Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:4]1([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1)[CH:2]=C.[O:27]=[O+][O-].[BH4-].[Na+].[Cl-].[NH4+]>ClCCl.O.C(OCC)(=O)C.CO>[CH2:20]([O:19][CH2:18][C@@:4]1([CH2:1][CH2:2][OH:27])[CH2:8][N:7]([C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:6](=[O:17])[CH2:5]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@]1(COCc2ccccc2)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@](CCO)(COCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A solution of (4R)-4-allyl-4-benzyloxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (4.00 g, 11.45 mmol) in dichloromethane (100 mL) was bubbled with ozone gas at −70° C. and stirred at the same temperature for 15 minutes. Ozone bubbling was stopped when the reaction solution was turned dark blue, and then the reaction solution was bubbled with nitrogen gas until the solution turned colorless. Sodium borohydride (434 mg, 11.45 mmol) and methanol (40 mL) were added at the same temperature, and the mixture was heated to room temperature over three hours. Sodium borohydride (325 mg, 8.58 mmol) was added, and the mixture was stirred at room temperature for further 24 hours. A saturated ammonium chloride solution was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (200 mL) and water (200 mL), followed by extraction with ethyl acetate (500 mL). The organic layer was washed with brine (200 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→1:9→0:1) to give 3.22 g (79%) of the title compound as a colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:28])[CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][C:17](=[O:28])[CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(NCC(=O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Reaction time: 0.5 h

Procedure:
Trietheylamine (1.65 ml, 11.8 mmol) was added to a stirring solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (1.02 g, 2.02 mmol) in DMSO (21 ml). The solution was stirred for 30 minutes before addition of sulfur trioxide pyridine complex (0.659 g, 4.14 mmol). After stirring overnight, additional triethylamine (1.0 ml, 7.17 mmol) was added, followed by sulfur trioxide pyridine complex (0.663 mg, 4.17 mmol) an hour later. After stirring for 1 h, the orange solution was diluted with ˜150 ml ethyl acetate and washed several times with water and then brine.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])C(=O)OC(C)(C)C)=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH2:38]([O:40][CH:41](O)[C:42]([F:45])([F:44])[F:43])[CH3:39]>CCO>[CH2:38]([O:40][CH:41]([NH:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][NH:23][CH2:31][CH2:32][O:33][CH3:34])=[CH:20][N:21]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1)[C:42]([F:45])([F:44])[F:43])[CH3:39]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: CCOC(O)C(F)(F)F
Solvent: CCO
Product: CCOC(Nc1ccc(Oc2ccnc3cc(-c4ccc(CNCCOC)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 76.2 %

Procedure:
A solution of 11 (2 g, 3.62 mmol), PTSA monohydrate (0.76 g, 3.98 mmol) and trifluoroacetaldehyde ethyl hemiacetal (2.38 mL, 18.11 mmol) in EtOH (50 mL) was heated to reflux overnight. More trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 9.13 mmol) was added and the reaction mixture was heated to reflux overnight. Once again, more trifluoroacetaldehyde ethyl hemiacetal (2 mL, 15.22 mmol) were added and the reaction mixture was heated to reflux overnight. Finally, another portion of trifluoroacetaldehyde ethyl hemiacetal (2 mL, 15.22 mmol) and PTSA monohydrate (0.76 g, 3.98 mmol) were added and the reaction mixture was heated to reflux for 5 days. The reaction mixture was concentrated and partitioned between AcOEt and water. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 14 (1.519 g, 2.76 mmol, 76% yield) as a pale orange sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.56 (d, J=1.4 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.2 Hz, 1H), 7.31 (t, J=9.1 Hz, 1H), 7.11-7.02 (m, 2H), 6.87 (dd, J=9.0, 1.8 Hz, 1H), 6.62 (dd, J=5.3, 0.8 Hz, 1H), 5.73-5.64 (m, 1H), 3.78 (s, 2H), 3.77-3.59 (m, 2H), 3.41 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J=5.7 Hz, 2H), 1.15 (t, J=7.0 Hz, 31-1), one NH proton is missing. MS (m/z): 551.6 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH:10]([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH3:16][CH:10]1[CH:11]([OH:15])[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CC(C)C1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)C1O

