Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[CH:25]=[C:24](C(C)(C)C)[C:23](O)=[C:22](C(C)(C)C)[CH:21]=1.[OH:36]C1C=C(C=CC=1)C=O>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:36])[CH:21]=1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Reactant: O=Cc1cccc(O)c1
Product: COc1c(O)c(C(=O)C=Cc2cccc(O)c2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-ethyloxycarbonyl dimethylmethyloxyacetophenone (starting material 1) and 3-hydroxybenzaldehyde according to general method 2 described earlier.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[Si:23]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH:33](I)[CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Si:23]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH:35]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[CH2:36]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(I)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Yield: 15.2 %

Procedure:
A solution of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (870 mg), 1-(tert-butyldimethylsilyl)oxy-3-iodocyclohexane (1.5 g), potassium tert-butoxide (472 mg) and 18-crown-6 (80mg) in N,N-dimethylformamide (10 ml) was stirred for 2 hours at room temperature. A reaction mixture was diluted with a mixture of ethyl acetate (150 ml) and n-hexane (50 ml), which was washed in turn with water (50-ml), 1N-aqueous sodium hydroxide solution (50 ml×3) and saturated sodium chloride in water (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (80 ml) eluting in-turn with 25%, 33% and 50% ethyl acetate in dichloromethane to give 3-[2-{3-(tert-butyldimethylsilyloxy)cyclohexyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (0.23 g).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:44]1[CH2:49][C@@H:48]2[CH2:50][C@H:45]1[CH2:46][NH:47]2)=O)(C)(C)C>CC#N.O>[CH:45]12[CH2:50][CH:48]([NH:47][CH2:46]1)[CH2:49][N:44]2[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[C:13](=[O:18])[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:11]3)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc(-c2noc(CCl)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2noc(CN3CC4CC3CN4)n2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 72.9 %

Procedure:
To a solution of 5-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (100 mg, 0.228 mmol) in MeCN (4 mL) was added K2CO3 (95 mg, 0.684 mmol) and (1s,4s)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (90 mg, 0.451 mmol). After 48 hours the mixture was diluted with water, then extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to a yellow oil. This residue was dissolved in 1:1 TFA/CH2Cl2 (6 mL) for 30 minutes, then the reaction mixture was concentrated and basified with NaHCO3 to pH˜9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica (2-8% 2M NH3 in MeOH/CH2Cl2) to provide 5-[5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-3-yl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (83 mg). 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.34 (d, 2H), 7.18 (d, 2H), 4.77 (s, 2H), 4.28 (s, 2H), 4.05 (dd, 2H), 3.57 (d, 2H), 3.20 (d, 1H), 3.13 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 3H), 2.61 (d, 1H), 1.86 (d, 1H), 1.64 (d, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([CH2:7][C:8]#[N:9])[CH2:4]1>[Ni].CCO>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([CH2:7][CH2:8][NH2:9])[CH2:4]1
Reactant: COC1CN(CC#N)C1
Agent: [Ni]
Solvent: CCO
Product: COC1CN(CCN)C1
Reaction time: 5 h
Yield: 52.1 %

Procedure:
A mixture of nitrile 276 (1.76 g, 14.0 mmol), cNH3 (7 mL) and Raney Nickel (50% slurry in water, 4.6 g) in EtOH (100 mL) was stirred under H2 (60 psi) for 5 h. The mixture was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated to give crude diamine 277 (950 mg, 52%) as a yellow oil, which was used without further purification: 1H NMR δ 4.03 (p, J=5.8 Hz, 1H, CHO), 3.58-3.63 (m, 2H, CH2N), 3.25 (s, 3H, OCH3), 2.88-2.93 (m, 2H, CH2N), 2.67 (t, J=6.0 Hz, 2H, CH2N), 2.52 (t, J=6.0 Hz, 2H, CH2N), NH2 not observed; MS (APCI) m/z 131 (MH+, 100%); HRMS (FAB+) calcd for C6H15N2O (MH+) m/z 131.1184, found 131.1183.
Reaction SMILES: BrC1C(C)=C([N+]([O-])=O)C=CC=1C.[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-])=O)[C:15]=1[CH2:24][C:25](=O)[C:26]([OH:28])=[O:27]>>[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:15]=1[CH:24]=[C:25]([C:26]([OH:28])=[O:27])[NH:21]2
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)C(=O)O)c1Br
Agent: Cc1ccc([N+](=O)[O-])c(C)c1Br
Product: Cc1ccc2[nH]c(C(=O)O)cc2c1Br

