Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:20](Br)([CH3:22])[CH3:21]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:20]([CH3:22])[CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (27.5 mmol) of 3,4-Dihydroxy-benzoic acid ethyl ester was dissolved in 110 ml of DMF and treated at 0° C. with 3.8 g (27.5 mmol) of potassium carbonate and 3.38 g (27.5 mmol) of isopropyl bromide. The solution was stirred for 16 h at RT, then a further 1.014 g (8.3 mmol) of isopropyl bromide was added. The reaction solution was heated at 50° C. for 3 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (5/1).
Reaction SMILES: C([Li])CCC.[CH2:6]([Cl:8])Cl.C(OCC)C.[CH3:14][O:15][C:16]([CH:18]([C:23](=[O:25])[CH3:24])[CH2:19]/[CH:20]=[CH:21]\[CH3:22])=[CH2:17]>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[Cl:8][CH:6]1[O:25][C:23]1([CH3:24])[CH:18]([C:16]([O:15][CH3:14])=[CH2:17])[CH2:19]/[CH:20]=[CH:21]\[CH3:22]
Reactant: ClCCl
Reactant: C=C(OC)C(C/C=C\C)C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(OC)C(C/C=C\C)C1(C)OC1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 28 ml. (45 mmol.) of 1.6 M n-butyl lithium in hexane was added dropwise and with stirring during 45 minutes to a solution of 3.2 ml. (50 mmol.) of methylene chloride in 20 ml. of diethyl ether, 20 ml. of petroleum ether, and 140 ml. tetrahydrofuran under nitrogen cooled to -95° in a toluene-liquid nitrogen slush. After 30 minutes, a solution of 6.72 g. (40 mmol.) of (Z)-2-methoxy-3-acetyl-1,5-heptadiene in 60 ml. of tetrahydrofuran was added dropwise during 45 minutes and the mixture was allowed to warm slowly to room temperature and then allowed to reflux for 3 hours. The mixture was then cooled, concentrated, poured into 200 ml. of saturated aqueous ammonium chloride, extracted with diethyl ether, the combined ethereal extracts washed with saturated aqueous sodium chloride, dried (Na2SO4) and concentrated to afford (Z)-1-chloro-1,2-epoxy-2-methyl-3-(1-methoxyethenyl)-5-heptene.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][F:22])[CH:16]=2)[CH:11]=[CH:10][C:9]=1[Cl:30])C.Cl>O1CCOCC1.CO.O>[C:26]([O:25][C:23]([N:19]([CH2:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][C:9]([Cl:30])=[C:8]2[CH2:7][C:6]([OH:31])=[O:5])=[CH:13][CH:14]=1)[CH2:20][CH2:21][F:22])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(CCF)C(=O)OC(C)(C)C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(=O)O)c2c1
Temperature: 45 °C

