Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:63])([F:62])[C:25]1[CH:26]=[C:27]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:28][N:29]1[C:33]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[C:32]([C:39]([C:41]2[C:42](CO)=[N:43][O:44][C:45]=2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])=[O:40])[N:31]=[N:30]1>ClCCl.CCOC(C)=O>[F:62][C:24]([F:23])([F:63])[C:25]1[CH:26]=[C:27]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:28][N:29]1[C:33]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[C:32]([C:39](=[O:40])[CH:41]([C:45](=[O:44])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])[C:42]#[N:43])[N:31]=[N:30]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1)c1c(CO)noc1-c1ccccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#CC(C(=O)c1ccccc1Cl)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-n1ccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add Dess-Martin periodinane (1.5 g, 3.54 mmol) to a solution of [1-(3,5-Bis-trifluoromethyl-benzyl)-5-imidazol-1-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone (0.7 g, 1.17 mmol) in dichloromethane (10.0 mL). Stir at RT for 4 h, dilute with EtOAc and wash with 2N NaOH, water and brine, then dry, filter, and concentrate. Recyrstallize crude material from dichloromethane to give the title compound. (0.10 g, 15%). MS [ES] 567.0 (M+H)+, 565.0 (M−H); 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.70 (s, 2H), 7.69 (s, 1H), 7.25 (br s, 2H), 7.19 (m, 2H), 7.03 (s, 1H), 6.98 (m, 1H), 5.68 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:13]2=[O:24])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][CH:33](Br)[CH2:34][CH3:35]>C(#N)CC>[CH:33]([O:23][C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH:15]=[CH:16][N:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:25])[CH3:1])=[CH:11][CH:10]=3)[C:13]2=[O:24])=[CH:22][CH:21]=1)([CH2:34][CH3:35])[CH3:32]
Reactant: CCC(C)Br
Reactant: CN(C)CCOc1ccc(-n2ccn(-c3ccc(O)cc3)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC#N
Product: CCC(C)Oc1ccc(-n2ccn(-c3ccc(OCCN(C)C)cc3)c2=O)cc1
Temperature: 80 °C

Procedure:
A solution of 1-[4-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in propionitrile (1 mL) was mixed with cesium carbonate (100 mg) and 2-butyl bromide (25 mg) and heated at 80° C. for 2 hours. The reaction solution was filtered and the concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 395.51 (C23H29N3O3); MS (ESI): 396 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16](Cl)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH3:19])=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CNC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonyl chloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) was added 1 drop of DMF followed by N-methylcyclohexylamine (349 μL, 2.68 mmol). The reaction mixture was stiffed at room temperature for two hours then stopped.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:15])([C:12](=[O:14])[CH3:13])[CH3:11])[CH:7]=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:15])([C:12](=[O:14])[CH3:13])[CH3:11])[CH:7]=[CH:6][C:5]=1[S:16]([NH2:1])(=[O:18])=[O:17]
Reactant: CC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)c1ccc(S(N)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of NH4OH (30 mL) was added a solution of 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzene-1-sulfonyl chloride (9.8 g, 33.2 mmol) in THF (150 mL) at 0° C. After stirring 2 h, volatiles were removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (100 mL×2). The combined extracts were dried over MgSO4, concentrated and purified by column chromatography (Hex/EtOAc=4:1 to 2:1) to give 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzenesulfonamide (8.9 g, 96% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.27 (d, J=2.2 Hz, 1H), 5.09 (s, 2H), 2.04 (s, 3H), 1.52 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:17]([CH2:16][CH2:15][O:14][CH3:13])[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: COCCN
Product: COCCN1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and 2-methoxyethylamine (Aldrich Cat No. 241067). LCMS (M+H)+=270.0/272.0.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].[CH:58](OC)=[O:59]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:58]=[O:59])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: COC=O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC=O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone(30 mg) is mixed with methyl formate (0.5 ml) and is stirred at 0° C. for 1 hr. The reaction mixture is allowed to warm to room temperature and then is stirred overnight. The excess methylformate is removed with nitrogen flow and the crude mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=O)[CH2:6]Br)[CH3:2].[S:10]([N:20]1[C:28]2[C:23](=[N:24][C:25]([NH2:29])=[CH:26][N:27]=2)[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O1CCOCC1>CC#N>[S:10]([N:20]1[C:28]2[N:27]=[CH:26][C:25]3[N:24]([CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])[N:29]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2c(cnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 72 h
Yield: 75.5 %

