Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:38])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[N:11](CC2C=CC(OC)=C(OC)C=2)[N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:38])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)[NH:11][N:10]=1
Reactant: COc1ccc(Cn2nc(NC(=O)OC(C)(C)C)cc2NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nccc(Oc3ccc(CC(=O)Nc4cc(N)n[nH]4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
A mixture of N-[3-(N-tert-butoxycarbonylamino)-1-(3,4-dimethoxybenzyl)pyrazol-5-yl]-2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetamide (0.2 g) and trifluoroacetic acid (5 ml) was stirred at ambient temperature for 2 hours. The resultant mixture was evaporated. The residue was purified by column chromatography on silica using a solvent gradient from 49:1 to 9:1 of methylene chloride and a 3M methanolic ammonia solution as eluent. There was thus obtained the title compound (0.045 g); 1H NMR: (DMSOd6) 3.63 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 5.05 (br s, 2H), 5.58 (s, 1H), 6.5 (d, 1H), 7.23 (d, 2H), 7.41 (s, 1H), 7.45 (d, 2H), 7.51 (s, 1H), 8.5 (d, 1H), 10.35 (br s, 1H); Mass Spectrum: M+H+ 420.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)#[N:30].CC(O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O>[C:29]([CH:31]1[CH2:36][CH2:35][N:34]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:33][CH2:32]1)#[N:30]
Reactant: N#CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.09 g (27.3 mmol) of NaBH(OAc)3 were added batchwise to a suspension, cooled to 0° C., of 5.44 g (27.3 mmol) tert.butyl 4-oxo-piperidin-1-carboxylate, 3.00 g (27.2 mmol) 4-cyanopiperidine and 1.6 mL (28.0 mmol) AcOH in 400 mL DCM and the reaction mixture was stirred overnight, while warming up to RT. 400 mL water were added and the mixture was acidified with citric acid. The organic phase was separated off, the aqueous phase was made alkaline with saturated NaHCO3 solution and extracted exhaustively with DCM. The combined organic phases were concentrated by evaporation i. vac. and the residue was crystallised with a little DIPE.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[NH:24][N:23]=[C:22]([CH2:25][C:26]([NH2:28])=[O:27])[N:21]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[NH:24][N:23]=[C:22]([CH2:25][C:26](=[O:27])[NH2:28])[N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)Cc1n[nH]c(S)n1
Product: NC(=O)Cc1n[nH]c(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Yield: 58.4 %

Procedure:
7-ACA and 5-mercapto-1,2,4-triazol-3-ylacetamide were reacted as in example 23a to give the title compound, 58.4% yield; δ(CF3CO2H) 3.87 (2H, bs, C2 methylene), 4.38 (2H,s, --CH2CONH2), 4.55 (2H,bs, --CH2S--), 5.40 (2H,s, β-lactam protons), 7.1-7.8 (2H,m, --CONH2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]([F:41])([F:40])[CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([O:33]C4CCCCO4)[CH2:24][CH2:25]2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)[CH3:13]>CCOCC>[F:40][C:10]([F:41])([CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([OH:33])[CH2:24][CH2:25]2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)[CH3:13])[CH2:9][OH:8]
Reactant: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](CC(F)(F)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
To a suspension of lithium aluminium hydride (63 mg, 1.65 mmol) in ether (10 ml) the difluoroester (6) (1.40 g, 2.76 mmol) in ether (10 ml) was added and the mixture was stirred at 0° C. for 10 min and then stirred at room temperature for 10 min. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (100 g). Elution with n-hexane-ether (5:1) gave the alcohol (7) (1.13 g, 86%), viscous oil. 1H-NMR δ: 0.73 (3H, s, 18-H3), 1.03 (3H, s, 19-H3), 1.13 (3H, d, J=6 Hz, 21-H3), 3.33-4.10 (5H, m, 24-H2, 3-H, and THP), 4.76 (1H, m, THP), 5.38 (1H, m, 6-H). 19F-NMR δ: +43.3. MS m/z: 396 (M+-DHP), 378.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cccc(O)c2)CC1
Yield: 76 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C(OCC)(=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])[N:6]=[CH:7][C:8]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=c1cnc2ccc(F)c(F)c2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1
Yield: 14.2 %

