Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A round-bottomed separable flask (3,000 cc) equipped with a mechanical stirrer was charged with cyclopentyl alcohol (500 g, 5.80 mol) and p-toluenesulfonyl chloride (1,210 g, 6.35 mol), followed by the addition of pyridine (2,000 mL) under ice cooling to form a solution. The mixture was stirred for 8 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water (3,000 mL) and stirred thoroughly. The precipitating solids were isolated by filtration, washed thoroughly with water and dried to give a white crystal of cyclopentyl p-toluenesulfonate (1,117 g; yield=80.1%). MP: <30° C. 1H-NMR(CDCl3,TMS,ppm): δ1.23-2.07(8H,m), 2.45(3H,s), 4.98(1H,m), 7.38(2H,d,J=9.0Hz), 7.85(2H,d,J=9.0Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20](Cl)=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.[NH3:36]>>[CH:1]1([C:4]2[C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]4[C:15]([CH3:23])=[C:16]([C:20]([NH2:36])=[O:21])[N:17]([CH3:19])[N:18]=4)=[CH:10][C:9]=3[CH3:24])=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: Cc1cc(-c2nn(C)c(C(=O)Cl)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Product: Cc1cc(-c2nn(C)c(C(N)=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O

Procedure:
At room temperature, to 28%-Ammonia solution 50 ml was added 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carbonyl chloride (described in Reference Preparation example 117) 1.3 g. The mixture was stirred for twelve hours and concentrated under reduced pressure and added 10%-hydrochloric acid solution 10 ml. The precipitates were filtrated and were washed with water and were dried under reduced pressure to give 1-{3-cyclopropyl-2-[2-methyl-4-(5-aminocarbonyl-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 49”) 0.8 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O.[OH-].[Li+]>N1C=CC=CC=1.C1COCC1.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(Cl)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol) in pyridine (5 mL) at 0° C. was treated dropwise with cyclopropanecarbonyl chloride (118.3 μL, 1.304 mmol). The mixture was stirred at 0° C. for 60 minutes, and then the pyridine was removed in vacuo. The residue obtained was dissolved in THF (10 mL) and treated with lithium hydroxide hydrate (109.5 mg, 2.61 mmol) in water (1 mL). After 30 minutes, the THF was removed under reduced pressure, and water (5 mL) was added to the residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (165 mg, 64% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.03 (br s, 1H), 9.76 (s, 1H), 8.34 (d, 1H), 7.59 (s, 1H), 1.93-1.86 (m, 1H), 0.783 (d, 4H); LCMS (APCI+) m/z 298, 300 (M+H)+, Retention time=2.71 min (Method 2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[N+:17]([O-:19])=[O:18].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:12]=[C:11]2[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1c[nH]c2ccc(Cl)cc12
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cn(CCC(F)(F)F)c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Potassium carbonate (1.5 g, 11.1 mmol) was added to a solution of 5-chloro-3-nitro-indole (1.1 g, 5.6 mmol) and 3-bromo-1,1,1-trifluoropropane (1.2 g, 6.7 mmol) in ACN (20 mL) at rt. The mixture was heated to 80° C. and stirred overnight. The reaction mixture was filtered and concentrated to give 1.6 g (100%) of the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ 2.69-2.76 (2H, m), 4.47 (2H, t, J=7.2 Hz), 7.31 (1H, d, J=8.8 Hz), 7.38 (1H, dd, J=2.0, 8.8 Hz), 8.11 (1H, s), 8.30 (1H, d, J=2.0 Hz).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=1)C1C=CC=CC=1.COC(O)C.C(Cl)[Cl:33].Cl>CO.[OH-].[OH-].[Pd+2]>[ClH:33].[CH:15]1([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[NH2:8])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: ClCCl
Reactant: c1ccc(CN(Cc2ccccc2)c2cccc(C3CCCC3)c2)cc1
Agent: [Pd+2]
Agent: COC(C)O
Agent: Cl
Solvent: CO
Product: Nc1cccc(C2CCCC2)c1

Procedure:
N,N-Dibenzyl-3-cyclopentyl-aniline (6.07 g, 17.03 mmol) was hydrogenated over Pd(OH)2 (600 mg) under 10 bars in a mixture of MeOH (80 ml), methoxyethanol (20 ml), CH2Cl2 (20 ml) and concentrated HCl (1.63 ml) for 20 h, The catalyst was removed by filtration and the solvent was removed under reduced pressure. The residue was partitioned between CH2Cl2 and water. The pH was set to about 10 by adding NaOH in pellets. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 2.65 g of the expected aniline. The hydrochloride was obtained by treatment with ethereal HCl: 2.38 g, yield: 71%. HPLC: 100%.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=O)[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][C:11]=2[N:23]=1)=O.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:14]1[N:15]=[C:10]2[CH:9]=[CH:8][C:7]3=[N:6][N:5]=[C:3]([CH2:2][Cl:1])[N:23]3[C:11]2=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(CCl)NNc1ccc2[nH]c(=O)c(-c3ccccc3)nc2n1
Product: ClCc1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-N′-(2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)acetohydrazide (104) (230 mg, 0.698 mmol) and phosphoryl chloride (4 mL, 42.9 mmol) was heated under microwave irradiation at 150° C. for 1.5 hours. The solvent was evaporated, and the residue was diluted with EtOAc, washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated under reduced pressure to give 3-chloro-9-(chloromethyl)-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (10-2).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:3][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([N:34]2[CH2:35][CH2:36][N:31]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:32][CH2:33]2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:4]
Reactant: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
The title compound of Example 24 is converted to its acid chloride and is reacted with N benzylpiperazine by the method of Example 23 to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:3][C:2]([C:38]2[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: OB(O)c1cccnc1F
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
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
Solvent: O
Product: Cn1nccc1-c1cc(-c2cccnc2F)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
10 mg of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in DMF/H2O=1:1 (0.46 mL), and 3.2 mg of (2-fluoropyridin-3-yl)boronic acid, 0.8 mg of Pd(PPh3)4 and 7.4 mg of Na2CO3 were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, DMF was removed by concentrating under reduced pressure. After extracting with EA, the extract was treated with MgSO4 and concentrated under reduced pressure. The residue was separated by PLC (developing solvent, EA) to obtain 3.2 mg (28% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 4-methoxybenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.81 (3H, s), 5.17 (2H, s), 5.75 (1H, d, J=2.0 Hz), 6.91-6.93 (2H, m), 7.34-7.39 (3H, m), 7.57 (1H, d, J=2.0 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4O2, 307; Found, 307.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19]([NH2:22])(=[O:21])=[O:20])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C.[C:52](O)(=[O:54])[CH3:53]>ClCCl.C(OCC)(=O)C>[C:52]([NH:22][S:19]([CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[CH2:16][CH2:15]1)(=[O:21])=[O:20])(=[O:54])[CH3:53]
Reactant: NS(=O)(=O)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NS(=O)(=O)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
To a stirred solution of the product of Example 105 (141 mg, 0.28 mmol) in dichloromethane (10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol), dimethylaminopyridine (66 mg, 0.57 mmol) and acetic acid (0.035 mL, 0.58 mmol). The mixture was stirred for 18 hours, diluted with ethyl acetate (20 mL), washed with 2N aqueous hydrochloric acid (20 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica eluting with ethyl acetate: dichloromethane:iso-hexane 2:1:1, to afford the desired product (90 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:16][CH2:17][OH:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30]I.[H-].[Na+].Cl>C1COCC1.[NH4+].