Procedure:
3-Bromo-2-oxo-propionic acid ethyl ester (0.090 mL, 0.72 mmol) was added to a mixture of 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (0.180 g, 0.624 mmol, prepared using E from Example #3 Step E and HCl) and 1,4-dioxane (3.5 mL) under nitrogen. After about 3 days, the volatiles were removed under reduced pressure. The residue was slurried in Et2O (5 mL) and then filtered to afford a tan powder. The solid was slurried in MeCN (3.50 mL) under nitrogen. PFPAA (0.40 mL, 2.1 mmol) was added. After about 30 min, the volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3/water (2:1, 20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc/heptane to afford ethyl 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate (0.181 g, 75%): LC/MS (Table 1, Method n) Rt=0.70 min; MS m/z: 385 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[NH:22][C:11]3=[CH:12][C:13]4[C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=4[CH:18]=[C:10]3[N:9]=2)=[N:4][NH:5][C:6]=1[CH3:7].[C:23](Cl)(=[O:25])[CH3:24]>>[CH3:21][C:14]1([CH3:20])[C:13]2[CH:12]=[C:11]3[NH:22][C:8]([C:3]4[C:2]([NH:1][C:23](=[O:25])[CH3:24])=[C:6]([CH3:7])[NH:5][N:4]=4)=[N:9][C:10]3=[CH:18][C:17]=2[NH:16][C:15]1=[O:19]
Reactant: Cc1[nH]nc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4)c1N
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4)n[nH]c1C

Procedure:
N-[3-(7,7-Dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-5-methyl-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-5-methyl-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (60 mg, 0.21 mmol) and acetyl chloride. The title compound was obtained as white powder (3.7 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:35][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:33][CH3:34])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 82 %

Procedure:
A mixture of N-[4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 154, 440 mg, 0.93 mmol), iron (311 mg, 5.56 mmol), NH4Cl (37.2 mg, 0.70 mmol), ethanol (15 mL) and water (5 mL) was heated at reflux for 1.5 h. After cooling the mixture was concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (20 mL) for 15 minutes and then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (10 mL) and then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (339 mg, 82%) as a yellow solid after trituration with diethyl ether; 1H NMR: 1.73-1.83 (1H, m), 2.00-2.10 (1H, m), 2.20 (6H, s), 2.81-2.90 (1H, m), 2.92-3.00 (2H, m), 3.11-3.16 (1H, m), 3.17-3.24 (1H, m), 3.73 (3H, s), 4.28 (2H, br s), 6.71 (1H, s), 7.07 (1H, td), 7.20 (1H, d), 7.27 (1H, s), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.30 (1H, d), 8.53 (1H, d), 8.76 (1H, s), 8.79 (1H, d); m/z: ES+ MH+ 445.33.
Reaction SMILES: C[O-:2].[Na+].C([C:7]1[CH:19]=[CH:18][C:10]2[C:11](=[O:17])[C:12]([Br:16])=[C:13]([CH3:15])[O:14][C:9]=2[CH:8]=1)(=O)C.Cl>CO>[Br:16][C:12]1[C:11](=[O:17])[C:10]2[CH:18]=[CH:19][C:7]([OH:2])=[CH:8][C:9]=2[O:14][C:13]=1[CH3:15]
Reactant: C[O-]
Reactant: CC(=O)c1ccc2c(=O)c(Br)c(C)oc2c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1oc2cc(O)ccc2c(=O)c1Br
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2.2 ml of sodium methylate (8% of Na (w/v) in methanol) are added under an inert atmosphere to a suspension of 2.3 g (7.7.10-3 mol) of 7-acetyl-3-bromo-2-methyl-4H-1-benzopyran-4-one in 40 ml of methanol. After 30 minutes, the reaction mixture is hydrolyzed with an iced solution of hydrochloric acid. The precipitate formed is filtered off and then washed until the pH of the washings is neutral. 1.9 g (yield: 96%) of the expected product are thus obtained.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.[F:17][C:18]([F:37])([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)O>ClCCl>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([F:7])[C:18]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])([F:37])[F:17])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(O)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(F)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Yield: 71.6 %