Procedure:
A mixture of 1-benzyl-3,5-dimethyl-4-hydroxypiperidine (1.0 g, 4.56 mmole) and 20% palladium hydroxide (0.3 g) in methanol (20 ml) was stirred at room temperature in hydrogen atmosphere (1 atm.) for 4 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,5-dimethyl-4-hydroxypiperidine. Yield 0.5 g (90%), C7H15NO, m/z 130 (M+1), PMR (CDCl3): 0.9 (6H, m, 2×CH3), 1.44 (1H, m, H3), 1.7 (1H, m, H5), 2.3 (1H, m, H6), 2.46-2.84 (2H, m, H2 & H6), 2.98 (1H, m, H2), 3.3-3.7 (1H, m, H4).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1cccc(F)c1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccc(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-fluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 319(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:25]=1)([OH:15])[CH2:6][CH2:5]2.[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[ClH:44]>C1(C)C=CC=CC=1.C(Cl)Cl.CCOCC.C(C(CCCC)C([O-])=O)C.[Sn+2].C(C(CCCC)C([O-])=O)C>[ClH:44].[ClH:44].[C:42](=[O:43])([O:15][C@:7]1([CH2:16][CH2:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:25]=2)[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C@@H:8]1[CH:12]([CH3:14])[CH3:13])[NH:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CCN(C)CCCCCc1nc2ccccc2n1C
Reactant: O=C=Nc1ccccc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Sn+2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@@]1(CCN(C)CCCCCc1nc2ccccc2n1C)OC(=O)Nc1ccccc1
Yield: 65 %

Procedure:
A solution of 2.32 g (0.005 mol) of [1S,2S]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-[2-[methyl-[5-(1-methyl-2-benzimidazolyl)pentyl]amino]ethyl]-2-naphthalenol and 0.6 g (0 005 mol) of phenyl isocyanate in 5 ml of toluene is treated with 7.5 mg of tin(II) 2-ethylhexanoate and heated to 100° for 15 hours. After concentration under reduced pressure the oily residue is chromatographed on 160 g of silica gel with methanol/methylene chloride (3:2) as the elution agent. The oily product obtained is dissolved in methylene chloride and treated with an excess of hydrogen chloride in ether. There are obtained 2.15 g (65%) of [1S,2S]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-[2-[methyl-[5-(1-methyl-2-benzimidazolyl)pentyl]amino]ethyl]-2-naphthyl carbanilate dihydrochloride, m.p. 157°-160°, as a colourless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:18]=[O:19])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.6 %

Procedure:
To a −78° C. solution of 1-chloro-3,5-difluoro-benzene (5.0 g, 34 mmol) in THF (70 mL) at was added n-butyl lithium (1.6 M in hexane, 19 mL). After 50 min, DMF (5.2 mL, 67 mmol) was added and the reaction was allowed to warm to rt over 18 h. After the addition of 0.5 M HCl (150 mL) and ether (150 mL), the aqueous layer was extracted with Et2O (3×). The combined organic extracts were dried and concentrated to provide a yellow solid. The crude material was dissolved in warm hexanes and a small amount of white solid formed upon cooling. This white solid was filtered off and discarded. The filtrate was concentrated to provide the title compound as a light yellow solid (2.5 g, 41%). 1H NMR (CDCl3): 10.3 (s, 1H), 7.06 (d, J=8.1 Hz, 2H).
Reaction SMILES: O(C1C=C(CCCC(C2C=CC(OC)=CC=2)(C)C)C=CC=1)C1C=CC=CC=1.[O:28]([C:35]1[CH:36]=[C:37]([CH2:42][CH:43]=[CH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)([CH3:47])[CH3:46])[CH:38]=[CH:39][C:40]=1[F:41])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O(C1C=C(C=CCC(C2C=CC(OC)=CC=2)(C)C)C=CC=1F)C1C=CC=CC=1>>[O:28]([C:35]1[CH:36]=[C:37]([CH2:42][CH2:43][CH2:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)([CH3:46])[CH3:47])[CH:38]=[CH:39][C:40]=1[F:41])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(C(C)(C)C=CCc2ccc(F)c(Oc3ccccc3)c2)cc1
Agent: COc1ccc(C(C)(C)CC=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Agent: COc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Product: COc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1

