Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]=[O:29]>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]([OH:29])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Nc1c(F)cccc1F
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccccc1)N(O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1,3-difluoro-2-nitrosobenzene (143 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[CH:23][CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[C:31]([N:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[CH:23][CH:22]=2)=[CH:3][C:2]=1[NH:1][CH:41]1[CH2:42][CH2:43][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39][CH2:40]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1N
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)ccc2C(C)(C)C)CC1

Procedure:
The title compound was prepared from N-(3-amino-4-tert-butyl-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide and Boc-piperidin-4-one by a method analogous to that described in Example 42. MS (ES+): 584 (M+H), Calc'd for C33H41N7O3—583.7.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH:24]1([C:22]2[N:13]=[C:12]([C:11]3[C:3]([CH3:2])=[N:4][N:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=34)[S:14][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C1CCCCC1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1CCCCC1
Yield: 94.7 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-cyclohexyl-3-oxopropanoate (870 mg, 3.7 mmol) produced in the above and 2-propanol (50 mL) as starting materials and in the same manner as in Example 11-B (vi), the title compound (455 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:13][CH3:14])[CH3:12].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:13][CH3:14])[CH3:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC1(C)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.52 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) was dissolved in dimethoxyethane (22 cm3). After 15 min., 3-chlorophenylboronic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0 g) in water (10 cm3) was added and the reaction was heated under reflux. After 2 h the mixture was cooled, poured into water and extracted with EtOAc (×2), the combined organic extracts were washed with sodium hydroxide solution (1N, ×2) water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, 5:1) to afford 5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g, 0.58 mmol, 29%): 1H NMR (CDCl3) δ 1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s, 3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H), 7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]#[N:14])[C:7]=2[CH:15]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+]>C(OC(=O)C)(=O)C.[Ni].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][NH:14][C:16](=[O:18])[CH3:17])[C:7]=2[CH:15]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)N(CC#N)CCO2
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2c(c1)N(CCNC(C)=O)CCO2
Reaction time: 12 h

Procedure:
The compound obtained in Step E (590 mg; 2.88 mmol) is dissolved in a Parr reactor with acetic anhydride. Raney nickel (10% by weight, 60 mg) and sodium acetate (1.5 eq.; 4.33 mmol; 355 mg) are then added. The mixture is left for 12 hours at 50° C. under a hydrogen pressure of 40 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The residue obtained is taken up in water and then extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4, and then concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (4/6) then AcOEt/MeOH (95/5)). The title product is obtained in the form of white crystals after washing with ether.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[C:19]2[C:10]([CH:11]=[C:12]3[C:17](=[CH:18]2)[CH:16]=[CH:15][CH:14]=[CH:13]3)=[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=12.[B:25](OC)([O:28]C)[O:26]C.O>C1COCC1>[CH:14]1[C:15]2[C:20]3[C:19]([CH:18]=[C:17]([B:25]([OH:28])[OH:26])[C:16]=2[CH:11]=[CH:12][CH:13]=1)=[CH:10][C:9]1[C:8](=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:7]=3
Reactant: Brc1cc2cc3ccccc3cc2c2ccccc12
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cc2cc3ccccc3cc2c2ccccc12
Reaction time: 2 h

Procedure:
52 ml (130 mmol) of n-butyllithium (2.5 M in n-hexane) are added dropwise with vigorous stirring at −78° C. to a suspension of 30.7 g (100 mmol) of 5-bromobenz[a]anthracene in 1000 ml of THF, and the mixture is stirred for a further 2 h. 16.7 ml (150 mmol) of trimethyl borate are added to the red solution in one portion with vigorous stirring, the mixture is stirred at −78° C. for a further 30 min., then warmed to room temperature over the course of 3 h, 300 ml of water are added, and the mixture is stirred for 30 min. The organic phase is separated off and evaporated to dryness in vacuo. The solid is taken up in 100 ml of n-hexane, filtered off with suction, washed once with 100 ml of hexane and dried in vacuo. Yield: 24.8 g (91 mmol), 91%, purity about 90% (NMR) of boronic acid, with varying amounts of boronic anhydride and borinic acid. The boronic acid can be used in this form without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+].CO.Cl>O>[F:1][C:2]([F:14])([F:15])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccc(C#CC(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C#CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a 100 mL round bottom flask was added 4-(3,3,3-trifluoroprop-1-ynyl)benzoate (0.68 g, 2.9 mmol), lithium hydroxide (0.71 g, 29 mmol), and methanol (30 mL): water (10 mL). The mixture was stirred at room temperature for 30 minutes, heated at reflux for 1 hour, and reduced in vacuo. Water (100 mL) was added and the mixture was cooled to 0° C. HCl (10 N) was added slowly to the stirred solution until the pH of the solution reached 5. A yellow precipitate formed and was filtered, washed with cold water (3×100 mL), and dried under vacuum to afford 0.540 g (86%) of 4-(3,3,3-trifluoroprop-1-ynyl)benzoic acid as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([O:25][CH3:26])[C@@H:9]([N:13](C(OCC1C=CC=CC=1)=O)[CH3:14])[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([O:25][CH3:26])[C@@H:9]([NH:13][CH3:14])[CH:10]([CH3:11])[CH3:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN[C@@H](C(C)C)[C@@H](CC(=O)OC(C)(C)C)OC