Procedure:
A solution of 0.24 mL (1.8 mmol) of diethylaminosulfur trifluoride in 5 mL of dichloromethane was cooled to -78° C. (dry ice-acetone bath) and treated dropwise with a solution of 0.50 g (1.6 mmol) of 2,2-difluoro-1-(4-methylphenyl)-2-phenylsulfonylethanol in 2 mL of dichloromethane. The cooling bath was removed and 30 minutes later 2 mL of saturated NaHCO3 was added with vigorous stirring. The organic layer was removed, washed with on 2 mL portion of water, dried (MgSO4), and concentrated in vacuo to give a residue which was crystallized from toluene-hexane, affording 0.36 g (71% yield) of 2-(4-methylphenyl)-1-phenylsulfonyl-1,1,2-trifluoroethane; mp 80°-82° C.; IR (KBr) 2924, 1447, 1352, 1185, 1163, 1117, 1054, 1013, 787, 757, 720, 686, 603, 567, 533, cm-1 ; 1H NMR (CDCl3) δ 2.36 (s, 3H), 6.10 (ddd, 1H, JHF =44, 18, 5 Hz), 7.16-8.07 (m, 9H); 19F NMR (CDCl3, relative to CFCl3) -44.0 ppm (dt, 1F J=44, 16 Hz), -109.3 ppm (dd, 1F, J=247, 15 Hz), -118.8 ppm (dt, 1F, J=248, 17 Hz); mass spectrum (70 eV) m/e (relative intensity) 314 (11, M+), 172 (41), 123 (100), 77 (31). Anal. Calcd. for C15H13F3O2S: C, 57.32; H, 4.17. Found: C, 56.90; H, 4.47.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.OO.[ClH:23]>CO>[Cl:23][C:3]1[CH:4]=[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Reactant: Cl
Agent: OO
Solvent: CO
Product: O=S(=O)(Nc1cc(Cl)c(O)c2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
0.987 g N-(4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (3) was suspended in 10 ml methanol, to which was added 3 ml hydrogen peroxide solution (35%). The mixture was stirred at r.t. for 2 h. Additional 3 ml hydrogen peroxide solution was added followed by 1 ml HCl solution (4 M in dioxane). The reaction was continued for another 2 h. The organic solvent was removed via rotavap and the residue was redissolved in ethyl acetate (100 ml). Washed with water (20 ml×3) and brine (20 ml×2), the organic phase was dried over Mg2SO4. The organic phase was filtered and concentrated. The crude product was separated via flash chromatography (Hex/EtOAc) affording 244 mg (22.2%) brown solid, m.p.: 113-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:28])[C:8]2[O:14][C:13]3[C:15]([Cl:24])=[CH:16][C:17]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[CH:18][C:12]=3[CH2:11][S:10](=[O:26])(=[O:25])[C:9]=2[CH:27]=1)=[O:4].[CH3:29][NH:30][CH3:31].Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:28])[C:8]2[O:14][C:13]3[C:15]([Cl:24])=[CH:16][C:17]([NH:19][C:20](=[O:23])[CH2:21][N:30]([CH3:31])[CH3:29])=[CH:18][C:12]=3[CH2:11][S:10](=[O:25])(=[O:26])[C:9]=2[CH:27]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN(C)C)cc(Cl)c1O2

