Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[O:5][CH:6]=1.S(Cl)([Cl:14])=O>ClC(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([Cl:14])=[O:11])[O:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cc(Br)co1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1cc(Br)co1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of (E)-3-(4-bromofuran-2-yl)acrylic acid (3.8 g, 17.51 mmol) in 35 mL of trichloromethane was added a solution of 2.6 mL of thionyl chloride in 200 μL of DMF. The reaction mixture was refluxed for 1 h and after cooling to room temperature concentrated to give 4 g (97% yield) of the title compound as light brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH2:19][O:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:10][O:11]CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH2:19][O:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)C(COCc1ccccc1)COCC1COC(C)(C)O1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(CO)COCC1COC(C)(C)O1
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To a solution of crude [2-Benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.25 g, 3.06 mmol) in MeOH (10 mL) was added Pd/C (300 mg). The mixture was transferred to an autoclave reactor, charged with 55 psi of hydrogen, and stirred. After 1.5 h, LCMS analysis indicated the completion of the reaction. The reaction mixture was then filtered through celite and concentrated under reduced pressure to give [1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-2-hydroxy-ethyl]-methyl-carbamic acid tert-butyl ester (0.875 g, 95%), which was used without purification. LRMS (M−Boc+H+) m/z 220.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[NH2:1][C:2]1[C:3]([C:7](=[N:17][O:18][C:28](=[O:31])[CH2:29][CH3:30])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1N
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (0.1 g, 0.37 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) in dichloromethane (4 mL) was treated with propanoyl chloride (38 μL, 0.44 mmol) and stirred for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (57 mg, 47%). LCMS for C12H12ClFN5O3 (M+H)+: m/z=328.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[CH:49]=[CH:54][C:53]([CH3:55])=[CH:52][C:51]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1ccc(C)cc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cc(C)ccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2-(2-hydroxy-4-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.55 (EtOAc); Rt=5.73.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[N:30]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:29]=[N:28][N:27]=1>>[CH:11]1[C:2]([O:1][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[N:29]=[N:28][N:27]=2)=[CH:3][C:4]2[CH2:5][CH2:6][C:7]([NH:8][C:9]=2[CH:10]=1)=[O:12]
Reactant: ClCCCCc1nnnn1C1CCCCC1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Reaction time: 5 h
Yield: 84.8 %

Procedure:
A mixture of 10 grams of 6-hydroxy-3,4dihydroquinolin-2(1H)-one (Compound I, 0.0613 mole), 4.05 grams of flaked potassium hydroxide (0.0650 mole) and 1.5 grams of K2CO3 (0.011 mole), was stirred in 130 ml of 1-botanol in a flask equipped with a soxhlet extraction apparatus containing 28 grams of 3 Å molecular sieves. The mixture was heated to reflux while passing the solvent over the molecular sieves for 30 minutes. Thereafter 18 grams of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole (Compound II, 0.0742 moles, which are 1.2 equivalents with respect to Compound I) were added and the reflux was allowed to continue for about 5 hours. The reaction mixture was cooled thereafter to room temperature, and the solid product was collected by filtration, washed with 1-butanol and water and dried at 50° C. overnight to afford 19.2 grams of crude Cilostazol at 70.0% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]=1.Br.C(N(CC)CC)C>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ccc(I)cn1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (420 mg, 1.5 mmol) and 2-amino-5-iodopyridine (330 mg, 1.5 mmol) in ethanol (6.7 mL) containing hydrobromic acid (48%, 84 μL, 0.75 mmol) and triethylamine (105 μL, 0.75 mmol) was heated under reflux under argon overnight. After cooling to room temperature, the mixture was evaporated and poured onto hydrochloric acid (0.5 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (170 mg, 28%) which was obtained as a light yellow solid. MS: m/e=402.1 [M+H]+.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]([OH:6])=[O:5].[CH:9]1([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-:37].[Na+]>>[C:4]([OH:6])(=[O:5])[C:3]([OH:30])=[O:37].[CH:9]1([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: [OH-]
Agent: Cc1cccc(CC(=O)N(c2cccnc2)C2CCN(C3CCCC3)CC2)c1
Agent: [Na+]
Product: O=C(O)C(=O)O