Procedure:
A aqueous solution of NaOH (2 M, 0.59 ml, 1.17 mmol) was added at RT under an atmosphere of argon to a solution of (7-{[tert-butoxycarbonyl-(2-fluoro-ethyl)-amino]-methyl}-2-chloro-naphthalen-1-yl)-acetic acid ethyl ester (249 mg, 0.59 mmol) in dioxane (2.7 ml). The slightly turbid mixture is rendered clear by the addition of 6 drops of MeOH. After warming to 45° C. for 2.5 h, HPLC analysis indicated complete consumption of starting material. Removal of solvent yielded a residue, which was taken up in water. After acidification to pH 4 by the addition of 1 M HCl, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was used directly in the next step. ES+-MS: 413.3, 415.5 [M+H+H2O]+. ES−-MS: 394.2, 396.2 [M−H]−.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH2:20][CH2:21]O)[CH2:17][CH2:18]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:15][N:16]1[CH2:20][CH2:21][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])([C:11]([O:13][CH3:14])=[O:12])[CH2:18][CH2:17]1
Reactant: CN(CCO)CCO
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C1(S(=O)(=O)c2ccccc2)CCN(C)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
2-(Phenylsulfonyl)acetic acid, methyl ester (205 mg, 0.95 mmol) was dissolved in THF (20 ml), then treated with N-methyl-diethanolamine (111 μl, 0.97 mmol), 1,1′-(azodicarbonyl)-dipiperidine (483 mg, 1.91 mmol) then tributylphosphine (197 μl, 1.91 mmol). After 10 minutes the mixture was warmed to 40° C. After stirring for 3 hours the solvents were removed and the residue purified by flash column chromatography on silica gel eluted with 25-75% ethyl acetate in hexanes to give N-(N-methyl-4-(phenylsulfonyl)-isonipecotic acid, methyl ester (47 mg).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:21]([CH2:22][C:23]3[O:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=2)[CH2:8]1>O1CCCC1>[N:4]([CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:21]([CH2:22][C:23]3[O:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=2)[CH2:8]1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: Cc1ccc(Cn2c(NC3CCN(CCN)C3)nc3cccnc32)o1
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(NC3CCN(CCN=C=S)C3)nc3cccnc32)o1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred mixture of 4.2 parts of N,N-methyltetraylbis[cyclohexanamine] and 90 parts of tetrahydrofuran were added 10.6 parts of carbon disulfide. After stirring for 10 minutes, a solution of 6 parts of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo-[4,5-b]pyridin-2-amine in 36 parts of tetrahydrofuran was added dropwise to the thus obtained mixture (exothermic reaction, the temperature rose to 26° C.). Upon complete addition, stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was taken up in 240 parts of acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 6.9 parts (100%) of N-[1-(2-isothiocyanatoethyl)-3-pyrrolidinyl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine as a residue (compound 171).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC=CC=1.[ClH:28]>O>[ClH:28].[ClH:28].[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
10.00 kg (52.84 mol) 1-benzylpiperidone (K) were taken and 9.21 kg (105.68 mol) morpholine (L) as well as 50.0 L toluene were added. Then the reaction mixture obtained was heated to reflux temperature using the water separator (110° C.) and stirred until no more water separated off. Then the mixture was hydrogenated at 4 bar and an internal temperature of 60° C. in the presence of 0.50 kg Raney nickel catalyst in 6 L ethanol. The catalyst was separated off and washed with 20 L ethanol. Then the solvent was distilled off completely in vacuo. Then 80.0 L ethanol were added and at 50° C. 16.05 kg (132.10 mol) hydrochloric acid (30%) were metered in. The resulting suspension was cooled to 20° C. and stirred for 30 minutes at 20° C. The product was centrifuged off and dried.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1>>[Cl:3][CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OCC1COc2ccccc2O1
Product: ClCC1COc2ccccc2O1

Procedure:
A mixture of thionyl chloride (36.0 g, 0.3 mol) and 2-hydroxymethyl-1,4-benzodioxan (25.0 g, 0.15 mol) was stirred and heated under reflux for 0.75 h. The reaction mixture was concentrated under reduced pressure, and the residue was distilled, to afford 2-chloromethyl-1,4-benzodioxan, b.p. 140°-146°/22 mm Hg.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH:16][C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)CCC(=O)O)c2c(Cl)cc(Cl)cc2N1

