O.[F:7][C:8]([F:19])([F:18])[CH:9]([C:11]1[CH:16]=[CH:15]C(S)=[CH:13][CH:12]=1)[OH:10]>CCO.C1COCC1>[F:7][C:8]([F:18])([F:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:1]([S:2][S:3][CH3:6])=[CH:13][CH:12]=1)[OH:10]
Reactant: OC(c1ccc(S)cc1)C(F)(F)F
Reactant: CSS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CSSc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
Methanethiosulfonic acid S-methyl ester (0.02 ml, 0.22 mmol) was dissolved in an EtOH (0.46 mL) and saturated NaCO3/H2O (pH 8) solution (0.8 mL) under argon at 0° C. A solution of 2,2,2-trifluoro-1-(4-mercapto-phenyl)-ethanol (5) (22 mg, 0.11 mmol) dissolved in THF (1.5 mL) under argon was added dropwise. After 10 minutes, the reaction temperature was raised to room temperature. After 36 hours, the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL). The combined organic phases were dried over Na2SO4 and under reduced pressure. Flash chromatography on silica gel using 0-30% acetone/hexane gave Compound 15 as a yellow oil (23 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 4H), 5.02 (q, J=6.7 Hz, 1H), 2.45 (s, 3H); 19F NMR (376 Hz, CDCl3) δ −78.79 (d); 13C NMR (100 MHz, CH3OD): δ 137.6, 134.2, 128.8, 126.4, 124.6 (q, JCF=281.7 Hz), 71 (q, JCF=31.5 Hz), 21.5.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: COC(=O)C1CNCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(C)=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (10 g, 51.65 mmol) was dissolved in dichloromethane (130 mL). Triethylamine (7.20 mL, 51.65 mmol) was added followed by acetic anhydride (4.87 mL, 51.65 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to give methyl 1-acetyl-4-oxopiperidine-3-carboxylate (6.10 g, 59.3%), which was used in the next step as such.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19][CH2:20][CH2:21][NH2:22]>C(O)C>[Br:19][CH2:20][CH2:21][NH:22][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: NCCBr
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1NCCBr

Procedure:
The compound was prepared by reacting 2,4-dichloro-3,5-dinitrobenzotrifluoride with 2-bromoethylamine in an ethanol solution. The resultant product melted at 88°-92° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([C:49]1[CH:50]=[C:51]([CH:56]=[C:57]([CH2:60]C)[C:58]=1[OH:59])[C:52]([NH:54]O)=[NH:53])[CH3:48]>C(Cl)Cl>[CH2:47]([C:49]1[CH:50]=[C:51]([C:52]2[N:54]=[C:9]([C:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=3)[O:11][N:53]=2)[CH:56]=[C:57]([CH3:60])[C:58]=1[OH:59])[CH3:48]
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Reactant: CCc1cc(C(=N)NO)cc(CC)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 2-isobutyl-6-methyl-isonicotinic acid hydrochloride (2.18 g, 9.53 mmol) and DIPEA (3.69 g, 28.6 mmol) in DCM (10 mL), TBTU (3.67 g, 11.44 mmol) is added. The mixture is stirred for 5 min before 3,5-diethyl-4,N-dihydroxy-benzamidine (1.85 g, 9.53 mmol) is added. The mixture is stirred at rt for 1 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 2-isobutyl-6-methyl-isonicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min, [M+1]+=370.06) is dissolved in dioxane (50 mL) and heated to 100° C. for 4 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (1.97 g) as a colourless oil; LC-MS: tR=0.93 min; [M+1]+=352.16; 1H NMR (CDCl3): δ 7.85 (s, 2 H), 7.75 (s, 1 H), 7.70 (s, 1 H), 5.05 (s br, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.69 (s, 3H), 2.37 8 s, 3H), 2.19 (hept, J=7.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1.[BrH:26]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:26])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1
Reactant: COc1ccc(CO)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Reactant: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CBr)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl alcohol (195 mg, 0.57 mmol) in acetic acid (glacial, 3 mL) was added HBr (48%, 1 mL) and the resulting mixture heated at reflux for 2 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 200 mg of crude 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl bromide. To a stirred solution of 2,4-thiazolidinedione (133 mg, 1.14 mmol) in anhydrous THF (6 mL) was added, at −78° C. under argon, n-BuLi (1.6M in hexane, 1.5 mL, 2.4 mmol) dropwise. The mixture was maintained at −78° C. for 15 minutes and then warmed to 0° C. for 30 minutes to complete the dianion formation. Upon recooling to −78° C., 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl bromide was added in THF (3 mL). After 30 minutes the orange solution was allowed to warm to room temperature. After 1.5 hours, the solution was treated with 2N HCl, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane 2:8) to give 61 mg of 5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl]thiazolidine-2,4-dione (24% for 3 steps from benzaldehyde). 