Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[C:10](=O)([O-])[O-].[K+].[K+].CI>COCCOC>[CH3:1][C:2]1([CH3:9])[N:7]([CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)NCCNC1=O
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: CN1CCNC(=O)C1(C)C
Temperature: 42.5 °C
Reaction time: 9 h
Yield: 73.9 %

Procedure:
3,3-dimethylpiperazin-2-one (50 grams) is suspended in 1,2-dimethoxyethane (DME) (150 ml) and potassium carbonate (70 grams) is added. Methyl iodide (66.4 grams) is added during half an hour, while the mixture is cooled slightly, allowing the temperature to reach 50° C. The mixture is stirred 9 hours at an oil bath at 40-45° C., and a sample is withdrawn for NMR, which indicates, that there is still 8% starting material left (singal at 2.8 ppm). More methyl iodide is added (4.6 grams), and the mixture is stirred for another 2½ hour at 40° C., and a new NMR sample shows full conversion. The mixture is filtered, and the filter cake is washed with DME. The filtrate is evaporated to dryness giving 41 grams of the title compound. NMR complies with the structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8].O.[O-:33][C:34]#[N:35].[K+]>N1C=CC=CC=1>[NH:1]([CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8])[C:34]([NH2:35])=[O:33]
Reactant: N#C[O-]
Reactant: COc1ccc(CCNC(=O)CN(CCCN)c2cc(C)nc(-n3ccnc3)n2)cc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CCNC(=O)CN(CCCNC(N)=O)c2cc(C)nc(-n3ccnc3)n2)cc1
Temperature: 80 °C

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide (135 mg, 0.32 mmol) (a compound of formula (Yc6)) in pyridine (1.5 mL) was added water (1.5 mL) solution of potassium cyanate (64 mg, 0.76 mmol). The mixture was stirred and heated in an oil bath at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (9:1 CH3CN/NH4OH) to afford 2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide, a compound of formula (Yc9); as a white solid; NMR (DMSO-d6, 90 C.) 8.4 (s, 1), 7.8 (s, 1), 7.05 (d, 2), 7.0 (s, 1), 6.75 (d, 2), 6.4 (s, 1), 4.1 (s, 2), 3.7 (s, 3), 3.5 (m, 2), 3.25 (m, 2), 3.05 (m, 2), 2.65 (t, 2), 2.3 (s, 3), 1.7 (m, 2) ppm.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[CH3:21][O:22][CH2:23][CH2:16][CH2:15][S:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([OH:5])=[O:7])[CH2:13][CH2:12]1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCSC1CCN(C(=O)O)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][OH:31])[CH:26]=[CH:27][CH:28]=1)=[N:6]2
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: OCCc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(Nc3cccc(CCO)c3)ncc12
Yield: 53.8 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 2-(3-bromophenyl)ethanol (0.012 mL, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave 2-[3-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]ethanol (0.020 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.13 (s, 1H), 8.91 (d, J=7.9 Hz, 1H), 8.85 (s, 1H), 8.74 (bs, 1H), 7.89-7.75 (m, 3H), 7.76 (s, 1H), 7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.22 (s, 1H), 7.00 (d, J=7.7 Hz, 1H), 3.81 (t, J=7.0 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.57 (s, 3H). m/z 414 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:18][CH:19]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cccnc1Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1107.4 %

Procedure:
Take up 2-[4-(2-aminoethyl)phenoxy]nicotinamide (0.0555 g, 0.216 mmol) in methanol (2.1 mL). Add benzaldehyde (0.022 mL, 0.216 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.0082 g, 0.216 mmol) and stir for 6 hours before loading directly onto an SCX column. Wash the column with methanol then elute with 2.0 M NH3 in methanol. Purify by flash chromatography, eluting with 4% (2.0 M NH3 in methane) in dichloromethane to give the title compound (0.831 g, 79%): TOF MS ES+ 348.2 (M+H)+, HRMS calcd for C21H22N3O2 348.1712 (M+H)+, found 348.1721, time 0.35 min; TLC [silica gel 60 F254, 5% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.20.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[C@H]1CCN(CCCl)C1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CC[C@H](F)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.4 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.51 g, 1.6 mmol) in DMSO (5.0 mL) was added (S)-1-(2-chloroethyl)-3-fluoropyrrolidine (0.24 g, 1.6 mmol) and Cs2CO3 (3.1 g, 9.5 mmol). The reaction mixture was stirred at ambient temperature for 18 h, and then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×20 mL). The organic extracts were washed with brine (3×20 mL) and dried (Na2SO4). Purification by flash chromatography (silica gel, CH2Cl2/80:18:2 CH2Cl2/MeOH/NH4OH, 100.0 to 0:100), followed by additional flash column chromatography (silica gel, CH2Cl2/10% MeOH in CH2Cl2, 100:0 to 10:90), followed by treatment with activated charcoal, followed by final purification by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (58.3 mg, 8%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.45-7.37 (m, 6H), 7.31-7.30 (m, 1H), 6.12-6.10 (m, 2H), 5.16 (dt, J=55.5, 4.5 Hz, 1H), 5.07 (s, 2H), 4.58 (t, J=7.0 Hz, 2H), 3.01 (br m, 2H), 2.97-2.93 (m, 2H) 2.92-2.90 (m, 1H), 2.56 (br s, 1H), 2.17-2.03 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.9 min.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:29]([N:31](CC)CC)[CH3:30].[ClH:36].C(=N)(OCC)C.Cl>CO.C(OCC)(=O)C>[ClH:36].[ClH:36].[C:29]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][N:16]2[CH2:17][CH2:18][N:13]([S:10]([C:7]3[CH2:8][O:9][C:4]4[CH:3]=[C:2]([Br:1])[CH:28]=[CH:27][C:5]=4[CH:6]=3)(=[O:11])=[O:12])[CH2:14][C:15]2=[O:26])[CH2:21][CH2:22]1)(=[NH:31])[CH3:30]
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Br)cc3OC2)CCN1NC1CCNCC1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=N)N1CCC(NN2CCN(S(=O)(=O)C3=Cc4ccc(Br)cc4OC3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 188.2 %