Procedure:
In the same manner as described in (2) of Synthesis Example 1, the mixture of 1-(3-phenoxy-4-fluorophenyl)-4-(4-methoxyphenyl)-4-methyl-2-pentene and 1-(3-phenoxy-4-fluorophenyl)-4-(4-methoxyphenyl)-4-methyl-1-pentene obtained according to the above (1) was treated to give quantitatively 1-(3-phenoxy-4-fluorophenyl)-4-(4-methoxyphenyl)-4-methylpentane.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[NH2:9][N:10]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:12]([CH3:19])[C:11]1=[O:20]>Cl.C(O)C>[CH3:19][N:12]1[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:14][N:10]([N:9]=[CH:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[C:11]1=[O:20]
Reactant: Cn1c(C(C)(C)C)cn(N)c1=O
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: Cn1c(C(C)(C)C)cn(N=Cc2cccnc2)c1=O

Procedure:
4.3 g of 3-formylpyridine and two drops of concentrated hydrochloric acid are added to a solution of 6.8 g of 1-amino-2,3-dihydro-3-methyl-2-oxo-4-tert-butyl-1H-imidazole in 50 ml of ethanol. The reaction mixture is refluxed for 30 minutes with stirring and then substantially concentrated. The liquid residue is dissolved in a small amount of diethyl ether, and the solution is cooled to 0°. The crystals which have separated out are filtered off with suction and dried. This gives the title compound which melts at 116°-121°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@H:22]1[CH2:31][O:32][CH2:33][CH2:34][OH:35])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@H:22]1[CH2:31][O:32][CH2:33][CH:34]=[O:35])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Under nitrogen atmosphere at -70° C., to a solution of oxalyl chloride (4.31 ml) in dichloromethane (200 ml) were added dropwise dimethyl sulfoxide (7.01 ml), a solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxypyrrolidine (17.57 g) in dichloromethane (50 ml) and triethylamine (37.8 ml). The reaction mixture was stirred at the same temperature for 2 hours and then allowed to warm to ambient temperature. Precipitate was filtered off and to the filtrate was added a mixture of ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate and active carbon was added thereto. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (9:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-(2-oxoethyl)oxymethyl-4-methanesulfonyloxypyrrolidine (15.7 g).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:50][CH2:51][CH2:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1)=[O:30]
Reactant: NCCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCCc1cccnc1
Yield: 21 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(2-aminoethyl)pyridine, the title compound was obtained as a white powder in 21% yield: mp 172-173° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.35-7.16 (m, 5H), 5.81 (br s, 1H), 4.46 (s, 2H), 4.08-4.03 (m, 2H), 3.65-3.59 (m, 2H), 3.47-3.42 (m, 2H), 2.92-2.87 (m, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.4, 152.8, 150.1, 148.9, 148.1, 136.2, 134.3, 134.2, 129.6, 123.5, 121.4, 117.5, 47.2, 42.0, 41.8, 40.9, 33.0, 17.1; MS (ES+) m/z 506.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:40])[CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cccc(Cl)c3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3cccc(Cl)c3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.2 %

Procedure:
Using 7-(2,3-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and acetic acid (0.025 mL, 0.444 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.033 g, 61%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]([C:16]([OH:18])=[O:17])[CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=43)[C:8](=[O:23])[C:7]=2[CH:24]=1.S(Cl)(Cl)=O.[CH3:29]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:15]([C:16]([O:18][CH3:29])=[O:17])[C@@H:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=43)[C:8](=[O:23])[C:7]=2[CH:24]=1
Reactant: COc1ccc2c(c1)C(=O)N1CCc3ccccc3C1C2C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1c2ccc(OC)cc2C(=O)N2CCc3ccccc3[C@H]12

