Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:20].C(OCC)C>C(O)C>[C:12]1([C:11]2[C:2](=[S:20])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(N)=S
Reactant: Clc1nc2ccccc2cc1-c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: S=c1[nH]c2ccccc2cc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-phenylquinoline (3.4 g.) and thiourea (1.2 g.) in ethanol (20 ml.) was refluxed for one hour. The solution was allowed to cool to ambient temperature and diethyl ether (10 ml.) was added. The solid which precipitated was filtered off, dispersed in M-sodium hydroxide (70 ml.), and heated on a steam bath for 2 hr. The reaction mixture was acidified with 2 M-hydrochloric acid. The resulting mixture was filtered, and the solid residue was stirred with hot ethanol (50 ml.) and filtered. There was thus obtained as the solid residue 3-phenylquinolin-2-thione, m.p. 242°-4°.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[S:11])[CH3:9])[NH:6][C:5]1=[O:19])[CH3:3].N1C=CN=C1.[CH2:25]([Si:27]([CH2:31][CH3:32])([CH2:29][CH3:30])Cl)[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([Si:27]([CH2:31][CH3:32])([CH2:29][CH3:30])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[S:11])[CH3:9])[NH:6][C:5]1=[O:19])[CH3:3])[CH3:26]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (477 mg, 1.51 mmol) is dissolved in dry N,N-dimethylformamide (3 ml), and thereto are added imidazole (260 mg, 3.79 mmol) and triethylchlorosilane (456 mg, 3.0 mmol), and the mixture is stirred at room temperature for five hours. The reaction solution is diluted with ethyl acetate (30 ml) and washed with water. The aqueous layer is extracted with ethyl acetate (20 ml), and the organic layers are combined, washed twice with brine, dried over sodium sulfate, and evaporated to remove the solvent. The resulting oily residue is purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-triethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (342 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2cc(C(=O)OC(C)(C)C)c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cc(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.072 g (0.151 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 1.56 g (13.7 mmol) trifluoroacetic acid. Having stirred at room temperature for 1 hour, concentration to dryness is carried out on the rotary evaporator. Two dissolution steps in toluene and respective concentration on the rotary evaporator leave as the crude product a reddish solid which is recrystallized from petroleum ether/ethyl acetate (67:33) and yields the product as a white solid.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:39][CH2:38]1.CC(O)C>C(Cl)Cl>[F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH:46][CH2:45][CH2:44][CH2:43][N:40]6[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]6)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Reactant: CN1CCN(CCCN)CC1
Solvent: ClCCl
Solvent: CC(C)O
Product: CN1CCN(CCCNc2nccc(-c3cccnc3Oc3ccc(Nc4nc5cc(F)c(F)cc5[nH]4)cc3)n2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A resealable pressure vial was charged with 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.14 g, 0.28 mmol), 3-(4-methylpiperazin-1-yl)propan-1-amine (0.18 g, 1.13 mmol), and 2-propanol (1.89 ml, 0.15 M). The reaction vessel was sealed and the mixture stirred at 70° C. for 16 h. The reaction mixture was cooled to RT, diluted with DCM, and washed with Aq. NaHCO3. The organic layer was collected, dried over Na2SO4, and concentrated to afford brown residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 5,6-difluoro-N-(4-(3-(2-(3-(4-methylpiperazin-1-yl)propylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=572.2 [M+H]+. Calc'd for C30H31F2N9O: 571.62.