Procedure:
A solution of 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-(4-piperidinylamino)-2-piperazinone (104 mg) and triethylamine (272 mg) in methanol (10 ml) was combined with ethyl acetoimidate hydrochloride (272 mg) and stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, washed with a 1N aqueous solution of sodium hydroxide and brine, dried and concentrated. The residue obtained was suspended in ethyl acetate, combined with a 4N solution of hydrochloric acid in ethyl acetate to precipitate a hydrochloride, which was collected by filtration and dried to obtain the title compound (243 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Clc1cccc(-c2csc(Br)n2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3Cl)cs2)CC1
Yield: 7.4 %

Procedure:
A solution of 2-bromo-4-(2,3-dichlorophenyl)-1,3-thiazole (3.68 mg, 12.3 mmol), tert-butyl piperazine-1-carboxylate (4.44 g, 24.6 mmol) and potassium carbonate (1.65 g, 12.3 mmol) in dimethylformamide (40 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 376 mg (7.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][F:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)C.CN(C)C=O>[F:28][CH2:27][CH2:26][CH2:25][CH2:24][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: FCCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccccc2N2CCN(CCCCF)CC2)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), 1-bromo-4-fluorobutane (19.8 mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2 hours at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-(4-fluorobutyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10]1.O1CCCC1.[BH4-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1([CH2:12][O:13][NH2:14])[CH2:11][CH2:10]1
Reactant: Cc1cc(OCC2(CON3C(=O)c4ccccc4C3=O)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC2(CON)CC2)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of N-{1-[[5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}phthalimide (5.4 g, 9.5 mmol), as prepared in the preceding step, in ethanol (100 mL)/tetrahydrofuran (100 mL)/water (50 mL) was added sodium borohydride (1.15 g, 30.0 mmol). The reaction mixture was stirred at ambient temperature overnight. 2N HCl was added to adjust the pH to 1-2, the mixture was heated to 50° C. for 2 hours. The reaction mixture was concentrated to about 100 mL, water (50 mL) was added and the mixture was neutralized to pH 8-9 with 2N NaOH. The mixture was extracted into ethyl acetate (3×100 mL) and the organic phase was washed with brine (2×100 mL) and then dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (4:1 ethyl acetate/hexane) to give the title compound as a white solid (3.6 g, 86%). 1H-NMR (300 MHz, CDCl3) δ8.45 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 6.61 (s, 1H), 6.58 (s, 2H), 5.44 (br s, 2H),3.76 (s, 2H), 3,63 (s 2H), 3.45 (s, 3H), 2.23 (s, 3H), 0.57-0.65 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[S:18]([CH2:22][CH2:23]O)[CH2:19][CH2:20][OH:21].Cl.CN(C)CCCN=C=NCC.CCOCC.CCCCCC>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][CH2:22][S:18][CH2:19][CH2:20][OH:21])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OCCSCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCSCCO)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 15.0 g, 65 mmol), 2,2′-thiodiethanol (40 g, 325 mmol) and N,N-dimethylaminopyridine (DMAP, 1.59 g, 13 mmol) in dichloromethane (400 mL) at room temperature was added 1-(3-(dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 14.98 g, 78 mmol) as a solid, in portions. After stirring for 3 hours at room temperature, TLC analysis indicated the reaction was complete. The reaction mixture was partitioned between CH2Cl2 and water, and the water layer was washed with more CH2Cl2. The combined organic layer was washed with water, 0.1 N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated under vacuum, and the residue was purified via column chromatography, 5% ethyl acetate/dichloromethane. The appropriate fractions were combined, and the solvent evaporated. Trituration of the residue with ether/hexane gave the title compound as a white solid (17.72 g, 81% yield). Mp 58-61° C. 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.67 (d, J=0.9 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.14 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 3.86 (q, J=7.2 Hz, 1H), 3.60 (app q, J=6.0 Hz, 2H), 2.69 (t, J=6.6 Hz, 2H), 2.61 (t, J=5.9 Hz, 2H), 2.00 (t, J=6.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 352 (MNH4+); Anal. calcd. for C18H22O4S: C, 64.65; H, 6.63; S, 9.59; Found: C, 64.62; H, 6.59; S, 9.47.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[CH3:11][C:12]1[C:13]([CH:19]([CH:22]2[CH2:24][CH2:23]2)[CH:20]=O)=[N:14][CH:15]=[CH:16][C:17]=1[Cl:18].[C:25](OC)(=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C(O)C>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]2[C:13]([C:12]=1[CH3:11])=[C:19]([CH:22]1[CH2:24][CH2:23]1)[CH:20]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:25]2=[O:31]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1c(Cl)ccnc1C(C=O)C1CC1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Piperidine (7 mL, 70.9 mmol) and acetic acid (5.5 mL, 95 mmol) were added to a solution of 2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-acetaldehyde (4.98 g, 23.75 mmol) in absolute ethanol (200 mL). Dimethyl malonate (16.44 mL, 144 mmol) was added and the reaction mixture was stirred at 100° C. for 5 h (the reaction mixture turned into a red solution). The solvent was evaporated under reduced pressure. The resulting mixture was diluted with ether (100 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was separated and dried over sodium sulfate. The mixture was evaporated to dryness. Dowtherm A (110 mL) was added. This reaction mixture was heated to 240° C. under microwave irradiation and stirred at this temperature for 0.5 h during which the reaction mixture turned into a black solution. The residue was purified by reversed phase flash chromatography using a 5%-100% acetonitrile gradient in water with 1% TFA yielding the cyclized methyl ester (4 g, 51.4%). ESI-MS m/z: 292 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 3.95 (s, 1H), 3.01 (s, 1H), 2.35-2.27 (m, 1H), 1.03-1.08 (m, 2H), 0.72-0.76 (m, 2H); 13C NMR (100 MHz CDCl3) δ ppm 166.6, 155.4, 148.4, 145.5, 142.3, 130.7, 129.0, 117.6, 115.6, 105.4, 52.3, 19.6, 17.0, 9.9 (2CH2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][NH:13]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH3:21])=[O:5])[CH3:2].[ClH:22].O1CCOCC1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CCO.CCCCCC.CCOC(C)=O>[ClH:22].[NH:12]([C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C@H:7]([CH3:21])[CH2:8]1)[NH2:13]
Reactant: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)C[C@H]1C
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](NN)C[C@H]1C
Reaction time: 8 h