Procedure:
To a solution of t-butyl-(3R,4S)-4-(N-benzyloxycarbonyl-N-methylamino)-3-methoxy-5-methylhexanoate (3.855 g, 10.17 mmol) in 100 ml methanol was added 10% Pd/C (0.541 g) and the mixture was hydrogenated until completion of the deprotection (tlc control). The catalyst was removed by filtration and the filtrate concentrated in vacuo. The resulting amorphous solid (2.49 g) can be crystallized from ether by adding a solution of HCl in dioxane.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:34])[CH2:32][CH2:33]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of tert-butyl {1-[4-(2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclopropyl}carbamate (27 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0° C. dropwise. After being stirred at room temperature for 30 min, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (NH-silica gel: 10-100% chloroform in hexanes then 10% methanol in chloroform) gave the product (25 mg, quant.). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.07 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.49 (d, J=6.9 Hz, 2H), 7.38-7.20 (m, 7H), 7.14-7.07 (m, 3H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 1.06-1.00 (m, 2H), 0.99-0.93 (m, 2H). LCMS: 442 [M+H].
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[C:23]2[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][CH:16]=[C:15]2[C:2]1[N:3]=[CH:4][C:5]2[NH:6][CH2:7][CH:8]3[CH2:14][O:13][CH2:12][CH2:11][N:9]3[C:10]=2[N:1]=1
Reactant: COc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cn(C(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c12

Procedure:
A TFA salt of the title compound was prepared in a manner similar to EXAMPLE 8 using tert-butyl 3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-7-methoxy-1H-indole-1-carboxylate (60 mg, 0.137 mmol) in CH2Cl2 and TFA. 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.05 (m, 1H), 3.27-3.30 (m, 1H), 3.53-3.66 (m, 1H), 3.76-3.90 (m, 1H), 3.91-3.98 (m, 5H), 3.97-4.06 (m, 1H), 4.08-4.18 (m, 1H), 4.68-4.84 (m, 1H), 6.33-6.45 (br s, 1H), 6.79-6.87 (m, 1H), 7.09-7.20 (m, 1H), 7.38-7.46 (m, 1H), 7.80-7.89 (m, 1H), 8.15-8.23 (m, 1H), 12.18-12.29 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C18H19N5O2S, 338.15. found 338.4.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=O.Cl.[NH2:19][OH:20].C[O-].[Na+]>CO>[OH:20]/[N:19]=[CH:1]/[C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-n2cccc2C=O)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-n2cccc2/C=N/O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
Methyl 3-(2-formylpyrrol-1-yl)benzoate (5.0 g) was added to a mixture of hydroxylamine hydrochloride (1.5 g) and 28% methanolic sodium methoxide (4.2 g) in methanol (50 ml) and the mixture was stirred for 4 hours at ambient temperature. The solvent was removed by concentration and the residue was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and ethyl acetate (19:1). The first eluted fractions containing the desired product were collected and evaporated in vacuo and the residue was triturated with a mixture of diisopropyl ether and n-hexane to give methyl 3-[(E)-2-hydroxyiminomethylpyrrol-1-yl]benzoate (Compound A) (0.8 g). The further eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-[(Z)-2-hydroxyiminomethylpyrrol-1-yl]benzoate (Compound B) (1.43 g) as an oil.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[OH:19][C:17]1[CH:16]=[CH:15][N:14]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[C:13](=[O:12])[CH:18]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: Oc1ccnc(O)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Temperature: 150 °C

Procedure:
A mixture of methyl 4-iodobenzoate (0.421 g, 1.6 mmol), 2,4-dihydroxypyridine (0.174 g, 1.34 mmol), CuI (25 mg, 0.134 mmol) and K2CO3 (200 mg) in DMF (2 mL) was heated to 150° C. in a sealed vial for 4 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/e 246 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[CH3:15][CH:14]([C@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)[CH3:16].[C:19]([OH:21])([C:18]([F:23])([F:22])[F:17])=[O:20]
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.180 mmol) dissolved in dichloromethane (5.4 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours at room temperature. The mixture was concentrated to afford (3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol as a TFA salt. 1H NMR (500 MHz, CDCl3) δ 3.91-3.62 (m, 1H), 3.60-3.36 (m, 2H), 2.47-2.10 (m, 2H), 2.05-1.79 (m, 2H), 1.07 (d, J=6.6, 3H), 1.01 (d, J=6.7, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[N:19]=[C:18]3[CH2:20][CH2:21][CH2:22][C:17]3=[CH:16][CH:15]=2)[CH:3]=1.CO.[NH3:25]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[N:19]=[C:18]3[CH2:20][CH2:21][CH2:22][C:17]3=[CH:16][CH:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate (554 mg, 1.74 mmol) was suspended in ammonia 7M in methanol (11.8 g, 15.0 mL, 105 mmol). The flask containing the mixture was sealed and stirred at room temperature for 18 h. The precipitated off-white solid was separated by filtration and dried under high vacuum to give 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxamide (375 mg, 75%) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.92 (s, 1H), 8.95 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 2.78-3.00 (m, 4H), 2.07 (quin, J=7.6 Hz, 2H); LC-MS 290.0 [M+H]+.
Reaction SMILES: [O:1]=O.[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[OH-].[NH4+].[NH4+].[NH4+].[NH4+].[OH-].[OH-].[OH-].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:3][C:4]1[C:5](=[O:1])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=1)[CH:7]=2
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: O=O
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Yield: 89.6 %

