Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:16](=[O:39])[N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:16]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:39]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccc(-c4ccccc4)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccc(-c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a stirred solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (30 mg) in DCM (10 mL) at room temperature. The solution was stirred at room temperature for 4 hours, quenched with aqueous NaOH (1N, 10 mL), diluted with EtOAc (100 mL) and washed with aqueous NaOH (2×50 mL.) The organic phase was dried over Na2SO4 and concentrated in vacuo to give 2-amino-3-(4-chlorophenyl)-1-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-propan-1-one as a colorless oil (23 mg.) 1H NMR (CDCl3, 400 MHz) δ 8.77 (1H, s), 8.02-8.00 (2H, m), 7.98 (1H, s), 7.64 (2H, d, J7.4 Hz), 7.53 (2H, t, J7.7 Hz), 7.44 (1H, t, J7.3 Hz), 7.30 (2H, d, J8.6 Hz), 7.17 (2H, d, J8.6 Hz), 3.98 (1H, t, J7.3 Hz), 3.87-3.60 (6H, m), 3.42-3.34 (2H, m), 2.97 (1H, dd, J7.4 and 13.3 Hz), 2.84 (1H, dd, J7.0 and 13.7 Hz.) The oil was taken up into THF (10 mL) and treated with HCl (1.0M in Et2O, 10 mL) and concentrated in vacuo to give the bis hydrochloride salt of 2-amino-3-(4-chlorophenyl)-1-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-propan-1-one as a solid (21 mg).
Reaction SMILES: [CH:1]1([CH2:4][C:5](Cl)=[O:6])[CH2:3][CH2:2]1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH2:23])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH:23][C:5](=[O:6])[CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)CC1CC1
Product: Cc1nc(NC(=O)CC2CC2)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopropylacetyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 27% yield; m.p. 136-139° C.; 1H NMR (CDCl3, 300 MHz) δ 7.34-7.24 (m, 5H), 5.97 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.60 (s, 3H), 2.39 (d, J=7.2 Hz, 2H), 1.05-1.00 (m, 1H), 0.71-0.68 (m, 2H), 0.27 (q, J=4.8 Hz, 2H); MS (ES+) m/z 330.1 (M+1).
Reaction SMILES: Cl[S:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[CH3:8][C:9]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH:12]([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]([C:3]([S:2][N:19]1[CH2:18][CH2:17][N:16]=[C:15]1[CH:12]([O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:9]=1[CH3:8])[CH2:13][CH3:14])([CH3:7])[CH3:6])#[N:5]
Reactant: CCC(Oc1cccc(C)c1C)C1=NCCN1
Reactant: CC(C)(C#N)SCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Oc1cccc(C)c1C)C1=NCCN1SC(C)(C)C#N

Procedure:
With continuous stirring and cooling, 4.1 g of α-(chlorothio)-isobutyronitrile are added dropwise at 0° to 10° C. to a solution of 6.97 g of 2-[1-(2,3-dimethylphenoxy)-propyl]-2-imidazoline of the formula ##STR4## and 4 g of triethylamine in 80 ml of toluene. The reaction mixture is stirred for 1 hour at room temperature, then the toluene phase is washed repeatedly with water and dried. The toluene is then evaporated off, affording 1-(2-cyano-prop-2-ylthio)-2-[1-(2,3-dimethylphenoxy)-propyl]-2-imidazoline of the formula ##STR5## in the form of a yellow viscous oil with a melting point of 58°-60° C. The following compounds of the formula I can be obtained by procedures analogous to the one described in this Example: ##STR6##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@@H:8]2O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.O>O1CCCC1>[Cl:20][C@@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C@H:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1
Reactant: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2c(c1)[C@@H](Cl)C[C@H]2c1ccccc1
Temperature: 25 °C

Procedure:
A solution of (1S,3S)-6-chloro-3-phenylindan-1-ol (Va) (17 g) (synthesized as in example 8) in tetrahydrofuran (130 ml) is cooled with an ice bath. Thionyl chloride (9.9 g) in tetrahydrofuran (50 ml) is added drop wise at 4-5° C., and then the mixture is stirred over night at ambient temperature. A mixture of water and ice (approximately 25 ml) is added, and stirring is continued until all the ice has melted. The phases are separated, and the organic phase is washed twice with sodium bicarbonate (5% in water, 25 ml). The water phases are then combined, extracted with the organic phase, and then extracted with ethyl acetate (50 ml). The organic phases are then combined, dried with magnesium sulfate, filtered, and evaporated to dryness using a rotary evaporator. Yield 18.7 g (102%) of the title compound as an oil, which partly solidifies. The content of (1S,3R)-3,5-dichloro-1-phenylindan is 18% according to NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)([CH2:14][N:15](C)[C:16](=O)C(F)(F)F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:23]2[CH:24]=[CH:25][C:26]([I:29])=[CH:27][CH:28]=2)([CH2:14][NH:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNCC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 83 %