Procedure:
To a suspension of trans-2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9a) (225 mg, 0.819 mmol) in ethyl acetate (50 ml) was added a solution of potassium carbonate (50 ml). The mixture was shaken until no solid remained (5 min). The organic layer was retained and washed with brine (50 ml) before drying (Na2SO4). The solvent was removed in vacuo. The residue was redissolved in xylene (20 ml) and succinic anhydride (90 mg, 0.901 mmol) was added. The mixture was heated, with stirring, in an oil bath (80° C.) for 16h. The precipitate was removed by filtration and washed with ether to give the title compound as a colourless crystalline solid. δ (DMSO, 250 MHz), 1.65 (1H, ddd, J=13.0, 12.7 and 3.7 Hz, CHACHBHCCHD), 2.15 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.18-2.41 (4H, m, CO(CH2)2CO), 3.73 (3H, s, CH3), 3.94 (1H, dd, J 13.0 and 3.0 Hz, CHACHBHCCHd), 5.01 (1H, m, CHACHBHCCHD), 6.69 (1H, J=2.1 Hz, 6-H or 8-H), 6.86 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.91 (1H, s, ArNHCH), 8.23 (1H, d, J=7.2 Hz, NHCO).
Reaction SMILES: [O:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH3:6][CH:7]([CH3:13])[CH2:8][C:9](=[CH2:12])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>[CH2:8]([C:9]1[CH2:12][CH2:4][C:3]([CH3:5])([CH:2]=[O:1])[CH2:11][CH:10]=1)[CH:7]([CH3:13])[CH3:6]
Reactant: C=CC(=C)CC(C)C
Reactant: C=C(C)C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)CC1=CCC(C)(C=O)CC1
Yield: 47.5 %

Procedure:
Anhydrous AlCl3 (0.6 g, 4.1 mmol) was suspended in toluene (250 ml) with vigorous stirring and a slow flow of nitrogen applied. Methacrolein (90% tech., 14 ml, 160 mmol) was added at room temperature over 10 min causing a slight increase in temperature. After stirring for 15 min, 5-methyl-3-methylenehex-1-ene 2 (25 g, 140 mmol) was added over 30 min causing the temperature to rise further to 31° C. The reaction mixture was stirred for 2 h and then quenched with sat. NaHCO3 solution (200 ml). After brief agitation the phases were separated and the lower aqueous phase extracted with toluene (300 ml). The combined organic phases were washed with sat. sodium potassium tartrate solution (2×200 ml) and water (300 ml), dried (Na2SO4) and concentrated in vacuo. The oil was purified by short Vigreux distillation at reduced pressure to give 3a as a colorless oil (12 g, 48% yield) containing ca. 10% GC of an isomer 3′a.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:11]Br.[CH2:17]([O:19][C:20]([C@:22]1([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:27]([NH2:28])[CH2:26][C@@H:25]2[C@H:23]1[C@@:24]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[CH3:18].[Cl-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:19][C:20]([C@:22]1([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[C@H:27]([NH:28][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:8]([Cl:7])[CH:9]=2)[CH2:26][C@@H:25]2[C@H:23]1[C@@:24]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[CH3:18]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.3 %

Procedure:
42 μL of pyridine and 123 mg of 3,4-dichlorobenzylbromide were added to 175 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.88 mL of chloroform at ice-cooling, and then the mixture was stirred for 3 days at room temperature. A saturated aqueous solution of sodium chloride was added thereto, and the mixture was extracted five times with chloroform. The organic layers were combined and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=100:1 to 50:1, followed by hexane-ethyl acetate=5:1), thereby yielding 98 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[S:10]1[CH:11]=[CH:12][C:8]([CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:9]1
Reactant: BrCc1ccsc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1cn(Cc2ccsc2)cn1

Procedure:
In a 3 neck, round-bottomed flask reflux a mixture of 11.6 g (0.17 mol) imidazole, 30 g (0.17 mol) 3-bromomethylthiophene, 46 g (0.33 mol) K2CO3 and 400 ml dry acetone. After refluxing for 4 hours filter the reaction mixture and wash the inorganic solids with acetone. Remove the acetone under vacuum and partition the residue betwen H2O/EtOAc. Wash the EtOAc layer several times with H2O, dry (Na2SO4) and concentrate the washed material to obtain a pale yellow oil.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH3:18])=[CH:12][N:11]=1>C(#N)C>[Cl:9][C:10]1[N:11]=[CH:12][C:13]([CH2:16][N:17]([CH3:18])[C:3]([NH2:8])=[N:4][N+:5]([O-:7])=[O:6])=[CH:14][CH:15]=1
Reactant: CNCc1ccc(Cl)nc1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C(N)=N[N+](=O)[O-]
Yield: 31.2 %