Procedure:
From 3.9 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide (E)-2-butenedioate, the free base is liberated in the conventional manner with a diluted sodium hydroxide solution. After extraction with 2,2'-oxybispropane, the latter is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 3 parts of N-(1-cyclopentyl-4-piperidinyl)-3-methyl-N(3-pyridinyl)benzeneacetamide ethanedioate; mp. 192.6° C.
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][NH:3][CH2:2]2.[I-].[Na+].Cl[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1>>[C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1)[CH2:2]2
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: C1NC[C@H]2C[C@@H]12
Agent: [I-]
Agent: [Na+]
Product: NC(=O)c1ccc(OCCCN2C[C@H]3C[C@H]3C2)cc1
Reaction time: 16 h

Procedure:
0.004 mole of (1R,5S)-3-azabicyclo[3.1.0]hexane and 0.002 mole of sodium iodide are added to the reaction mixture of Step 1 at ambient temperature. Refluxing is then resumed for 16 hours. The precipitate is filtered off and rinsed with acetonitrile. The filtrate is concentrated to dryness. The residue is taken up in dichloromethane. The resulting solution is extracted with sodium hydroxide solution and then with water, before being dried over magnesium sulphate and concentrated to dryness. The residue is purified by a preparative chromatography technique on a Lichroprep RP-18 phase.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:14]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc2ccccc2c1

Procedure:
2-Cyanonaphthalenes are prepared by refluxing 2-formylnaphthalene with hydroxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding which is refluxed with acetic anhydride in the presence of an acid catalyst to furnish 2-cyanonaphthalene.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(O)CCCBr
Reactant: OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a mixture of 4-bromobutyric acid (1 g), benzyl alcohol (0.65 g) and triphenyl phosphine (1.57 g) in tetrahydrofuran (12 mL) was added diethylazodicarboxylate (40% toluene solution, 2.88 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give the title compound (0.69 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[H-].[Na+].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br.Cl>CN(C)C=O>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][CH2:2][C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:3]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Reactant: Clc1ccccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
A solution of 1.706 g of ethyl 3-acetylamino-4-nitrobenzoate in 12 ml of N,N-dimethylformamide were added 0.406 g of 60% sodium hydride while being cooled with ice, and the mixture was stirred at room temperature for 40 minutes. A solution of 1.806 g of 2-chlorobenzyl bromide in 10 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into cold 1-N hydrochloric acid, and the mixed solution was extracted twice with ethyl acetate. The organic layer was washed with 1-N hydrochloric acid and then with water, and was dried. The solvent was distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and hexane at a ratio of from 1:10 to 1:4) to give 2.08 g of oily ethyl 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzoate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:19]=[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]=2[CH3:34])=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:19]=[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]=2[CH2:34][Br:1])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Yield: 110.4 %

Procedure:
4.8 g of N-bromosuccinimide and 20 mg of benzoyl peroxide are added to a solution of 10.73 g of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate in 200 ml of CCl4 and the mixture is then refluxed for 16 hours. The insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 14.13 g of the expected product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]2[N:18]([CH2:28][CH3:29])[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1.[BH4-].[Na+]>CO>[CH2:28]([N:18]1[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:31]=[CH:30][C:17]1=2)[CH3:29]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN)ccc21
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCNCc3ccncc3)ccc21
Temperature: 25 °C

