Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[C:16]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:25][CH3:26])(=[O:11])=[O:10].[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:34]([CH3:35])[C:30]=2[CH:29]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][O:25][C:13]1[CH:14]=[CH:15][C:16]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:33]1[S:32][C:31]2[CH:40]=[CH:41][C:28]([Cl:27])=[CH:29][C:30]=2[C:34]=1[CH3:35])(=[O:38])=[O:37])(=[O:10])=[O:11]
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of of N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (0.5 mmol, prepared as in Example A) in DCM (1 mL) and pyridine (1 mL), 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (0.55 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 202 mg of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethanesulfonyl-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.32 min, MS: 655.4 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 2.14 (s, 3H), 4.29 (s, 3H), 6.33 (bs, 1H), 6.54 (d, 1H), 6.98 (t, 1H), 7.24 (t, 1H), 7.35 (d, 1H), 7.45 (dd, 1H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.75 (d, 1H), 8.14 (bs, 1H), 8.17 (dd, 1H), 8.31(d, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O:10]C)=O)[C:4]([O:6]C)=O.Cl.[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:6][C:4]1[C:3]([O:2][CH3:1])=[C:8]([OH:10])[N:27]=[C:25]([C:24]2[CH:28]=[CH:29][C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][CH:23]=2)[N:26]=1
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(OC)C(=O)OC
Agent: Cl
Product: COc1c(O)nc(-c2ccc(OCc3ccccc3)cc2)nc1O

Procedure:
In process (A), dimethyl methoxymalonate and 4-benzyloxybenzamidine hydrochloride are reacted to obtain 4,6-dihydroxy-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine (1), which is then chlorinated with phosphorus oxychloride to obtain a dichloro derivative (2). The compound (2) is debenzylated by hydrogenation using palladium-on-carbon to obtain 5-methoxy-2-(4-hydroxyphenyl)pyrimidine (3), which is again protected with a benzyl group [(3)→(4)], followed by demethylation [(4)→(5)]. Compound (5) is reacted with an optically active 3-fluoroalkyl mesylate to obtain compound (6). After removing the benzyl protective group by hydrogenation with palladium-on-carbon [(6)→(7)], compound (7) is reacted with an optically active 3-fluoroalkyl mesylate to obtain compound (8).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][CH2:26][C:27](=O)[CH2:28][CH3:29]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:27]([CH2:28][CH3:29])[CH2:26][CH3:25])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CCC(=O)CC
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CCC(CC)=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C

Procedure:
The product of Example 268D (0.073 g, 0.2 mmol) was reacted with pentan-3-one (0.86 g, 10.0 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN(C)CCCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-dimethylbutane-1,4-diamine according to general procedure 1 providing the intermediate (300 mg, 74%) as a yellow oil: Rf=0.40 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=9.6 Hz, 1H), 7.45 (s, 1H), 6.38 (d, J=9.6 Hz, 1H), 6.07 (brs, 1H), 3.40 (quart, J=5.2 Hz, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.25 (s, 6H), 1.76 (quin, J=6.6 Hz, 2H), 1.64 (quin, J=6.8 Hz, 2H); ES-MS: (M+H)=312, 314 m/z.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:47][C:48]1[CH:49]=[C:50]([CH:60]=[C:61]([F:63])[CH:62]=1)[CH2:51][NH:52][C:53](=[O:59])[CH:54]([CH3:58])[C:55](O)=[O:56].CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[F:47][C:48]1[CH:49]=[C:50]([CH:60]=[C:61]([F:63])[CH:62]=1)[CH2:51][NH:52][C:53](=[O:59])[CH:54]([CH3:58])[C:55]([NH:1][CH:2]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4])=[O:56]
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-1-(3,4-dihydro-1H-isoquinolin-2-yl)-3-(1H-indol-3-yl)-propan-1-one (57 mg, 0.18 mmol) was placed in a disposable polypropylene tube and dissolved in DMF (1 ml). TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate, 65 mg, 0.2 mmol) and N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (49 mg, 0.2 mmol) were added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=545.3 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1.CS(O)(=O)=O>C(Cl)Cl>[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][NH:1][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
Sodium azide (0.431 g, 6.63 mmol) was added slowly to a mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol) and methanesulfonic acid (15 mL, 231 mmol) in DCM (30 mL) at 0° C. The mixture was stirred at rt for 15 hrs, then was carefully quenched with 1 M aqueous sodium hydroxide (50 mL). The aqueous layer was extracted with DCM (3×50 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 hexane-EtOAc to EtOAc) to give 7-bromo-3,4-dihydroisoquinolin-1(2H)-one as white solid (650 mg, 61%). 1H NMR (400 MHz, chloroform-d) δ 8.35 (1 H, br. s.), 7.08-7.17 (1 H, m), 6.98-7.06 (1 H, m), 6.95 (1 H, d, J=1.98 Hz), 2.93 (2 H, t, J=7.59 Hz), 2.49-2.68 (2 H, m). Mass spectrum m/z 226, 228 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][N:26](C(OC=C)=O)[CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:35].CCOCC>C(O)C>[ClH:35].[ClH:35].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][NH:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)CN(C(=O)OC=C)C1)C2c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1CNCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNCC1=O)N2
Temperature: 25 °C