Procedure:
A mixture of 0.676 g of S-methyl-N-nitroisothiourea, 0.783 g of 2-chloro-5-(methylaminomethyl)pyridine and 6 ml of acetonitrile was refluxed for 17 hours, and concentrated. The residue was recrystallized from ethanol to obtain 0.38 g of 1-(6-chloro-3-pyridylmethyl)-1-methyl-2-nitroguanidine (Compound No. 7).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6](Cl)(=[O:8])=[O:7])=[N:2]1.O1CCCC1.S(Cl)(Cl)(=O)=O.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:8])=[O:7])=[N:2]1
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccccc1)c1nc[nH]n1
Reaction time: 16 h

Procedure:
To a flask was added 10 g of thoroughly dried 1,2,4-triazole-3-sulfonyl chloride and 150 ml of tetrahydrofuran. The resulting mixture was stirred under nitrogen until most of the sulfonyl chloride dissolved. Phenol, 6.2 g, was then added at room temperature followed by the slow addition of 9 ml of triethyl amine. A precipitate became apparent and the resulting mixture was stirred for an additional 16 hours. The tetrahydrofuran was evaporated from the mixture and the residue washed with 200 ml of water followed by extraction with 200 ml of ethyl acetate. The ethyl acetate solution was dried using sodium sulfate, filtered and concentrated to yield 10.77 g of the desired intermediate as a white solid.
Reaction SMILES: [C:1]([CH:4]1[CH:9]=[CH:8][CH2:7][N:6]2[C:10](=[O:20])[N:11]([CH2:14][CH2:15][C:16](OC)=[O:17])[C:12](=[O:13])[N:5]12)([OH:3])=[O:2].[NH3:21]>CO>[C:16]([CH2:15][CH2:14][N:11]1[C:10](=[O:20])[N:6]2[CH2:7][CH:8]=[CH:9][CH:4]([C:1]([OH:3])=[O:2])[N:5]2[C:12]1=[O:13])(=[O:17])[NH2:21]
Reactant: N
Reactant: COC(=O)CCn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2
Solvent: CO
Product: NC(=O)CCn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2
Reaction time: 72 h
Yield: 85 %