[Cl-]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:19]3[C:20](=[O:29])[C:21]4=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]4[C:23]3=[O:24])[CH2:16][CH2:17][O:18][CH3:30])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COc1ccc(C(CCO)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCCC(c1ccc(OC)c(OC2CCCC2)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-(3'-cyclopentyloxy-4'-methoxyphenyl)-3-phthalimido-1-propanol (786 mg, 1.99 mmol) and methyl iodide (0.25 mL, 4.0 mmol) in THF (1 0 mL) at room temperature, was added NaH (160 mg, 60%, 4.0 mmol). The mixture was stirred at room temperature for 1 h, and then was refluxed for 35 minutes. The mixture was allowed to cool to room temperature. To the resulting mixture was added a few drops of NH4Cl, then HCl (1N, 25 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (25 mL), and dried over Na2SO4. Removal of solvent and chromatography (silica gel 100 grams, 1:5 EtOAc:hexane) gave 3-(3'-cyclopentyloxy-4'-methoxyphenyl)-1-methoxy-3-phthalimidopropane as an oil, (510 mg, 63% yield). The oil solidified upon standing at room temperature to give a white solid: mp, 77.5°-80.0° C.; 1H NMR (CDCl3)δ1.58-1.96 (m, 8H, C5H8), 2.45-2.55 (m, 1H, CHH), 2.70-2.85 (m, 1H, CHH), 3.26 (s, 3H, CH3), 3.39 (t, J=6 Hz, 2H, CH2), 3.81 (s, 3H, CH3), 4.78-4.80 (m, 1H, OCH), 5.46 (dd, J=7, 9.3 Hz, 1H, NCH), 6.79 (d, J=8.3 Hz, 1H, Ar), 7.06-7.10 (m, 1H, Ar), 7.17-7.26 (m, 1H, Ar), 7.67-7.69 (m, 2H, Ar), 7.78-7.82 (m, 2H, Ar); 13C NMR (CDCl3)δ24.08, 31.30, 32.76, 51.94, 56.00, 58.71, 69.71, 80.37, 111.63, 115.09, 120.53, 123.12, 131.92, 131.96, 133.81, 147.53, 149.55, 169.37; Anal Calcd for C24H27NO5 : C, 70.40; H, 6.65; N, 3.42. Found: C, 70.32; H, 6.61; N, 3.31.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].CC(C)=O.O.[C:15]([OH:24])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CC(C)=O.O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:15]([O-:24])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21]
Reactant: O=C(O)CCCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])CCCCC(=O)[O-]
Temperature: 25 °C
Yield: 139.1 %

Procedure:
9.75 g (2.5 molar equivalents) of the metformin free-base was stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at 40° C., and then a solution of 4.41 g (1 molar equivalent) of adipic acid in acetone-water was added dropwise thereto and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 11.47 g (yield: 93.9%) of metformin adipate.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]([F:12])([F:11])[CH3:10])[C:4]([O:6][CH3:7])=[O:5].[CH2:13]1[C:17]2([CH2:22][CH2:21][N:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>C(#N)C>[CH2:13]1[C:17]2([CH2:18][CH2:19][N:20]([S:23]([NH:2][C@@H:3]([CH2:8][C:9]([F:11])([F:12])[CH3:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:25])=[O:24])[CH2:21][CH2:22]2)[CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)[C@@H](N)CC(C)(F)F
Reactant: O=S(=O)(Cl)N1CCC2(CCCC2)CC1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)(F)F)NS(=O)(=O)N1CCC2(CCCC2)CC1

Procedure:
In a reaction vessel, 100 mg of methyl (S)-2-amino-4,4-difluoropentanoate hydrochloride (0.49 mmol) were admixed with 320 mg of N,O-bis(trimethylsilyl)-acetamide (3.2 eq.) in 3 ml of acetonitrile. The reaction mixture was treated at 100° C. in a microwave for 30 min. 128 mg of 8-azaspiro[4.5]decane-8-sulfonyl chloride (1.1 eq.), dissolved in 2.5 ml of acetonitrile, were then added and the resulting reaction mixture was treated at 100° C. in a microwave for a further 2.5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). Methyl (S)-2-(8-azaspiro[4.5]decane-8-sulfonylamino)-4,4-difluoropentanoate was obtained as a colorless amorphous material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([O:24]C)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCCC2)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of Methyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclopentanecarboxylate (2.8 g, 8.0 mmol, Step 6) in MeOH (11 mL), 2 N aqueous NaOH solution (6 mL) was added at room temperature (exothermic). The