Procedure:
A suspension of 14 g (43.3 mmol ) of 10-methoxy-8-oxo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine-13-carboxylic acid in 100 ml of methanol is prepared in a 500 ml three-necked round-bottomed flask, 3.2 ml (44.11 mmol) of thionyl chloride are added dropwise and the mixture is heated to reflux for 4 h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[Cu][C:13]#[N:14]>CN1CCCC1=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11]
Reactant: N#CCc1cc(Br)ccc1N
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#CCc1cc(C#N)ccc1N
Temperature: 25 °C

Procedure:
2 mmol of (2-Amino-5-bromo-phenyl)-acetonitrile [882855-95-0] and 4 mmol of copper (I) cyanide are heated at 200° C. in 2 ml of N-methylpyrrolidinone for 4 h. After cooling to room temperature, the solution is diluted with water and extracted with ethyl acetate (3×). The organic layer is separated, dried over magnesium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][O:30][CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:32](=[O:33])[CH2:31][O:30][CH2:29][C:28]([OH:35])=[O:34])[CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCNCCNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=C1COCC(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)COCC(=O)N(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
37.14 g (100 mmol) of the bis(benzyloxycarbonylaminoethyl)-amine described in Example 1a is dissolved in DMF, mixed in an ice bath with 17.4 g (150 mmol) of diglycolic anhydride (Janssen Chimica) and 21 ml (150 mmol) of triethylamine and then stirred overnight at room temperature. The solution is concentrated by evaporation in a vacuum, the residue is taken up in ethyl acetate and shaken out with diluted hydrochloric acid. The organic phase is dried with sodium sulfate and after filtration from drying agent, it is crystallized by adding hexane.
Reaction SMILES: [CH3:1][N:2]1[C:20](=[O:21])[N:5]2[C:6]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:7]=3[O:8][C:9]3([CH2:12][O:11][CH2:10]3)[C:4]2=[N:3]1>CO.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]2[O:8][C:9]3([C:4]4[N:5]([C:20](=[O:21])[N:2]([CH3:1])[N:3]=4)[C:6]=2[CH:16]=1)[CH2:10][O:11][CH2:12]3
Reactant: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC21COC1
Agent: [Pd]
Solvent: CO
Product: Cn1nc2n(c1=O)-c1cc(N)ccc1OC21COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
2-Methyl-8-nitrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazine-4,3′-oxetan]-1(2H)-one (150 mg) and 10% Pd—C were suspended in methanol (10 mL). The reaction mixture was shaken at room temperature under H2 atmosphere (30 psi) for one hour. The catalyst was filtered off over celite and washed with methanol (5×50 mL). The filtrate was evaporated to give 8-amino-2-methylspiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazine-4,3′-oxetan]-1(2H)-one (120 mg). m/z=261.16 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][C:20]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(O)[CH2:14][CH2:13]1)=[O:11])[CH3:8]>C(C(C)=O)C>[CH2:7]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:20]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)N1CCC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1

Procedure:
In a 100 ml round-bottomed flask, 9.7 g of potassium carbonate are added in small portions to a solution of 6.2 g of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid ethyl ester (Example 10) in 62 ml of methyl ethyl ketone.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH2:27][CH2:28][CH2:29][C:30](=[O:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(N(C(C)C)CC)(C)C>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]4[C:25](=[O:26])[N:24]5[CH2:27][CH2:28][CH2:29][C:30](=[O:31])[C:23]5=[N:22][C:21]=4[CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2=O
Temperature: 26 °C
Reaction time: 0.25 h

Procedure:
To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (0.62 grams) taken in methanol added 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-9) (0.94 grams), diisopropyl ethyl amine (0.75 grams) and refluxed the reaction for 23 hrs. Cooled the reaction mixture to 26° C. and stirred for 15 minutes. Filtered the precipitated solid. Washed the solid with chilled methanol and dried. Separated the compound with column chromatography using chloroform/methanol as an eluent.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)([OH:3])=[O:2].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:15][CH3:16])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)CCCCCC1=CCCC1=O

Procedure:
A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 26) and 90 mg. of p-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO4), and evaporated to give 1.371 g. of a light yellow oil.