Procedure:
The compound was prepared via 3-bromo-2,4-dimethylnitrobenzene (m.p. 52° C) and 3-(2-bromo-3-methyl-6-nitrophenyl)pyruvic acid (m.p. 196° C).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=O)=[O:10].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([Cl:14])(=[O:12])=[O:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(Br)c(S(=O)(=O)O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
50 g of 2-bromo-5-methylbenzenesulfonic acid and 41.5 g of PCl5 are carefully heated in 500 ml of toluene until the evolution of gas commences. After the reaction has subsided the mixture is boiled under reflux until the evolution of gas has ended (2 h). The mixture is cooled and the toluene and POCl3 are removed in vacuo. The residue is carefully poured onto about 1 l of ice, the mixture is subsequently stirred for 1 h and then the product is filtered off with suction. Drying at 60° C. in vacuo gives 36 g of a colorless solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([Li])(C)(C)C.[B:23](OC)([O:26]C)[O:24]C.CCCCCC>C1COCC1.CC(=O)OCC>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([B:23]([OH:26])[OH:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: COB(OC)OC
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(B(O)O)c(C)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 1.00 g (2.91 mmol) of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine in 60 mL of dry THF is cooled to −78° C. 4.12 mL (7.00 mmol) of 1.7 M tert-butyllithium in hexanes is added and reaction is stirred at −78° C. for 1 hour. 0.818 mL (7.30 mmol) of trimethyl borate is added and reaction is followed by MS and TLC (1:1 Hexane:EA) Indication of product is observed by mass spectrum. The reaction is allowed to stir for an additional hour, quenched with 1 N hydrochloric acid, and diluted with ethyl acetate. The organic layer is separated, and the aqueous layer is extracted three times with 100 mL of ethyl acetate. The extracts are combined, dried over MgSO4, filtered, and concentrated. The reaction residue is triturated in hexanes and a solid is filter off. MS, ES+=262.2 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][Cl:3])=[CH:20][CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCc1ccc(Oc2ccccn2)cc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4.4 gram (0.037 mole) of thionyl chloride in 75 mL of dry methylene chloride was cooled to 0° C., and 0.07 gram (catalyst) of pyridine was added. A solution of 5.0 grams (0.025 mole) of (4-(2-pyridyloxy)phenyl)methanol in 25 mL of methylene chloride was then added drop wise. Upon completion addition of addition, the reaction mixture was allowed to warm to 22° C. where it stirred for 30 minutes. After this time an aliquot of the reaction mixture was taken up in ethyl acetate and treated with solid sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The NMR spectrum was consistent with the proposed structure. Inasmuch as this compound is unstable, it was used without further purification. The yield was estimated at about 5.0 grams.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:15][C:14]([C:16](OCC)=[O:17])=[N:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[OH:17][CH2:16][C:14]1[S:15][C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[CH:12][N:13]=1
Reactant: CCOC(=O)c1ncc(NC(=O)OC(C)(C)C)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cnc(CO)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
NaBH4 (1.1 g, 29.2 mmol) was added portion wise to a solution of Ethyl 5-(tert-butoxycarbonyl amino)thiazole-2-carboxylate (Intermediate Z, 4 g, 14.6 mmol) in MeOH (40 mL) at 0° C. over a period of 30 mins and stirred at RT for 16 h. After completion, solvent was evaporated, the solid residue was dissolved in ice water (50 mL) and extracted with EtOAc (2×50 mL) The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude was purified by column chromatography by using SiO2, eluting with EtOAc:Petroleum ether (2:8) to afford Tert-butyl (2-(hydroxymethyl)thiazol-5-yl)carbamate (2.9 g, 84.8%) as white solid.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:42]CC2C=CC=CC=2)=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][C:15]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C:28]4[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[CH:41]=1)C1C=CC=CC=1.Br.O.C(OCC)(=O)C>C(O)(=O)C>[OH:8][C:9]1[C:10]([OH:42])=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][C:15]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C:28]4[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[CH:41]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)C3=Cc4cc(OCc5ccccc5)c(OCc5ccccc5)cc4CCC3)CC2)cc(OC)c1OC
Agent: Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C(=O)N2CCN(C(=O)C3=Cc4cc(O)c(O)cc4CCC3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
In acetic acid (40 ml) is dissolved 1-(2,3-dibenzyloxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (4.0 g). To the solution is added an acetic acid solution of 30% hydrobromic acid (40 ml). The mixture is stirred at room temperature for one hour. To the reaction mixture is added water and ethyl acetate, and the mixture is shaken. The organic layer is washed with water and an aqueous solution of sodium hydrogencarbonate, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, acetone:ethyl acetate:hexane:methylene chloride=2:1:1:1) to give 1-(2,3-dihydroxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.25 g). This product is recrystallized from ethyl acetate to give colorless crystals, m.p. 206°-207° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][NH:17]2.Br[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCCC1
Reactant: ClCCCOc1ccccc1Nc1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccccc1Nc1nc(Cl)nc2c1ncn2C1CCCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9H-purin-6-yl)-amine (3 mmol), bromo-cyclopentane (4.1 mmol) and potassium carbonate (water free, 3.6 mmol) are suspended in DMF (20 ml) and heated up to 50° C. and the mixture is stirred at this temperature for 5 hours. After cooling to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=20:1) as mobile phase. The product containing fractions are combined and evaporated. The product is crystallized from diethyl ether/pentane, filtered off and dried. A solid powder with mp. 110-112° C., Rf=0.78 (CH2Cl2/MeOH=20:1) is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:29])[NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)(O)[O-:31].[Na+].C=O>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:29])[NH:18][CH:19]([CH2:30][OH:31])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC(CO)C(=O)c1ccc(Cl)cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a stirred solution of the 4-[2-(4-chlorophenyl)-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (8.91 g, 21.5 mmol), prepared as in Part B, and sodium bicarbonate (0.19 g, 2.3 mmol) in a mixture of water (10 mL) and dimethyl sulfoxide (50 mL) in a 50° C. water bath is added aqueous formaldehyde (3.30 mL, 44.0 mmol). After 6 h, the mixture is diluted with water (1 L) and allowed to stand overnight at RT. Filtration gives gummy solids which are triturated with ethyl acetate to give the desired product as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]=[C:43]=[O:44])[CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])[CH:37]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (70 mg, 0.19 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (64.9 uL, 0.48 mmol) (Aldrich), followed by the addition of 3-isocyanato-benzoic acid methyl ester (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 70 mg, 68%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:21][CH:19]1[CH2:20][N:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]([F:6])([F:22])[F:23])=[N:9][N:10]=3)[N:13]=2)[CH2:18]1)(=[O:4])=[O:3]
Reactant: OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Methanesulfonyl chloride (0.929 mL, 12 mmol) was added dropwise to a stirred partial solution of 1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)azetidin-3-ol (2.59 g, 10 mmol) and triethylamine (1.951 mL, 14 mmol) in DCM (17 mL) at 0° C. The solution was allowed to warm to ambient temperature and stirred for 30 minutes. The precipitate was collected by filtration, washed with a little DCM, a little ethanol and ether. It was dried under vacuum to afford 6-[3-(methanesulfonyloxy)azetidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.400 g, 71.2%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH2:15]=O>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([CH3:15])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=O
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C
Yield: 91 %