Procedure:
4-Pyridine carbaldehyde(0.15 ml) was added to a methanol solution (10 ml) of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.51 g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound(0.38 g) as a colorless oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13](=O)([O-])O.[Na+]>CO.S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
15 g (0.09 mol, 1 eq) of 3-(4-hydroxyphenyl)propanoic acid are dissolved in 50 ml of methanol and 4 drops of sulfuric acid are added. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by addition of 50 mL of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 14.9 g of methyl 3-(4-hydroxyphenyl)propanoate are obtained. Yield=92%
Reaction SMILES: O1C[CH2:5][CH:4]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=4)[N:20]=3)[CH2:11][CH2:10]2)[CH2:3]C1.O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=C>C(Cl)Cl>[C:4]([O:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([F:27])([F:25])[F:26])=[N:22][N:23]=3)[N:20]=2)[CH2:13][CH2:14]1)([CH3:5])([CH3:29])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(COC4CCOCC4)CC3)nn12
Agent: C=C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
A stirred solution of [1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]methanol (obtained as described in Example 294, preparation of starting materials) (151 mg, 0.5 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) in DCM (2 mL) was cooled to −70° C. and 2-methylpropene (1 mL, 10.48 mmol) was condensed in from a cylinder. The mixture was stirred for 2 days at ambient temperature in a sealed tube. The tube was re-cooled to open then allowed to warm to ambient temperature with stirring. The solution was diluted with DCM and washed with 2M aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-(tert-butoxymethyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (98 mg, 54%) as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH2:20][C:21]#[CH:22]>O1CCCC1>[CH3:18][N:19]([CH2:20][C:21]#[CH:22])[C:15]([C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:16]
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: C#CCNC
Solvent: C1CCOC1
Product: C#CCN(C)C(=O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 20.8 g of 9-anthroyl chloride in 100 ml of tetrahydrofuran is added at 10°-15° to a solution of 14.2 g of N-methylpropargylamine in 50 ml of tetrahydrofuran. After stirring at room temperature for 3 hours, the solvent is removed and the residue is stirred with methylene chloride and 5% aqueous sodium bicarbonate solution. The methylene chloride layer is dried and concentrated to give 23.3 g of crude N-methyl-N-propargyl-9-anthramide as an oil. H nmr spectrum: τ 1.7-2.9 (m, 9); 5.4 (d, 2.5 Hz, 1.3); 6.4 (d, 2.5 Hz, 0.7); 6.7 (s, 0.9); 7.4 (s, 2.1); 7.7 (t, 2.5 Hz, 0.7) and 8.0 (t, 0.3). The spectrum shows the presence of two rotamers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CCOCC1
Temperature: 60 °C
Yield: 88.8 %

Procedure:
To a solution of methyl 2-(4-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-yl)acetate (0.73 g, 2.67 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (0.3 g, 5.34 mmol) at room temperature. Upon completion of addition, the reaction mixture was heated at 60° C. for 4 hours and then partitioned between ethyl acetate (30 mL) and 1N HCl (10 mL). The ethyl acetate layer was separated, washed with brine (20 mL), dried over sodium sulfate and concentrated to yield the title compound (0.615 g) as a white solid. MS found: (M−H)+=258.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)=[C:16]([N+:31]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)=[C:16]([NH2:31])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c(N)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.45 mmol) obtained in Step 2 was dissolved in ethanol (1.0 mL), and the solution was added with iron (0.50 g, 8.9 mmol) and water (1.0 mL) under ice-cooling, followed by stirring at 40° C. for 1 hour. To the reaction mixture under ice-cooling, water was added and the mixture was neutralized. Then, the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain (E)-4-{3-amino-4-[2-(1H-indazol-3-yl)vinyl]phenyl}piperazine-1-carboxylic acid tert-butyl ester (63 mg, 34%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:19][NH:1][C:2]2[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1n[nH]cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a suspension of 3-aminopyrazole-4-carboxylic acid (3.56 g, 0.023 mol) in 400 ml of methanol was added 3-cyclopentyloxy-4-methoxybenzaldehyde (5.06-g, 0.023 mole) and 95% sodium cyanoborohydride (1.85 g, 0.028 mol). The reaction mixture was stirred for 16 hours and then the methanol was evaporated under reduced pressure. The residue was treated with 100 ml of 15% aqueous NaOH and extracted twice with 100 ml portions of ether. The aqueous layer was acidified to pH 5 with 5N aqueous HCl and extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate extracts were evaporated under reduced pressure and the residue was triturated with ether to give 3.7 g (49%) of the title compound, mp 134-136°, after recrystallization from methanol.
Reaction SMILES: [Cl-:1].[NH2:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.[N:29]1([S:34](N2C=C[N+](C)=C2)(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1>CC#N>[Cl-:1].[N:29]1([S:34]([NH:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: COC(=O)C[C@@H](N)C[N+](C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](C[N+](C)(C)C)NS(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-amino-4-methoxy-N,N,N-trimethyl-4-oxobutan-1-aminium chloride (35 mg) in anhydrous MeCN (5 mL) is treated with triethyl amine (2.5 equiv.) and 3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.5 equiv.). The reaction mixture is stirred at ambient temperature for 16 h then concentrated under reduced pressure and the resulting residue is purified on silica gel using MeOH/DCM (0->80%).