Reaction SMILES: [CH3:1][N:2]1[C:6](C(O)=O)=[C:5]([C:10]([OH:12])=[O:11])[N:4]=[C:3]1[NH:13][CH:14]([CH3:16])[CH3:15]>CN(C)C(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:10]([OH:12])=[O:11])[N:4]=[C:3]1[NH:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Nc1nc(C(=O)O)c(C(=O)O)n1C
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc(C(=O)O)cn1C
Temperature: 180 °C
Yield: 88 %

Procedure:
A mixture of 1-methyl-2-isopropylamino-4,5-dicarboxyimidazole (910 mg; 4 mmol) and 20 ml of N,N-dimethylacetamide is heated at 180° C. under argon for three hours. The solvent is evaporated under reduced pressure; the residue, taken up with minimum ethanol, is precipitated with tetrahydrofuran. The mother liquors are concentrated until precipitation is obtained. The 1-methyl-2-isopropylamino-4-carboxyimidazole is obtained with a yield of 88%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[C:24](Cl)(=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[CH2:17]([NH:16][C:14]([C:4]1[S:3][C:2]([NH:1][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:6][C:5]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of 2-amino-N,4-dibenzylthiazole-5-carboxamide (0.053 g, 0.16 mmol) in tetrahydrofuran (5 mL) at 0° C. was added hydrocinnamoyl chloride (0.03 mL, 0.20 mmol), DMAP (cat.) and triethylamine (0.3 mL, 2.10 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound in 49% yield (0.036 g); 1H NMR (CDCl3, 400 MHz) δ 7.35-7.15 (m, 15H), 4.56 (d, J=5.6 Hz, 2H), 4.37 (s, 2H), 3.03 (t, J=7.6 Hz, 2H), 2.74 (t, J=7.6 Hz, 2H); MS (ES+) m/z 456 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][C:13]([OH:15])=[O:14])(=O)C.[OH-].[NH4+].C(Cl)Cl.CO.CC(O)=O>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([CH2:12][C:13]([OH:15])=[O:14])[CH:7]=1
Reactant: CC(=O)Oc1ccc(F)cc1CC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)Cc1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (7p) (3.5 g, 16.5 mmol) was dissolved in 65 mL of MeOH, and 7 mL of ammonium hydroxide (49.5 mmol) was added. The mixture was stirred at room temperature overnight and then checked by TLC (DCM/MeOH/AcOH (9:1:0.15)), HPLC and MS. No starting material was observed. The material was concentrated to dryness to give the desired product (8p) which was carried onto the next step directly. MS (APCI−) m/z 168.9 (M−H), 338.7 (2M−H) was detected.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH:28]2[C:33]([F:35])([F:34])[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH:28]2[C:33]([F:35])([F:34])[CH2:32][CH2:31][N:30]([CH3:38])[CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2CNCCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CN(C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h
Yield: 64.6 %

Procedure:
A suspension of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-piperidin-3-ylmethoxy)-pyridazine dichloride (0.17 mmol, 90 mg), 37% paraformaldehyde (0.4 mmol, 32 mg), and 1 drop of acetic acid in 5 mL of DCM was stirred for 5 min then added sodium triacetoxyborohydride (0.4 mmol, 85 mg) and continued stirring for 0.5 h at room temperature. Quenched with water, solvent was evaporated; the residue was diluted with ethyl acetate, and then washed with saturated NaHCO3 solution, brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-1-methyl-piperidin-3-ylmethoxy)-pyridazine (52 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCl.C(N(C(C)C)CC)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To a solution of 1-benzyl-4-aminopiperidine (1.13 g) in dichloromethane (10 ml) were added a solution of 4-fluorobenzoyl chloride (0.99 g) in dichloromethane (1 ml) and diisopropylethylamine (1.09 ml) under cooling on an ice-water bath. The mixture was warmed to ambient temperature slowly under stirring. The mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, water, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol=15:1). After rinse with diisopropyl ether-n-hexane (1:1), N-(1-benzylpiperidin-4-yl)-4-fluorobenzamide (1.31 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[C:11]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([OH:12])[C:10]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>COCCOC>[CH3:35][S:32]([O:22][CH2:21][C:10]1([CH2:19][O:20][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:9][CH2:8][CH:7]([CH2:6][C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:11]1([OH:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)(=[O:34])=[O:33]