1H NMR (500 MHz; CDCl3): δ1.27 (s, 6H); 1.26 (s, 6H); 1.69 (s, 4H); 2.08 (s, 3H); 3.12 (dd, J1=14.0 Hz, J2=9.5 Hz, 1H); 3.50 (dd, J1=14.0 Hz, J2=4.0 Hz, 1H); 3.76 (s, 3H); 4.54 (dd, J1=9.5 Hz, J2=4.0 Hz, 1H); 6.89 (d, J=8.0 Hz, 1H); 7.03 (d, J=2 Hz, 1H); 7.07 (s, 1H); 7.14 (s, 1H); 7.17 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.95 (br, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][C:36]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:37])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[ClH:63]>O1CCOCC1>[ClH:63].[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][C:36]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:37])[N:26]=3)=[CH:23][N:24]=[C:19]2[NH:18][CH:17]=1)=[O:15])([CH3:11])[CH3:12]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CC(=O)N3CCOCC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)nn(CC(=O)N3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a stirred solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(2-morpholino-2-oxoethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.118 mmol) in dioxane (40 mL) was bubbled HCl gas until saturation and then stirred at room temperature for 16 hours. The mixture was concentrated and the residue was triturated with methanol (1 mL), solvent decanted and solid dried to afford N-(1-hydroxy-2-methylpropan-2-yl)-2-(6-methyl-1-(2-morpholino-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide hydrochloride (44 mg, 71%) as a yellow solid. LCMS: (M+H)+=492; 1H NMR (300 MHz, DMSO+D2O): δ 9.07 (s, 1H), 8.44 (d, 1H, J=8.4 Hz), 8.36 (s, 1H), 7.45 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 5.55 (s, 2H), 3.72-3.65 (m, 8H), 3.47 (brs, 2H), 2.53 (s, 3H), 2.36 (brs, 2H), 1.46 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]([O:19]C)=[O:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.[OH-].[Na+].Cl>C1COCC1.CO>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxylate (16 g, 41.4 mmol) and 1 N NaOH (85 mL, 85 mmol) in THF/MeOH (1:1) (v/v) (300 mL) was heated at 80° C. bath for 1 h. Volatile solvents were removed in vacuo. The residue was diluted with H2O, acidified with 1 N HCl (2.2 equiv) and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (Na2SO4) and concentrated to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: COc1cccc(-n2nc(C(=O)O)cc2-c2cccc(F)c2)c1
Product: COc1cccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cccc(F)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 80A in analogy to the synthesis of the compound of Example 1. 27 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([S:6][C:7]([CH3:27])([CH3:26])[C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH2:4][OH:5].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:39]=[CH:38][C:33](/[CH:34]=[CH:35]/[CH:36]=O)=[CH:32][CH:31]=1>>[CH3:26][C:7]([S:6][C@@H:3]1[CH2:4][O:5][C@@H:36](/[CH:35]=[CH:34]/[C:33]2[CH:38]=[CH:39][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:31][CH:32]=2)[O:1][CH2:2]1)([CH3:27])[C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=C/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(SC(CO)CO)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Product: CC(C)(S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction was carried out in the same manner as in Example 4 using (RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 55 and trans-4-(trifluoromethyl)cinnamaldehyde as described in Reference example 22 to obtain the title compound as a colorless foam.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[C:24]([CH:35]=1)[C:25]([N:27]([CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH3:28])=[O:26]>>[Cl:19][C:20]1[C:21]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[N:22][CH:23]=[C:24]([CH:35]=1)[C:25]([N:27]([CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH3:28])=[O:26]
Reactant: CN(C)CCCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Product: CN(C)CCCN(C)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol and 5,6-dichloro-N-[3-(dimethylamino)propyl]-N-methylnicotinamide, and in the same manner as in Example 65 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (58 mg) was obtained as a yellow amorphous solid.