Procedure:
4-(4-Iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.42 mmol) was dissolved in MeOH (4.5 mL) and H2O (0.6 mL) and K2CO3 (0.29 g, 2.1 mmol, 5 eq.) was added. The mixture was stirred and heated at 70° C. for 4 h, cooled to room temperature and then partitioned between H2O (20 mL) and CH2Cl2 (20 mL). The aqueous layer was washed with CH2Cl2 (3×10 mL) and the combined organic washes were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 4-(4-iodo-phenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 83%). 1H NMR (CDCl3): δ 7.78 (dd, 2H), 7.18 (dd, 2H), 3.74 (m, 2H), 3.22 (m, 2H), 2.73 (s, 2H), 2.38 (s, 3H), 2.23 (m, 2H), 1.88 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C@@H:13]([CH3:20])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O)=CC=1.[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24]>>[C:16]([O:15][CH2:14][C@H:13]([CH3:20])[CH2:12][CH2:11][CH2:22][CH:23]([CH3:25])[CH3:24])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](C)COC(C)(C)C)cc1
Reactant: CC(C)C[Mg]Br
Product: CC(C)CCC[C@@H](C)COC(C)(C)C
Yield: 76 %

Procedure:
Coupling of (R)-(+)-4-tert. butoxy-3-methyl-1-butanol p-toluenesulfonate with isobutylmagnesium bromide was carried out using the procedure of Example 47. (R)-(+)-1-tert. Butoxy-2,6-dimethylheptane was obtained in 76% yield as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
2.9 g (7.6 mmol) of ethyl 7-chloro-8-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 10 ml of acetic acid, 10 ml of water and 1 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:20])[CH3:19].CC([O-])(C)C.[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:28][CH:27]=3)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3′,4′-dichloro-4-fluorobiphenyl-3-carbonitrile (173 mg, 0.650 mmol), 4-isopropoxyaniline (108 mg, 0.715 mmol), and KOtBu (154 mg, 1.375 mmol) in DMSO (4 mL) was stirred at rt for 1.5 h, The mixture was diluted with ethyl acetate, washed with H2O and brine, and then dried over Na2SO4. The solvent was removed and the product was purified by silica gel chromatography (eluting with hexane containing 0 to 8% ethyl acetate) followed by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=50:50 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min). This afforded 99 mg of 3′,4′-dichloro-4-(4-isopropoxyphenylamino)-biphenyl-3-carbonitrile which still contained some impurities according to the LC/MS but was used as such for next step. MS (ESI) m/z 397.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][CH2:20][CH2:19][CH2:18][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCCN1CCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc2c(NCCCN3CCCC3)ccnc2c1

Procedure:
3.08 g from 7.72 g of 4,7-dichloroquinoline and 5 g of 3-(pyrrolidin-1-yl)-propylamine (reaction duration 16 hours at 140° C.); the base was converted with isopropanolic hydrochloric acid into the dihydrochloride which when recrystallized from acetonitrile/ethanol, yielded colourless crystals, m.p.: 204°-206° C.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]([O:13][CH3:14])[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=2[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[C:34]([CH2:33][C:30]1[S:31][CH:32]=[C:28]([C:2]2[C:6]3[C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=3[N:4]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=2)[CH:29]=1)#[N:35]
Reactant: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
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: COc1ncc(C#N)c2c1c(-c1csc(CC#N)c1)cn2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A mixture of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (250 mg) obtained in Step H of Example 33, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl)acetonitrile (292 mg), tetrakis(triphenylphosphine)palladium(0) (90 mg), 2M aqueous sodium carbonate solution (0.781 mL) and DME (3.0 mL) was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (220 mg).
Reaction SMILES: C(S)C.[H-].[Na+].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23]C)[CH:16]=2)=[CH:9][N:8]=1>CN(C)C=O>[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([OH:23])[CH:16]=2)=[CH:9][N:8]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: COc1cc(O)cc(Cc2cnc(N)nc2N)c1
Temperature: 25 °C

Procedure:
A solution of 32.2 g. of ethylmercaptan in 310 ml. of dimethylformamide was added dropwise with cooling and nitrogen gasification to a suspension of 25 g. of 50% sodium hydride in 310 ml. of dimethylformamide. The mixture was subsequently treated with a solution of 27 g. of 2,4-diamino-5-(3,5-dimethoxybenzyl)pyrimidine in 310 ml. of dimethylformamide, stirred at 100° C. for 17 hours, cooled down to room temperature and concentrated under a high vacuum. The residue, dissolved in a small amount of water, was filtered, the filtrate was extracted three times with 50 ml. of benzene each time and the aqueous phase was adjusted to pH 4-5 with concentrated hydrochloric acid while cooling with ice-water. Subsequently, it was brought to pH 9 with concentrated ammonia and the precipitated product, 23.3 g. of α-(2,4-diamino-5-pyrimidyl)-5-methoxy-m-cresol of melting point 254°-255° C. (from methanol) was isolated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O.CCOC(C)=O>[CH2:10]([NH:9][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(NCc1ccccc1)C1CCNCC1
Yield: 34.7 %

