Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]O)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:17]3[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]3)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCN1CCCc2ccc(CO)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(CCOC)CCC3)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-(2-Methoxyethyl)-1,2,3,4-tetrahydroquinolin-7-yl)methanol (357 mg, 0.807 mmol) and ethyl 1H-pyrazole-4-carboxylate (113 mg, 0.807 mmol) were dissolved in THF (5 ml). Triphenylphosphine (317 mg, 1.210 mmol) was added, and, after cooling to 0° C., a 40% solution of DEAD in Toluene (0.479 ml, 1.210 mmol) was added dropwise. The reaction mixture was stirred for 2 hr at 0° C., then overnight at 20° C. The reaction mixture was diluted with AcOEt and washed with 1N HCl, and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative-HPLC (Waters SunFire Prep C18 OBD 5 μm 19*50, Flow 20 mL/min, ACN: 2 min at 5%, then to 100% within 17.5 min, RT 11.80 min) to give the title compound. HPLC (Method A) Rt=2.001 min; MS (Method A) [M]+=343.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[N+:22]=[N-:23].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:21]2[CH:16]=[C:15]([CH2:14][NH:13][C:11](=[O:12])[C:10]3[CH:17]=[CH:18][CH:19]=[N:20][C:9]=3[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:23]=[N:22]2)=[CH:26][CH:27]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(NCc1cn(Cc2ccc(F)cc2)nn1)c1cccnc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.9 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 91 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2b (187 mg, 80%); mp: 197-199° C.; 1H NMR (300 MHz, CDCl3) δ 10.61 (s, 1H), 8.63 (brs, 1H), 8.24 (dd, J=4.4, 1.4 Hz, 1H), 7.98 (dd, J=, 8.0, 1.8 Hz, 1H), 7.64 (s, 1H), 7.63-7.58 (m, 2H), 7.41 (s, 1H), 7.23 (s, 1H), 6.98 (t, J=8.4 Hz, 2H), 6.88 (t J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 421 [M+H]+. Yield: 80%
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:46]([NH:49][CH3:50])(=[O:48])=[O:47])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([S:46]([NH:49][CH3:50])(=[O:48])=[O:47])[CH:6]=[CH:7][C:8]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: CNS(=O)(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(O)c1
Yield: 23.4 %

Procedure:
(S)-3-Methoxy-N-methyl-4-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzenesulfonamide (45 mg, 0.06 mmol) was treated with boron tribromide (1M in dichloromethane, 2.0 mL, 2.00 mmol) in dichloromethane (1 mL) and then with a solution of ammonia (7N in methanol, 5.0 mL, 35.0 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water methanol/acetonitrile 1:1) to obtain 8 mg (22% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=O)=[N:20]1.N1CCCCC1>CO>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:20]1
Reactant: O=C1COc2c1ccc(O)c2CN1CCOCC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.125 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.119 g, 63%).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[N:10]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.[Cl-].[NH4+]>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:19]([C:18]2[CH:17]=[CH:16][C:15]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:22][CH:21]=2)[OH:20])=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A Grignard reagent which is prepared by reacting 1.9 g of magnesium with 15 g of p-chlorobromobenzene in 40 ml of ether is added to a suspension of 6.2 g of 4-(1-imidazolyl)benzaldehyde in 70 ml of ether at 0° C. After the mixture is stirred at room temperature for an hour, the reaction mixture is poured into an aqueous ammonium chloride solution with caution. The mixture is extracted with chloroform and the chloroform is distilled off. The residue is purified column-chromatographically and recrystallized from toluene to give 8.6 g of α-(4-chlorophenyl)-4-(1-imidazolyl)benzenemethanol as white crystals, melting at 148.5°-149.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)(=O)C.[BH3-]C#N.