Procedure:
2.83 g (0.01 mol) of methyl 5-carboxy-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-propionate were dissolved in 50 ml of methanol. The solution was saturated with ammonia and stirred for 72 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was passed through an ion-exchange column (Zerolit 225, H+ form) and the eluate was evaporated to give a colourless solid. This solid was recrystallized from methanol to give 2.26 g (85%) of 2-(2-carbamoylethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 218°-220° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:45])(=[O:44])[N:30]([CH2:41][CH2:42][CH3:43])C(OCC3C=CC=CC=3)=O)=[CH:27][C:21]=2[S:20](=[O:47])(=[O:46])[N:19]=1>CO.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:30][CH2:41][CH2:42][CH3:43])(=[O:45])=[O:44])=[CH:27][C:21]=2[S:20](=[O:47])(=[O:46])[N:19]=1
Reactant: CCCN(C(=O)OCc1ccccc1)S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Agent: [Pd]
Solvent: CO
Product: CCCNS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of the product of Example 438 in methanol is treated with 10% palladium on carbon and stirred at 25° C. for 5 hours under hydrogen atmosphere. The resulting solution is then filtered and the filtrate concentrated under reduced pressure to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:46]=[CH:45][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(F)cc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.049 g, 0.108 mmol), (4-((4-fluorobenzyl)oxy)phenyl)boronic acid (0.040 g, 0.161 mmol) and 2M Na2CO3 (0.134 ml, 0.269 mmol) in DMF (2 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 10.76 μmol) was added, degassed for 5 min and placed in a pre-heated oil bath at 100° C. After 1.5 h at 110° C., cooled and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0372 g, 0.065 mmol, 59.9% yield) as tan color solid. LCMS (M+H)=577.6.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[NH:16][C:15]([C:17]([C:53]4[C:58]([CH3:59])=[CH:57][C:56]([CH3:60])=[CH:55][C:54]=4[CH3:61])=[C:18]4[N:52]=[C:21]([C:22]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=5)=[C:23]5[NH:41][C:26](=[C:27]([CH:33]6OCC(C)(C)C[O:34]6)[C:28]6[CH:29]=[CH:30][C:31]=2[N:32]=6)[CH:25]=[CH:24]5)[CH:20]=[CH:19]4)=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[NH:16][C:15]([C:17]([C:53]4[C:54]([CH3:61])=[CH:55][C:56]([CH3:60])=[CH:57][C:58]=4[CH3:59])=[C:18]4[N:52]=[C:21]([C:22]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=5)=[C:23]5[NH:41][C:26](=[C:27]([CH:33]=[O:34])[C:28]6[CH:29]=[CH:30][C:31]=2[N:32]=6)[CH:25]=[CH:24]5)[CH:20]=[CH:19]4)=[CH:14][CH:13]=3)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4ccc(C(C)(C)C)cc4)c4ccc([nH]4)c(C4OCC(C)(C)CO4)c4nc(c(-c5ccc(C(C)(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(-c2c3nc(c(-c4ccc(C(C)(C)C)cc4)c4ccc([nH]4)c(C=O)c4nc(c(-c5ccc(C(C)(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
Following a general procedure,22 a solution of 4 (43 mg, 0.05 mmol) in CH2Cl2 (5 mL) was treated with TFA/water (0.5 mL, 1:1) to give a biphasic solution. After stirring at room temperature for 2.5 h, CH2Cl2 was added. The organic layer was washed (saturated aqueous NaHCO3 and brine), dried (Na2SO4), concentrated, and chromatographed (silica, CH2Cl2/hexanes) to give a purple solid (34.8 mg, 92%): IR (neat) 1674, 1557, 1110 cm−1; 1H NMR δ−1.90 (s, 2H), 1.61 (s, 18H), 1.84 (s, 6H), 2.61 (s, 3H), 7.26 (s, 2H), 7.75-7.78 (m, 4H), 8.08-8.11 (m, 4H), 8.59 (d, J=4.4 Hz, 2H), 8.69 (d, J=4.4 Hz, 2H), 9.01 (d, J=5.2 Hz, 2H), 10.03 (br s, 2H), 12.50 (s, 1H); 13C NMR δ195.1, 151.2, 139.2, 138.7, 138.3, 137.7, 134.2, 128.0, 124.4, 124.0, 122.6, 107.7, 35.2, 31.9, 29.9, 21.8, 21.7; LD-MS obsd 721.86; FAB-MS obsd 721.3931, calcd 720.3828 (C50H48N4O); λabs 428, 528, 567, 600, 657 nm.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[N:18]=[C:19]([CH3:22])[S:20][CH:21]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[CH:29]1([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:17]4[N:18]=[C:19]([CH3:22])[S:20][CH:21]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCCC1
Reactant: Cc1nc(-c2nn3ccccc3c2-c2ccnc(F)c2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 3-(2-fluoro-4-pyridinyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine (220 mg, 0.71 mmol) and potassium carbonate (98 mg, 0.71 mmol) in cyclopentylamine (5 mL) was heated at 100° C. for 12 days. After cooling to room temperature, the solution was diluted with ethyl acetate and the organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (1:9 methanol/chloroform) gave N-cyclopentyl-4-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine (265 mg, 100%) as an oil. 1H NMR (CDCl3): δ 8.49 (d, 1H), 8.04 (d, 1H), 7.49 (d, 1H), 7.08 (t, 1H), 6.74 (t, 1H), 6.59 (d, 1H), 6.43 (s, 1H), 5.44 (d, 1H), 3.79 (m, 1H), 2.73 (s, 3H), 1.92–1.42 (m, 8H). MS m/z 376 (M+1).