Procedure:
A solution of the product from Example 4B (0.22 g, 0.41 mmol) in ethyl alcohol (5 mL) was treated with concentrated hydrochloric acid (0.10 mL), refluxed for 3 hours, allowed to cool to ambient temperature and treated with ether. The resulting solid precipitate was collected and dried to provide the title compound (0.12 g).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:13][C:14](O)=[O:15])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]([C:4]1[C:5]([CH2:13][CH2:14][OH:15])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1CC(=O)O)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc2c(cc1CCO)OCO2
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 6.25 g of (6-isopropyl-1,3-benzodioxol-5-yl)acetic acid (crude crystal) in 30 ml of tetrahydrofuran was dropwise added to a suspension of 1.6 g of lithium aluminum hydride in 40 ml of tetrahydrofuran under cooling with ice. The obtained mixture was stirred overnight. 1.6 ml of water, 1.6 ml of a 15% aqueous solution of sodium hydroxide and 4.8 ml of water were added to the resulting mixture successively under cooling with ice. The obtained mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 4.51 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[C:12](Cl)([Cl:14])=[O:13]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([Cl:14])=[O:13])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)N1CCCCN1
Product: CCOC(=O)N1CCCCN1C(=O)Cl

Procedure:
In the same way, 4-[2-(4-chlorobenzyloxy)-5-pyridyl]-1,2-tetramethylenetriazolidine-3,5-dione is prepared by reacting N-ethoxycarbonylhexahydropyridazine with phosgene to give N-ethoxycarbonyl-N'-chlorocarbonylhexahydropyridazine, which is then reacted with 5-amino-2-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=1)[NH2:1]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1cc(Cl)ccc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 85 %

Procedure:
2-Amino-4-chlorobenzonitrile (1000 mg, 6.6 mmol), sodium azide (555 mg, 8.5 mmol) and triethylamine hydrochloride (1175 mg, 8.5 mmol) were taken up in 15 mL of toluene. The suspension was heated to 100° C. overnight. After cooling, the reaction mixture was washed 3 times with 5 mL portions of water. The combined aqueous fractions were acidified with concentrated hydrochloric acid. The desired 5-Chloro-2-(1H-tetrazol-5-yl)aniline precipitated from aqueous solution and was isolated by filtration (1090 mg, 85% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.73 (d, 1H), 6.97 (d, 1H), 6.74 (dd, 1H); MS (electrospray) m/z 196 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCOc1ccc(Cl)nc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1ccc(OCOCC[Si](C)(C)C)cn1
Temperature: 150 °C