Reactant: OCC1(CO)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Reactant: CS(=O)(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(COS(C)(=O)=O)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-(4-chlorobenzyl)-2,2-bis(hydroxymethyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (0.50 g, 1.42 mmol) (Compound (4)) and triethyl amine (0.70 ml, 1.42×3.5 mmol) were dissolved in DME (15 ml). After adding mesyl chloride (0.30 ml, 1.42×2.7 mmol) under ice-cooling, the solution was removed from the ice bath and stirred for 5 hours at room temperature. After the stirring was complete, 1N aqueous solution of hydrochloric acid was added and then extracted using ethyl acetate. After washing the organic layer using a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, the organic layer was dried using anhydrous sodium sulfate and then concentrated. The concentrate was refined using a silica gel column to obtain white, viscous Compound (3).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:8]=[CH:9][CH:10]=1)[CH3:3].[CH3:16][N:17]=[C:18]=[S:19]>C(#N)C>[CH3:16][NH:17][C:18]([NH:15][CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=1)=[S:19]
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)NCCSCc1cccc(CN(C)C)c1

Procedure:
2-[[3-(N,N-Dimethylaminomethyl)phenyl]methylthio]ethanamine (5 g) and methyl isothiocyanate (1.62 g) were stirred at room temperature in acetonitrile for 18 hours. The solvent was removed and the residue was column chromatographed on silica using a mixture of ethyl acetate and methanol as eluent to give the title compound as a pale yellow oil. TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia (25:15:8:2) Rf 0.61.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.Br[C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[Mg].C1C[O:22]CC1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[O:22]
Reactant: COc1cccc(Br)c1
Reactant: N#Cc1ccncc1
Reactant: C1CCOC1
Agent: [Mg]
Product: COc1cccc(C(=O)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A solution of 4-cyanopyridine in THF was added to the Grignard reagent prepared from 3-bromoanisole (37.4 g, 200 mmole) and magnesium (4.8 g, 200 mmole) in THF (400 ml) at -78° C. The solution was allowed to warm to 25° C. and quenched with ammonium chloride solution. The organic layer was separated and washed with water and 3N hydrochloric acid. The acid washes were stirred for 0.5 hr and neutralized with 50% sodium hydroxide. The basic mixture was extracted with ether. The extracts were dried and concentrated in vacuo. The crude material was crystallized from hexane to give 4-(3-methoxybenzoyl)pyridine (27 g, 63.3%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].ClC[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](C3CCCCC3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:27][CH2:28][N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:34][CH2:35]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: O=C(CCCl)N1CCN(c2ccc(C3CCCCC3)cc2)CC1
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccccc5C5CCCCC5)CC4)c3C2=O)cc1

Procedure:
A target compound (136.1 mg, 0.251 mmol, 67.8%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (90 mg, 0.371 mmol) with potassium carbonate (76.8 mg, 0.556 mmol) and 3-chloro-1-{4-(4-cyclohexylphenyl)piperazin-1-yl}propan-1-one (136.6 mg, 0.408 mmol).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:5](=[O:11])([O-:4])[NH2:17].[C:13]([NH:17][C:2](=[O:4])[O:28][CH2:27][CH2:26][Br:25])([CH3:16])([CH3:15])[CH3:14]
Reactant: OCCBr
Reactant: CC(C)(C)N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)OCCBr
Product: NC(=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled solution of triphosgene (76 g, 0.256 mol, 0.75 eq.) in dry DCM (150 mL) was added, dropwise at 0° C. over a period of 3 hrs under a N2 atmosphere, a mixture of tert-butylamine (25 g, 0.3418 mol, 1.0 eq.), DMAP (2.08 g, 0.017 mol, 0.05 eq.) and triethylamine (67.1 g, 0.6836 mol, 2.0 eq.) in dry DCM (100 mL). After addition of the mixture was complete, the reaction mixture was stirred at RT for 12 hrs. The reaction mixture was cooled to 0° C. and 2-bromoethanol (106.8 g, 0.854 mol, 2.5 eq.) was added. The reaction mixture was then stirred at RT for 6 hrs, before being diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The resulting residue was distilled under reduced pressure to yield carbamate the sub-title compound as a colourless liquid. Yield: 28 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:28]([CH:35]([C:41]([OH:43])=[O:42])[C@@H:36]([C:38]([OH:40])=[O:39])[NH2:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:37][C@H:36]([C:38]([OH:40])=[O:39])[CH:35]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:41]([OH:43])=[O:42])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