Procedure:
To a 250-mL round-bottomed flask was added tert-butyl 2-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol) in EtOH (56.5 ml). Then hydrogen chloride, 4.0 M solution in 1,4-dioxane (72.0 ml, 288 mmol) was added into the reaction mixture. The overall mixture was allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by TLC (30% EtOAc in hexane; ninhydrin stain), which suggested reaction completion. The mixture was concentrated in-vacuo. The residue was diluted with hexane and concentrated in-vacuo. This gave (1S,2R,4S)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate hydrochloride (4.60 g) as white solid. This material was carried into the next step of the synthesis, without further purification. LCMS (ESI) m/z 201.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:14][C:10]=2[C:9](=O)[NH:8][N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:25])=[C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[S:12][C:11]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(=O)c2cc(-c3ccc(F)cc3)sc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nnc(Cl)c2cc(-c3ccc(F)cc3)sc12
Temperature: 90 °C

Procedure:
A mixture of 2-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-thieno[2,3-d]pyridazine-7-carboxylic acid ethyl ester (0.2 g, mmol) in phosphorous oxychloride (3 mL) was heated at 90° C. for 3 hours, cooled and evaporated to dryness. To the residue was added ice and ethyl acetate and then basified over potassium carbonate solid. The organic layer was separeted, washed with water, brine and dried over sodium sulfate. The organic layer was evaporated to dryness and the residue was purified by flash chromatography (silica gel, 5% acetone/hexane) to obtain 4-chloro-2-(4-fluorophenyl)-thieno[2,3-d]pyridazine-7-carboxylic acid ethyl ester as a solid (0.12 g). MS: m/z=338 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccc(F)cn1
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(F)cn2)nc2nc(N)sc12
Yield: 17.7 %

Procedure:
The title compound was prepared by General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (550 mg, 1.8 mmol) and 2-[(1R)-1-chloroethyl]-5-fluoropyridine (0.46 g, 2.9 mmol). The product was purified by flash column chromatography followed by preparative HPLC (Column: Reprosil, eluent isopropanol:heptane 20:80, flow: 16 mL/min) collecting the first eluting isomer, to yield 135 mg (18% yield) of the title compound.