Procedure:
To a mixture of compound 57A (154 mg, 0.593 mmol), N,N-dimethylprop-2-yn-1-amine (0.190 ml, 1.778 mmol), (PPh3)2PdCl2 (62.4 mg, 0.089 mmol), TEA (0.413 ml, 2.96 mmol) in DMF (3 ml) was added copper(I) iodide (11.29 mg, 0.059 mmol). The resulting mixture was heated at 150° C. in a Smith microwave synthesizer for 30 min and purified by flash chromatography to provide the desired compound 57B; LCMS (APCI) m/e 307.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].[C:21]1([CH3:31])[CH:26]=CC(S(Cl)(=O)=O)=C[CH:22]=1.C(O)(C)(C)C.N1C=CC=CC=1>CCOCC>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:16][C:21]([CH3:31])([CH3:26])[CH3:22])=[O:15]
Reactant: Cc1ccc2oc(-c3ccccc3C(=O)O)c(Br)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: Cc1ccc2oc(-c3ccccc3C(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
A mixture of 2-(3-bromo-5-methyl-2-benzofuranyl)benzoic acid (described in EP-A-0434249) (2.0 g), p-toluenesulphonyl chloride (2.5 g), tert-butanol (10 ml) and pyridine (3 ml) was stirred at 0° C. and allowed to warm to room temperature. Stirring was continued for 72 hours. The mixture was then diluted with ether (100 ml) and washed with 2M hydrochloric acid (75 ml) followed by an aqueous solution of 1M sodium bicarbonate (75 ml). The aqueous solutions were further extracted with ethyl acetate (100 ml) and the combined organic extracts were dried and evaporated in vacuo. Purification by flash column chromatography eluting with dichloromethane:hexane (3:7) gave the title compound (0.6 g) as a colourless gum.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O>C1(C)C=CC=CC=1>[OH:32][C:5]1[C:6]2[C:7](=[O:31])[C:8]3[C:13](=[C:12]([NH:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH:38]4[C:34]4[NH:33][CH:37]=[CH:36][CH:35]=4)[CH:11]=[CH:10][C:9]=3[NH:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH:38]3[C:34]3[NH:33][CH:37]=[CH:36][CH:35]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Reactant: O=Cc1ccc[nH]1
Solvent: Cc1ccccc1
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN3CCOC3c3ccc[nH]3)ccc(NCCN3CCOC3c3ccc[nH]3)c21

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 55 ml. of toluene containing 2.0 g. of pyrrole-2-carboxaldehyde is stirred and refluxed as for Example 1(B). The hot solution is filtered. The filtrate is concentrated and allowed to stand at room temperature. The title compound separates as blue-black crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][SiH:4]([CH3:6])[CH3:5].[C:9]([O:12]CC=C)(=[O:11])[CH3:10].C>[Pd]>[CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][Si:4]([CH3:6])([CH3:5])[O:12][C:9](=[O:11])[CH3:10]
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: C=CCOC(C)=O
Agent: [Pd]
Product: CC(=O)O[Si](C)(C)O[Si](C)(C)C
Temperature: 105 °C

Procedure:
A mixture containing 14.8 g of 1,1,1,3,3-pentamethyldisiloxane, 10.0 g of allyl acetate (acetic acid allylester) and 0.01 g of palladium supported on activated charcoal, in which the 0.1 g refers to the total weight of the charcoal and the palladium, is heated to boiling under reflux (approximately 105° C.) for 4 hours. The 1,1,1,3,3-pentamethyl-3-acetoxydisiloxane yield is quantitative.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH:24]=[CH:25][CH:26]=[C:27]([OH:28])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H][H]>[C].[Pd].C(O)(=O)C>[CH3:29][C:18]1[N:19]=[C:20]2[N:21]([CH2:24][CH2:25][CH2:26][CH:27]2[OH:28])[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O