Procedure:
4-Piperidinecarboxamide (10.2 g, 78.0 mmol) in DMSO (10 mL) was treated with benzyl bromide (20.0 mL, 168 mmol). The mixture was diluted with EtOAc and washed with 1N aq. HCl, 5N aq. NaOH, dried over MgSO4, and concentrated to give 5.90 g (35%) of N-benzyl-4-piperidinecarboxamide. [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:21]3[CH:22]=[C:23]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:25]=[CH:24]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: OC1CCC2(CCCC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Yield: 61 %

Procedure:
The mixture of spiro[4.5]decan-8-ol (0.915 g, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was taken up into DCM and subjected to chromatography purification with EtOAc/hexane (0:100 to 40:60) to give product as a white solid (1.02 g, 61%). LCMS Rt=2.58 min, m/z=339.34, (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4[CH2:20][CH:19]([C:21]5[N:25]=[C:24]([C:26]6[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=6)[NH:23][N:22]=5)[CH2:18]4)=[CH:12][CH:11]=3)[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:6][N:5]2[CH:39]=1.[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:39]1[N:5]2[CH:6]=[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4[CH2:20][CH:19]([C:21]5[N:25]=[C:24]([C:26]6[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=6)[NH:23][N:22]=5)[CH2:18]4)=[CH:12][CH:11]=3)=[N:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)cn6cc5-c5ccccc5)cc4)C3)n[nH]2)n1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)c(Br)n6cc5-c5ccccc5)cc4)C3)n[nH]2)n1
Yield: 32.9 %

Procedure:
50 mg (0.098 mmol) 2-Methyl-7-{4-{3-[5-(6-methylpyridine-2-yl)-1H-[1,2,4]triazole-3-yl)-azetidine-1-ylmethyl]-phenyl}-6-phenyl-imidazo[1,2-a]pyrimidine are dissolved in 3.9 mL chloroform. 19.1 mg (0.11 mmol) N-bromosuccinimide are added and the reaction mixture is heated for one hour at reflux. The solvent is evaporated and the residue is purified by chromatography (silicagel, eluents: dichloromethane/methanol). 19.1 mg (31.5%) of the desired compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:23]1([CH2:22][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN(Cc2ccccc2)C2CCNCC2)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl 4-[bis(phenylmethyl)amino]-1-piperidinecarboxylate D74 (160 g, 420 mmol) was dissolved in dichloromethane (DCM) (1 L) and TFA (188 mL, 2443 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 3 h then further 100 mL of TFA was added and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue treated with saturated solution NaHCO3 (1.5 L) and NaOH (3M solution; 200 mL) to basic pH. The aqueous phase was extracted with DCM (2×1.5 L). Combined organic layers were diluted with ethyl acetate (100 mL), washed with water (1×1 L) and brine (1×1 L) then dried on Na2SO4 and concentrated to obtain title material (118 g; 100%).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])([CH3:8])[CH3:9])=[CH:18][CH:17]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 98.6 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (170 mg) described in Preparation Example 39 and 1-(3,5-dimethylpyridin-2-yl)piperazine (138 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (270 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[C:60](=[O:69])[NH:61][C:62]3[C:67]([CH:68]=2)=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:55][CH2:54]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:53]3[CH2:54][CH2:55][CH:56]([C:59]4[C:60](=[O:69])[NH:61][C:62]5[C:67]([CH:68]=4)=[CH:66][CH:65]=[CH:64][CH:63]=5)[CH2:57][CH2:58]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1OCc2c(cc(Br)c3[nH]ncc23)C[C@H]1CC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
(S)-2-(4-Bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetic acid (90 mg, 0.265 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). N,N-Diisopropylethylamine (150 μl, 0.861 mmol) was added to the mixture followed by TBTU (94.5 mg, 0.294 mmol). 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (90.3 mg, 0.341 mmol) was added to the reaction mixture. Reaction stirred at room temperature for 3 hours. Reaction was quenched with water. Material was extracted twice with ethyl acetate. Organic phase was filtered. Filtrate was concentrated by roto-vap. Residue was purified by prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 19% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.98 (s, 1H) 12.21 (s, 1H) 8.86 (s, 1H) 8.13 (d, J=3.36 Hz, 1H) 8.05 (t, J=6.87 Hz, 1H) 7.81-7.93 (m, 2H) 7.70 (d, J=8.24 Hz, 1H) 7.57 (t, J=7.63 Hz, 1H) 6.38 (d, J=14.65 Hz, 1H) 6.00 (d, J=14.95 Hz, 1H) 4.98 (d, J=13.12 Hz, 1H) 4.48-4.56 (m, 2H) 3.67-3.74 (m, 1H) 3.54-3.67 (m, 1H) 3.30-3.53 (m, 3H) 3.04-3.16 (m, 1H) 2.95-3.04 (m, 1H) 2.36 (t, J=11.14 Hz, 1H) 2.28 (t, J=9.46 Hz, 1H) 1.91-2.04 (m, 1H) 1.77-1.90 (m, 1H). High resolution M/E (M+H)+=549.1132.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCCC2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.