Procedure:
Into a three-necked, 300-mL flask equipped with a stirrer, a molecular-oxygen-containing gas (air) inlet tube and a gas outlet tube (fitted with a condenser), 2,7-dibromofluorene (9.30 g, 0.029 mol) was charged, followed by its dissolution with toluene (100 g). Subsequent to addition of a 25% aqueous solution of tetraammonium hydroxide (0.77 g) and a 48% aqueous solution of sodium hydroxide (2.66 g), the resulting mixture was vigorously stirred at 60° C. for 3 hours while introducing air at a flow rate of 0.1 L/min. After completion of the stirring, the reaction mixture was allowed to stand, and the resulting toluene layer was collected. The toluene layer was then subjected to acid washing, followed by water washing until its pH arose to 7. Toluene was then distilled off to recover crude crystals of 2,7-dibromofluorenone. The content of 2,7-dibromofluorene in the crude crystals at that time was 0%. Those crude crystals were recrystallized from N,N′-dimethylformamide (15 g) to afford 2,7-dibromofluorenone as yellow crystals (8.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=5)[CH2:22][CH2:21]4)[C:15](=[O:33])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:34]=1.[CH3:35][NH:36][CH3:37]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28]([N:36]([CH3:37])[CH3:35])[N:27]=5)[CH2:24][CH2:25]4)[C:15](=[O:33])[CH2:14]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:34]=1
Reactant: CNC
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(Cl)n2)CC1
Solvent: CCO
Product: CN(C)c1nccc(N2CCC(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)CC2)n1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one (17 mg, 0.031 mmole) in ethanol (1 mL) is added a 40% solution of dimethylamine (11 mg, 0.094 mmole). This mixture is heated at 80° C. in a sealed tube 16 h. The reaction is concentrated and lyophilized to provide 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-dimethylamino-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one. 1H NMR (300 MHz, CDCl3) d 7.93-7.84 (m, 4H), 7.48 (dd, 1H), 5.84 (d, 1H), 4.32 (d, 2H), 3.87 (s, 2H), 3.47 (s, 4H), 3.26 (d, 2H), 3.14 (s, 6H), 1.99-1.90 (m, 1H), 1.62 (d, 2H), 1.27-1.17 (m, 2H); MS (Ion spray) 549 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[NH:11][CH2:10][C@H:9]1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:10][C@H:9]1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a stirred suspension of (2R,5R)-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (11 g, 45 mmol), potassium carbonate (6.79 g, 49.14 mmol) and acetonitrile (48 mL) was added benzyl bromoacetate (7.08 mL, 44.67 mmol) dropwise at ambient temperature. The reaction was stirred for 18 h at ambient temperature, then diluted with chloroform (150 mL), filtered and the filtrate concentrated. The crude oil was purified by column chromatography on silica gel (gradient elution, 0-70%, EtOAc/petrol), to give the title compound (16 g, 92%) as a pale yellow oil. 1H NMR (Me-d3-OD): 7.45-7.22 (5H, m), 5.21-5.12 (2H, m), 4.84 (2H, s), 4.16-4.03 (1H, m), 3.91 (1H, d), 3.62 (1H, d), 3.56-3.40 (2H, m), 3.31-3.19 (3H, m), 3.04-2.92 (1H, m), 2.80 (1H, dd), 2.68 (1H, dd), 1.48 (9H, s), 1.19 (3H, d).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21]I>CC(N(C)C)=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH3:21])[C:4]=2[CH:3]=1
Reactant: CCS(=O)(=O)NC1CCCCc2ccc(F)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)N(C)C1CCCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 0.81 g (3 mmol) of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepte (Example 1) in 10 ml of DMA was added dropwise under argon to a suspension of 0.12 g (4.1 mmol) of 80 percent sodium hydride in 5 ml of DMA. After stirring at RT for 3 h, 0.63 g (4.5 mmol) of methyliodide was added dropwise and the mixture was stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 0.64 g of 3-fluoro-5-(N-ethylsulfonyl-N-methylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:28]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCCCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -11° C. and -12° C. during 20 minutes. After stirring for 5 minutes, 8.9 g (0.088 mol) of hexylamine dissolved in 80 ml of dried chloroform are dropped to the above solution at -12° C. during 35 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then let to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.4 g (71.3%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 116°-118° C.