Procedure:
Commercially available 1,1-dimethylethyl (3R)-3-methyl-1-piperazinecarboxylate (2.78 g, 13.88 mmol), formaldehyde (37% in water) (1.94 mL), sodium triacetoxy borohoydride (5.03 g, 23.73 mmol) and DCM (200 mL) were stirred overnight. The solvent was removed, and 1N NaOH was added to the residue. The mixture was extracted with dichloromethane, and the organics were dried (Na2SO4) and concentrated in vacuo to provide 1,1-dimethylethyl (3R)-3,4-dimethyl-1-piperazinecarboxylate as a clear oil (2.70 g, 91%). LCMS: (M+H)+=215.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[CH:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:38]3[CH2:39][CH2:40][N:35]([CH:33]=[O:34])[CH2:36][CH2:37]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: O=CN1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(C=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-formylpiperazine. A yellow solid 99 was obtained (0.0159 g, 34%). 1H-NMR (CDCl3, 400 MHz) δ 3.62-3.65 (m, 2H), 3.68-3.72 (m, 2H), 3.75-3.78 (m, 2H), 3.83 (s, 3H), 3.86-3.89 (m, 2H), 6.95 (s, 1H), 7.02 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 7.46-7.52 (m, 3H), 7.86 (d, J=1.5 Hz, 1H), 8.16 (s, 1H), 8.30 (d, J=6.2 Hz, 1H), MS (APCI) m/z 474 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:37]([O-:39])=[O:38])=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([OH:25])[C:27]=1[N+:37]([O-:39])=[O:38]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 73.7 %

Procedure:
6.5 g of L-proline methyl ester and 10.5 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 10.7 g of 3-hydroxy-4-methoxy-2-nitrobenzoic acid dissolved in a mixture consisting of 180 ml of dichloromethane and 15 ml of N,N'-dimethylformamide, and then the same treatment as in Example 1 was carried out. Thus, there was obtained 12 g of 1-(3-hydroxy-4-methoxy-2-nitrobenzoyl)-L-proline methyl ester as a yellow-colored prismatic crystal having melting point of 108° to 110° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[Mg].[C:9]1([C:15]2([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[O:19][CH2:18][CH2:17][O:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.CCCCCCC.CCOCC>[CH3:24][C:23]([OH:25])([CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6])[CH2:22][CH2:21][CH2:20][C:15]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC(C)=CCCBr
Reactant: CC(=O)CCCC1(c2ccccc2)OCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CCOCC
Product: CC(C)=CCCC(C)(O)CCCC1(c2ccccc2)OCCO1
Reaction time: 0.75 h
Yield: 37.8 %

Procedure:
A Grignard reagent of 3.50 g (0.021 mol) of 5-bromo-2-methyl-2-pentene in 13 ml of ether and 0.62 g (0.026 mol) of magnesium turnings in 14 ml of ether was added slowly at −25° under N2 to a stirred solution of 5.54 g (0.024 mol) of 5-(2-phenyl-1,3-dioxolan-2-yl)-2-pentanone obtained under b) in 20 ml of ether. During the introduction, the temperature was left rising up to −5° C. and the reaction mixture left stirring for 45 min. Then a saturated solution of NH4Cl was added and the formation of a white precipitate was observed. Extraction with ether (2×), washing with water (3×), drying (Na2SO4) and concentrating gave 6.24 g of the crude product. Column chromatography (SiO2, heptane/ether 7:3) gave 2.53 g (38%) of a yellow oil.