Procedure:
A mixture of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one (formula-11) (5 grams), acetic acid (25 ml) and palladium carbon (4 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0 Kg/cm2 was applied to the above mixture at 32° C. for 9 hrs. The reaction mixture was filtered through a hyflow bed. The filtrate was treated with water (100 ml) and the pH of the filtrate was adjusted to 10 using aqueous sodium hydroxide solution. The solid formed was filtered, washed with water and dried at 50° C. to yield the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.Cl.[CH3:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:7][C:4]1[S:3][C:2]([N:12]2[CH2:13][CH2:14][CH:10]([CH3:9])[CH2:11]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: CC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(c2ncc(Br)s2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2,5-Dibromothiazole (250 mg, 1.029 mmole), 3-methyl-pyrrolidine hydrochloride (188 mg, 1.544 mmole), and K2CO3 (569 mg, 4.12 mmole) were combined in DMF (5 mL) then heated to 100° C. After stirring overnight the mixture was cooled to RT, diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-10 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (234 mg, 92%) as a pale yellow oil. 1H NMR (399 MHz, CDCl3): δ 7.06 (s, 1 H); 3.58-3.45 (m, 2 H); 3.45-3.35 (m, 1 II); 2.97 (dd, J=9.7, 7.7 Hz, 1 H); 2.47-2.36 (m, 1 H); 2.20-2.10 (m, 1 H); 1.73-1.63 (m, 1 H); 1.12 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:17][CH2:16]2)=[O:14])=[C:9](OC)[CH:8]=1)(=[O:6])=[O:5])(C)C.F[C:37]1C=CC(C(N2CCC3(C4C=NN(C)C=4C4C=CC=CC=4O3)CC2)=O)=CC=1C>>[CH3:33][N:29]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:18]3([CH2:19][CH2:20][N:15]([C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:1])(=[O:5])=[O:6])=[C:8]([CH3:37])[CH:9]=4)=[O:14])[CH2:16][CH2:17]3)[C:32]=2[CH:31]=[N:30]1
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1F
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(C)(=O)=O

Procedure:
(4-(Isopropylsulfonyl)-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was also synthesized using the procedures described above. (1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanone was synthesized from (4-fluoro-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures described above.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccncc1Br
Reactant: Br[Mg]CCCc1ccccc1
Product: OC(CCCc1ccccc1)c1ccncc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 3-bromo-pyridine-4-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:26])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:29](Br)[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CN(C)C=O>[CH:1]1([NH:7][C:8](=[O:26])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:31])=[CH:21][CH:20]=2)[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC(=O)c2ccccc2)cc1)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A mixture of N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine cyclohexylamide (0.68 g) obtained in Example 4, palladium black (0.10 g), cyclohexene (4 ml), and ethanol (20 ml) was allowed to react under reflux of ethanol for one hour, while stirring. After cooling, the solid was filtered off and the filtrate was concentrated under reduced pressure to obtain N-(t-butyloxycarbonyl-4-hydroxy-L-phenylalanine cyclohexylamide (I) (0.54 g). The compound (I) (0.54 g) was dissolved, without purification, in N,N-dimethylformamide (10 ml), followed by adding sodium hydride (0.06 g) thereto. The mixture was stirred at room temperature for 30 minutes. To this solution was added a solution of phenacyl bromide (0.30 g) in N,N-dimethylformamide (5 ml). The reaction was carried out at room temperature for 4 hours, followed by adding ice-water thereto. The resultant oily product was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide (II) (0.61 g) was obtained. From the compound (II), N-(trans-4-aminomethylcyclohexylcarbonyl)-4-phenacyloxy-L-phenylalanine cyclohexylamide hydrochloride (0.38 g) was obtained, following the procedure of Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+]>CCO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(Br)nc1
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A solution of 2-bromo-5-(bromomethyl)pyridine (example 40e) (6 g, 24 mmol) and NaCN (1.42 g, 29 mmol) in absolute EtOH (50 mL) was heated at 80° C. for 8 h. The mixture was then cooled to room temperature then evaporated. The residue was suspended in water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel (5-30% EtOAc/hexanes) to give 2.89 g (63%) of 2-(6-Bromopyridin-3-yl)acetonitrile. 1H NMR (400 MHz, dMSO): δ 4.07 (s, 2H), 7.66-7.68 (d, 1H), 7.72-7.73 (dd, 1H), 8.36-8.37 (d, 1H).