resulting solution was stirred at 70° C. for 4 h, then cooled to 5˜10° C. in ice-cold water bath. To the solution, 5 N HCl aq (6 mL) was added dropwise. The resulting solution (pH value was ca.6) was concentrated and to the residue, 2-propanol (40 mL) was added. This solution was concentrated and to the residue, CH3CN (40 mL) was added. The resulting mixture was stirred at room temperature for 2 h and it was filtered through a Celite pad (5.0 g) to remove NaCl. The filtrate was concentrated to give 2.4 g (quant) of the titled compound as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[NH:10])OC)[CH:2]=1.Cl.C([O:14][C:15](=O)[C@H:16]([CH3:18])[NH2:17])C.C(N(CC)CC)C>O1CCCC1>[CH3:18][CH:16]1[C:15](=[O:14])[NH:10][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: COC(=N)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1N=C(c2cccnc2)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A stirred mixture of methyl pyridine-3-carboximidate (10.6 g), alanine ethyl ester monohydrochloride (10 g), triethylamine (8.4 ml) and tetrahydrofuran (250 ml) was heated under reflux under nitrogen for 5 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and the solvent removed in vacuo. The residue was triturated with a 1:1 mixture of ether and ethyl acetate, and the resulting solid was collected by filtration and washed with ether. The two crops of solid were combined, suspended in water (130 ml), and the mixture was stirred at ambient temperature for 1 hour. The resulting solid was collected by filtration and dried in vacuo to give 4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as a yellow solid (4.9 g), m.p. 238-241° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:31]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:31])[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc(N3CCCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 88 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (22 mg, 0.052 mmol), ammonia (0.5 mL, 30% in water) and dioxane (2 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 23 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-(piperidin-1-yl)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (18 mg, 0.046 mmol, 88% yield). 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H); 9.27 (s, 1H); 8.35 (s, 1H); 7.97-8.06 (m, J=8.18, 1.46 Hz, 1H); 6.76 (d, J=8.92 Hz, 1H); 5.21 (s, 2H); 3.95 (s, 3H); 3.83 (s, 4H); 2.48 (s, 3H); 1.57-1.76 (m, 6H). m/z (ESI, +ve ion) 394.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][OH:27])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: C#CCO
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCC#Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
In a 1000 mL flask, 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (25.0 g, 65.3 mmol) and propargyl alcohol (4.4 g, 78.36 mmol) were diluted with triethylamine (250 mL). Then bis(triphenylphosphine)palladium(II) chloride (0.915 g, 0.0200 mmol), copper(I) iodide (0.320 g, 0.169 mmol) and triphenylphosphine (0.102 g, 0.150 mmol) were added. The reaction was heated to 70° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. A Brine solution was added to the filtrate and stirred for 15 minutes. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 15% ethyl acetate/petroleum ether as eluent to afford the title compound as yellow solid (8.00 g, 33%): mp 110-113° C.; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.39 (d J=8.4, 2H), 4.53 (d, J=4.8, 2H), 1.80-1.74 (brs, 1H); ES+API m/z 360 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Ethyl (S)-3-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]acrylate (252 mg) was dissolved in ethanol (10 ml), and 10% palladium on activated carbon (30 mg) was added to the solution, then the resulting mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtrated to remove the catalyst, and the filtrate was concentrated in vacuo. Recrystallization of the residue from diisopropyl ether gave ethyl (S)-3-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]propionate (236 mg) having a melting point of 101-102° C.