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:36]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (0.2 g, mmol) in dichloroethane (3 mL) was added morpholine (5 equiv.) in 5 mL MeOH and acetic acid (2 equiv.) and the mixture was stirred at room temperature for 15 minutes. Then NaBH3CN (1.5 equiv.) was added and the reaction stirred at room temperature for 16 hours. After completion (monitored by TLC), aqueous sodium bicarbonate was added to the reaction mixture till pH 7-8, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate:hexane to afford the title compound as an off-white solid. LCMS: 574.25 (M+1)+; HPLC: 97.17% (@254 nm) (Rt; 3.906; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (s, 1H), 8.20 (t, 1H), 8.01 (d, 1H, J=7.2 Hz), 7.50 (d, 1H, J=7.6 Hz), 7.46 (s, 1H), 7.27 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.83 (m, 2H), 3.59-3.61 (m, 6H), 3.22-3.30 (m, 2H), 3.08-3.10 (m, 2H), 3.03 (m, 1H), 2.43 (s, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][C:7]1[N:12]2[N:13]=[C:14]([CH3:25])[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:11]2[N:10]=[C:9]2[CH2:26][CH2:27][O:28][C:8]=12)[CH2:4][CH3:5]>C1(OC2C=CC=CC=2)C=CC=CC=1.CO.[C].[Pd]>[CH3:1][CH2:2][CH:3]([NH:6][C:7]1[N:12]2[N:13]=[C:14]([CH3:25])[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:11]2[N:10]=[C:9]2[CH:26]=[CH:27][O:28][C:8]=12)[CH2:4][CH3:5]
Reactant: CCC(CC)Nc1c2c(nc3c(-c4ccc(OC)cc4C)c(C)nn13)CCO2
Agent: [Pd]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC(CC)Nc1c2occc2nc2c(-c3ccc(OC)cc3C)c(C)nn12
Temperature: 250 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of the compound prepared in Example 2(6) (215 mg) in diphenyl ether (3 ml), 10% palladium carbon (150 mg) was added, and the mixture was stirred for 4 hours at 250° C. After the reaction mixture was cooled to room temperature, it was diluted with methanol (10 ml). The diluted solution was filtered though celite (registered trademark). The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (n-hexane:acetone=9:1) to give the title compound (150 mg) having the following physical data.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([O:17][C:25]3[CH:30]=[N:29][C:28]([CH:31]4[CH2:33][CH2:32]4)=[CH:27][N:26]=3)[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 2.323 g, 10 mmol) in tetrahydrofuran (60 mL) at room temperature was added potassium tert-butoxide (14 mL, 1 M in tetrahydrofuran). After 10 minutes, 2-bromo-5-cyclopropylpyrazine (2.249 g, 11.3 mmol) in tetrahydrofuran (3 mL) was added. The mixture was stirred at room temperature for 2 days. The mixture was concentrated and diluted with dichloromethane (200 mL). This solution was washed with water (30 mL), dried over sodium sulfate, and filtered. The organic phase was concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.78 (m, 3H), 2.08-2.38 (m, 5H), 2.70 (m, 1H), 2.83 (m, 2H), 3.53 (m, 3H), 5.24 (m, 1H), 7.28 (m, 5H), 8.12 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH2:20][CH3:21])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:22]>CO>[NH2:22][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH2:20][CH3:21])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: N
Solvent: CO
Product: CC[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: 75 °C
Reaction time: 72 h

Procedure:
To the compound from Step C (50 mg, 0.16 mmol) was added saturated ammonia in methanol (4 mL). The mixture was stirred at 75° C. for 72 h in a closed container, cooled and evaporated in vacuo. The crude mixture was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (29 mg) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:41][C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:56][CH2:55][C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[NH:52][C:51]3=[O:61])[CH2:46][CH2:45]2)=[O:43])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1>N1CCCCC1>[O:61]=[C:51]1[N:50]([CH:47]2[CH2:48][CH2:49][N:44]([C:42]([O:41][C@H:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:10](=[O:11])[N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)[CH2:14][CH2:13]3)=[O:43])[CH2:45][CH2:46]2)[CH2:56][CH2:55][C:54]2[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=2[NH:52]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN(C2CCN(C(=O)[C@@H](Cc3ccc(O)cc3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Solvent: C1CCNCC1