Procedure:
A mixture of Example 133 (0.4 g, 0.9 mmol), dimethylamine.HCl (0.44 g, 5.4 mmol) and potassium carbonate (0.75 g, 5.0 mmol) in 10 mL of dry DMF was stirred at 80° C. for 2 h. The reaction mixture was filtered and the solid obtained was washed with water. The filtrate was concentrated, treated with water and extracted with chloroform. The organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, 1% methanol/chloroform) to obtain the title compound. Yield: 0.26 g, (63.73%); 1H NMR (DMSO-d6): δ 1.96 (s, 6H, 2CH3), 2.17 (s, 2H, CH2), 2.3 (s, 3H, CH3), 3.51 (s, 3H, OCH3), 4.45 (s, 2H, CH2), 7.29 (s, 1H, Ar), 7.55 (s, 1H, Ar), 7.67 (s, 1H, Ar), 7.95 (s, 1H, Ar), 9.26 (s, 1H, NH); MS: m/e (EI+) 451 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1>>[OH:25][C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:3]=2)=[CH:17][CH:18]=1)([CH3:24])[CH3:23]
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Reactant: CC(C)(O)c1ccc(I)cc1
Product: CC(C)(O)c1ccc(Nc2nn(-c3ccccc3)cc2C#N)cc1

Procedure:
3-{[4-(1-hydroxy-1-methylethyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 11 Step 1 using 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (70 mg, 0.380 mmol) and 2-(4-iodophenyl)propan-2-ol (100 mg, 0.380 mmol) as the starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([NH:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 38.2 %

Procedure:
Ethyl 2-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylamino)-2-oxoacetate (prepared in Example 2; 36 mg, 0.10 mmol) and 2-morpholinoethanamine (65 mg, 0.50 mmol) were heated to 60° C. for 18 hours. The mixture was diluted with diethyl ether (1 mL) and filtered. The white solid was washed with diethyl ether (3×2 mL). The solid was dried under high vacuum. The product was obtained as a white powder (17 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.52 (d, J=6 Hz, 1H), 7.99 (m, 1H), 7.87 (m, 1H), 7.76 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 6.52 (d, J=6 Hz, 1H), 3.74 (m, 4H), 3.49 (m, 2H), 2.59 (m, 2H), 2.50 (m, 4H). LRMS (ESI pos) m/e 445 (M+1). HPLC: 100% purity (220 nm).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:29]([O:31]CC)=O)[CH:17]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C([NH2:39])=O>>[NH2:39][C:29]([C:18]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=2)[N:20]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:19]=1)=[O:31]
Reactant: CCOC(=O)c1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-n2nc(C(N)=O)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-(4-{[(tert-butoxycarbonyl)amino]-methyl}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (500 mg) and sodium methoxide (239 mg) in formamide 5 ml was stirred at 70° C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between AcOEt and brine. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give tert-butyl {4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate (512 mg) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:15][CH2:16]O>>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)CC1CCCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1CCCC1

Procedure:
Concentrated sulfuric acid (1 mL) was added to a solution of cyclopentylacetic acid (5.8 mL, 46 mmol) in anhydrous EtOH (15 mL) and heated to reflux for 3 hours. Thereafter, volatiles were removed under reduced pressure and the residue was diluted with water and ethyl acetate. The organic layer was separated, washed with 5% sodium bicarbonate, brine, dried over Na2SO4, and filtered. After evaporation of solvent under reduced pressure, a syrupy cyclopentylacetic acid ethyl ester was obtained and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:18]=[C:19]([CH2:23][C:24]([OH:27])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=CCc1cccc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1cccc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 95.5 %

Procedure:
To a solution of 2.0 g of 3-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetaldehyde and 1.0 g of sodium dihydrogenphosphate in 10 ml of water and 50 ml of dimethyl sulfoxide was added a solution of 2.0 g of sodium chlorite in water (10 ml) and the resulting mixture was reacted at room temperature for 20 minutes. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 2.0 g of crude 3-[1-(benzyloxycarbonyl)piperidin-4-yl]phenylacetic acid was obtained as a colorless oily substance. To a solution of 2.0 g of this oily substance in 50 ml of methanol was added 0.47 ml of thionyl chloride at 0° C. and the resulting mixture was reacted at room temperature for 2 hours. The reaction mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.2 g of the title compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CCOC(=O)N1CCC(c2cn(CCN3CCOCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B), starting with 11 g (40 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 9 g (48 mmol) of 4-(2-chloro-ethyl)-morpholine hydrochloride. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up and purification, 13.5 g (88% of yield) of 4-[1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.