Procedure:
7,8-Difluoroquinoxalin-2(1H)-one (Intermediate 155—a mixture of regioisomers containing 30% 5,6-difluoroquinoxalin-2(1H)-one, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 70-100% ethyl acetate in hexanes gave 320 mg of the product as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.O1CCCC1.CO.[OH-].[K+]>O>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (0.30 g), tetrahydrofuran (12 mL) and methanol (12 mL) was added a solution of potassium hydroxide (85%, 0.18 g) in water (10 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (267 mg, 94%) as pale yellow crystals. MS 524 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22].[NH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.CN1CCCC1=O.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:23][CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22]
Reactant: NC1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1Nc2nc(NC3CCC(CO)CC3)ncc2CN1c1ccccc1Cl
Temperature: 25 °C

Procedure:
Sulfone 11.1 (350 mg, 104 mmol) was combined with 4-aminocyclohexylmethanol 1:1 cis/trans) (400 mg, 3.3 mmol) (prepared as described in Chem.Ber.; GE; 96; 1963; 2377-2386) with 0.3 mL of 1-methyl-2-pyrrolidinone. The mixture was heated at 1000 for 2 hours at which time it was cooled to room temperature. The reaction mixture was added to water and extracted with ethyl acetate, washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 10:90 methanol/dichloromethane as eluant The column fractions containing the product were concentrated to a foam which was resuspended in methanol. Addition of hydrochloric acid (1.0M/Et2O, 1.0 equivalent) gave a salt which was filtered to give the hydrochloride salt of 3-(2-chlorophenyl)-7-(4-hydroxymethylcyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][OH:24]>[Pd].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])=[CH:4][C:3]=1[CH2:21][CH2:22][CH2:23][OH:24]
Reactant: Nc1c(C#CCO)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(-c2ccccc2C(F)(F)F)cc(CCCO)c1N
Reaction time: 16 h
Yield: 73 %