5.3 g (30 mmol) of t-butoxycarbonyl glycine was dissolved in 100 ml of purified THF and 4.6 ml (33 mmol) of triethylamine and 4.33 ml (33 mmol) of isobutyl chloroformate) were added thereto at -15° C. The mixture was stirred at this temperature for 10 minutes. To the resultant solution of a mixed acid anhydride was added a solution which had been prepared by dissolving 8.0 g (36 mmol) of β-benzyl-L-aspartic acid and 5.02 ml (36 mmol) of triethylamine in water and cooling to 0° C. The mixture was then stirred at 0° C. for 1 hour and further at room temperature for 15 hours. After removing the THF by concentration under reduced pressure, cold 10% citric acid was added thereto. The precipitate thus formed was extracted with ethyl acetate twice. The extracts were combined and washed 5 times with one fifth the volume of 5% citric acid and then 10 times with water (one tenth the volume thereof). The solution was dehydrated over anhydrous sodium sulfate and concentrated to dryness. Then the residue was dissolved in ether and precipitated with n-hexane. After repeating this precipitation procedure 3 times, the obtained product was dried, whereby 6.9 g of the titled compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](Cl)=[O:14])=[C:11]([CH2:16][O:17][CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-].[BrH:22]>C(Cl)Cl.CCOCC>[Br:22][CH2:21][C:13]([C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][O:10][C:11]=1[CH2:16][O:17][CH3:18])=[O:14]
Reactant: COCc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Reactant: C=[N+]=[N-]
Reactant: Br
Solvent: ClCCl
Solvent: CCOCC
Product: COCc1onc(-c2ccc(F)cc2)c1C(=O)CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methoxyrnethyl-isoxazole-4-carboxylic acid chloride (2.7 g, 10.0 mmol) in methylene chloride (50 mL) was added diazomethane solution in ether (0.1 N, 100 mL) at ice-bath cooling temperature. The reaction was stirred for 1.5 h at 0° C. and allowed to stand overnight in a freezer at 0° C. An aqueous solution of hydrobromic acid (>40 wt %, 70 mL) was added dropwise to the reaction solution at ice-bath cooling temperature. After complete addition, the resulting mixture was stirred at 0° C. for 0.5 h and then allowed to warm up to room temperature and stirred for 1.5 h. The organic layer was separated, and the aqueous phase was extracted with ether. The combined ether solution was then washed with water and brine, dried over sodium sulphate and evaporated to afford the crude title compound (3.8 g) which was obtained as a light yellow liquid. MS: m/e=328.0/330.4 [M+H]+.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[C:26]4([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:25][CH2:24][CH2:23][C:22]3=[O:32])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:34]1[CH:43]=[N:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:42]=[CH:43][C:34]=1[N:29]1[CH2:30][CH2:31][C:26]2([N:21]([CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH:13]=[CH:12][N:11]4[S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[C:22](=[O:32])[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1
Reactant: Clc1cnc2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(c4cnc6ccccc6n4)CC5)cccc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 103 %

Procedure:
To a stirred solution of 1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecan-2-one (TFA salt) (0.11 g, 0.201 mmol) in 5.0 mL DMF, 2-chloroquinoxaline (0.04 g, 0.241 mmol) and K2CO3 (0.084 g, 0.603 mmol) were added and the reaction mixture was stirred for 6 h at 80° C. under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound as a pale yellow solid (0.120 g). LCMS RtA=0.512, [M+H]+=579.9
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.O[CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(=O)([O-])O.[K+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(C)=O>[C:25]([CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]2[CH2:13][CH2:12][O:10][CH:7]([C:5]3[N:6]=[C:2]([Cl:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:29])=[CH:18][CH:19]=1)([O:27][CH3:28])=[O:26]
Reactant: O=C(CBr)c1csc(Cl)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1

Procedure:
Prepared by analogy to Example 32 by reaction of 5 g (0.005 mmol) of 2-chloro-4-bromoacetyl-thiazole with 5.6 g (0.021 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in 200 ml of acetone and 6.3 g (0.063 mol) of potassium hydrogen carbonate over 20 hours at room temperature. The reduction is carried out in 41 ml of trifluoroacetic acid using 3.5 g (0.029 mol) of triethylsilane for 24 hours. The crude product is purified on a silica gel column using methylene chloride/methanol=20:1 as eluant.