Product: O=C(O[C@H](Cc1ccc(O)cc1)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 250 mg (0.30 mmol) 9H-fluoren-9-ylmethyl 4-(1-{(R)-3-(4-hydroxy-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-piperazine-1-carboxylate (Example 123) in 4 mL piperidine was stirred for 30 min at RT. The reaction mixture was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 90:10:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=O.C>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][C:18]([C:14]3[S:13][CH:17]=[CH:16][N:15]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: O=Cc1nccs1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: C
Product: O=[N+]([O-])c1cc2oc(-c3nccs3)nc2cc1Cl
Yield: 63 %

Procedure:
To a flask equipped with a vigreux column was added 2-amino-4-chloro-5-nitro-phenol, thiazole-2-carbaldehyde, Darco KB and xylenes. The mixture was then refluxed overnight and the mixture was cooled, filtered and the solvent removed under vacuum. The resultant solid was recrystallized from Et2O to yield 4.76 g (63%) of a yellow colored solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[S:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:28]1[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>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>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[S:11][C:10]([C:16]3[CH:17]=[C:18]4[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:28]3[CH2:29][CH2:30][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:32][CH2:33]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccc(CNCC2CC2)s1
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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCC5CC5)s4)cc23)CC1
Yield: 20 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 19.1 mg of the title compound (20%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCN(C)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure described in Synthesis Example 2 was repeated by use of 4-t-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) and N-methylpiperazine, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([OH:21])=O)[CH2:17][C:6]=2[CH:5]=1.C(O)(=O)C.[F:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:44]=1[NH:43][C:42](=[O:45])[C:41]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[CH:40]2.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([N:49]3[CH2:50][CH2:51][CH:46]([C:41]4[C:42](=[O:45])[NH:43][C:44]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][C:35]=5[F:34])[CH2:47][CH2:48]3)=[O:21])[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(c2cc3cccc(F)c3[nH]c2=O)CC1
Yield: 13 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.22 mmol) and 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one acetate (90 mg, 0.29 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as tan solid in 13% yield. MS m/e (M+H)+=613.3. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.78 (s, 1H), 8.30 (s, 2H), 8.23 (s, 1H), 7.75 (d, J=19.53, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 7.21 (s, 1H), 7.12 (m, 3H), 5.40 (d, J=16.48, 1H), 4.64 (m, 4H), 4.13 (d, J=12.82, 1H), 4.00 (m, 1H), 3.17 (m, 2H), 3.04 (m, 2H), 2.94 (m, 1H), 2.67 (m, 1H), 2.44 (m, 1H), 1.94 (m, 1H), 1.86 (m, 1H), 1.57 (m, 1H), 1.42 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][C:32]=3[C:38]([F:40])([F:39])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: Fc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(C(F)(F)F)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-fluoro-2 trifluoromethyl-benzaldehyde. MS (ESI) m/z 552.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N([O-])=[O:11].[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-]>OS(O)(=O)=O.O>[OH:11][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: CC[C@H](C)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The synthesis was carried out in three steps, according to the following scheme: ##STR7## 1.1. Synthesis of(+)-(2S, 3S)-2-hydroxy-3-methylpentanoic acid [2]To a solution of (+)-L-isoleucine [1] (11.73 g, 89.4 mmol, [α]D20 =+40° (5% in 6M HCl)) in 300 ml of 1N aq. H2SO4 at 2° was slowly added (ca. 12 h) a solution of NaNO2 (19.5 g, 0.28 mol) in 300 ml of demineralised water. After stirring overnight at room temperature, 7.7 g of powdered NaHCO3 were added to bring the pH above 2. The solution was saturated with NaCl and extracted 6 times with ethyl acetate, maintaining the pH between 2 and 3 (1N aq. H2SO4, pH meter). After drying (Na2SO4), the organic layer was concentrated and the crude product (10.73 g, 91%) was recrystallised from hexane/ethyl acetate 9/1at -30° to give pure (+)-(2S,3S)-2-hydroxy-3-methylpentanoic acid [2].