Procedure:
3-(4-Amino-5-nitro-2′-trifluoromethyl-biphenyl-3-yl)-prop-2-yn-1-ol (148 mg, 0.440 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a magnetic stir bar, and dry EtOH (2 mL) was added via syringe. To the ethanol solution was added 10% Pd on activated carbon (27 mg), and the vial was capped with a rubber septum. Hydrogen gas was bubbled through the stirred solution for 3 min, and the reaction was stirred under an atmosphere of H2 at 1 atm for 16 h. The vial was vented, the reaction was filtered, and the filter was washed three times with MeOH (5 mL). The solvent was removed under reduced pressure to give 101 mg (73%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 7.68 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.3 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.61 (s, 1H), 6.60 (s, 1H), 3.65 (t, J=5.9 Hz, 2H), 3.48 (br. s., 4H), 2.66 (t, J=7.3 Hz, 2H), 1.86 (quin, J=6.6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (DMSO-d6): δ 6.90 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.49-7.61 (m, 4H), 7.66 (d, J=8.8 Hz, 2H), 8.81 (d, J=4.8 Hz, 2H), 10.26 (s, 1H). MS: M/z 456.9 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:7][N:8]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)CC1CNc2cccc([N+](=O)[O-])c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1CC(CC(=O)OC)c2c1cccc2[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of (±)-methyl (4-nitro-2,3-dihydro-1H-indol-3-yl)acetate from Step B (700 mg, 2.97 mmol), sodium carbonate (471 mg, 4.44 mmol), and potassium iodide (98 mg, 0.59 mmol) in acetone (15 mL) was added ethyl bromoacetate (9.9 mL, 88.9 mmol). The mixture was heated at reflux for 18 h, then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O (15 mL) and EtOAc (2×40 mL) and the organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a volume of 50 mL. Hexane was added to the EtOAc solution and a precipitate formed. The desired crystals were collected by vacuum filtration to give the title compound. MS: m/z=323 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC.[OH-].[Na+]>O.C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]([OH:20])[OH:16])=[C:3]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1nccc1-c1cc(Cl)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cn1nccc1-c1cc(Cl)ccc1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A 50-mL round-bottom flask was charged with 5-(2-bromo-5-chlorophenyl)-1-methyl-1H-pyrazole (992.0 mg, 3.65 mmol), diethyl ether (18 mL), and triisopropyl borate (1 mL, 4.38 mmol). The flask was cooled in a dry ice-acetone bath for 10 min, then n-BuLi (1.91 mL, 4.38 mmol) was added dropwise over a couple of minutes. Following the addition, the cooling bath was removed, and the mixture was warmed to room temperature. An aq. 2N NaOH solution (20 mL, 40 mmol) was added, and the resulting mixture was stirred vigorously for 2 h. The mixture was diluted with water and diethyl ether. The layers were separated, and the ethereal layer was extracted with water (2×). The aq. layers were combined, and the combined aq. mixture as washed with diethyl ether. The etheral layer was back-extracted once more, and the aq. layers were all combined. The combined aq. solution was acidified to about pH 1 with 3N aq. HCl to give a clear solution. The aq. solution was extracted with EtOAc (3×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM and concentrated in vacuo to give (4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)boronic acid (660 mg, 2.79 mmol, 76% yield) as a light-yellow foam. m/z (ESI) 237.0 (M+H)+.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:19]1[C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(C(F)(F)F)cc2)C1=O
Yield: 42.7 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g, 2.94 mmol) and 4-trifluoromethyl aniline (1.28 mL, 8.82 mmol) in ethanol (3 mL). 2-oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid 0.343 g (43%) was obtained as a bright yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.S(OC)(OC)(=O)=O.[NH3:18]>C(#N)C.CO>[NH:1]1[C:5]2=[N:6][C:7]([NH2:18])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: N
Solvent: CO
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: Nc1ccc2cc[nH]c2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide, 3-chlorobenzoic acid complex (1.5 g, 5.16 mmol) was suspended in acetonitrile (10 mL). Dimethyl sulfate (0.54 mL, 5.68 mmol) was added and the reaction mixture was warmed to 60° C. After 16 h, the mixture was transferred to a thick-walled pressure tube and 7M ammonia in methanol solution (11 mL) was added. The tube was sealed and warmed to 55° C. After 16 h, the solvent was evaporated and the residue was taken up in dichloromethane and 10% sodium carbonate solution. The aqueous layer was extracted with dichloromethane, and then the combined organic layers were washed successively with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried (sodium sulfate), filtered, and concentrated in vacuo. Purification by chromatography (silica, 10 to 80% ethyl acetate in hexanes) gave 1H-pyrrolo[2,3-b]pyridin-6-ylamine (316 mg, 46%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.73 (br. s., 1H) 7.70 (d, J=8.3 Hz, 1H) 6.99 (d, J=3.5 Hz, 1H) 6.38 (d, J=8.3 Hz, 1H) 6.36 (d, J=3.5 Hz, 1H) 3.82 (br. s., 2H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH:5]=[N:4][N:3]=[N:2]1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1>C(C)#N.C(OCC)(=O)C.O>[N:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cn1cnnn1
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Cn1cnnn1)OCc1ccccc1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Tetrazole-1-acetic acid (0.64 g), benzyl alcohol (0.65 g) and pyridine (0.80 ml) are dissolved in dry cyanomethane (10 ml) and thereto is added 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (1.72 g) under ice-cooling. After allowing to stand overnight, to the mixture are added water and ethyl acetate. The ethyl acetate layer is washed, dried and concentrated. The precipitated crystals are washed well with ether-petroleum ether to give benzyl tetrazole-1-acetate (815 mg), melting point: 69°-72° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[N:10]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>CO>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=[C:11]1[C:14](=[O:29])[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2Cc1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Cn2c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc3c(C(=O)O)cccc32)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
20 mg (0.04 mmol) 1-(3-Methoxy-benzyl)-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were suspended in 5 mL MeOH. 194 μl (0.19 mmol) of an aqueous 1 M LiOH-solution were added and the resulting mixture was stirred for 8 h at 60° C. After acidification with a 1 M HCL-solution the mixture was concentrated. The resulting residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give pure 1-(3-Methoxy-benzyl)-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid as a colorless amorphous solid. Yield: 44 mg MS (ES+): m/e=501.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:35][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:35].[CH3:34][N:2]([CH3:1])[C:3]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-[6-(1H-indol-3-yl)hexyl]acetamide (78 mg, 0.17 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.033 mol, 0.26 mmol) was added. After 1 h ether (10 ml) was added, and after 10 min the hydrochloride was isolated as a colourless solid with an m.p. of 160-164° C. in a yield of 87% (73 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O:14][C:15](=O)[NH:16][C:17]1[S:21][C:20]2[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[CH:18]=1)C1C=CC=CC=1>>[CH3:27][O:26][C:25]1[C:19]2[CH:18]=[C:17]([NH:16][C:15]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:14])[S:21][C:20]=2[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCOCC3)cc12

Procedure:
The title compound MS: mi/e=369.3 (M+H+) was obtained as a light brown solid (58% yield) by the reaction of morpholine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([CH3:29])=[CH:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 35.6 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (262 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 336 (168.7 mg, yield: 36%). 1HNMR (DMSO-d6, 400 MHz): δ9.04 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.91-7.87 (m, 2H), 7.76-7.71 (m, 1H), 7.48-7.45 (m, 2H), 7.36-7.34 (m, 1H), 7.14 (s, 1H), 4.30 (s, 2H), 3.14 (s, 2H), 2.52 (s, 3H). ESI-MS: m/z=474 [M+H+]