Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(CCOS(C)(=O)=O)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
Methyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate (Intermediate 41) (650 mg, 1.93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as described for Intermediate 6. The crude product was used without delay for the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([NH:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].Br[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][C:21]([NH:28][S:29](/[CH:32]=[CH:33]/[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)(=[O:31])=[O:30])([CH3:20])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: Brc1cccs1
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccs1
Temperature: 140 °C
Yield: 21.2 %

Procedure:
Palladium acetate (169 mg, 0.75 mmol) and triphenylphosphine (420 mg, 1.6 mmol) were added to a solution of ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (10 g, 45.7 mmol) and 2-bromo-thiophene (3.74 mL, 39.1 mmol) in N,N-dimethylformamide (75 mL). Triethylamine (14.7 mL, 105.5 mmol) was added and the mixture was flushed with nitrogen and heated at 140° C. for 16 hours. The mixture was cooled to room temperature and 1N HCl (250 mL) was added in one portion. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-thiophen-2-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (2.5g, 21% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH3:13][N:14]([CH3:15])[C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: CNC
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1cc(N)c([N+](=O)[O-])cn1
Yield: 113.6 %

Procedure:
In a microwave tube, a solution of 4-amino-2-chloro-5-nitropyridine (prepared as described for compound 9) (200 mg; 1.16 mmol) in ethanol (2 ml) was treated sequentially with dimethylamine hydrochloride (471 mg; 5.78 mmol) and triethylamine (781 μl; 6.96 mmol). The tube was quickly sealed and irradiated in the microwave (CEM Discover, 150 W, 85° C., 10 min). The ethanol was evaporated, dichloromethane (15 ml) was added to dissolve the products, and the solution washed with 1M sodium hydroxide solution (2×10 ml). The organic layer was dried (sodium sulphate), the mixture filtered and the filtrate evaporated to dryness to afford N2,N2-dimethyl-5-nitro-pyridine-2,4-diamine (240 mg, 114%).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[CH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[CH3:14][C:15]([OH:16])([C:8]#[C:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:17]
Reactant: C#CCN1CCCC1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CCN1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(pyrrolidin-1-yl)-prop-2-yne (prepared by the method of Biel and DiPierro J. Am. Chem. Soc. 1958, 80, 4609) (0.545 g) in dry tetrahydrofuran (15 ml) was treated at -78° C. with a solution of n-butyl lithium in hexanes (2.5 M, 2.2 ml) and the mixture was allowed to stir at -78° C. for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78° C. this mixture was treated with a solution of acetone (1 ml) in tetrahydrofuran (1 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5% methanol in dichloromethane was used as the eluant) to afford the product as an oil. MS(+ES), m/z: 168 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=O)[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=O.C([N:32](CC)CC)C.C(O)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:12]2[NH:32][C:24]([C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][CH:13]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)C=O
Reactant: CCN(CC)CC
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a mixture of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (350 mg), ethyl glyoxylate (polymer type, 47% toluene solution) (260 mg), triethylamine (0.31 mL), ethanol (15 mL) and tetrahydrofuran (5 mL) was added 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (280 mg) and the mixture was heated under reflux for 1 hr under argon atmosphere. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the obtained residue, ammonium acetate (1.36 g) and acetic acid (10 mL) was stirred at 120° C. for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (140 mg, yield 31%) was obtained as a pale-brown oil from a fraction eluted with hexane-ethyl acetate (1:1-1:2, volume ratio). MS: 406 (MH+).
Reaction SMILES: C(N(CC)CC)C.C(O[O:12][C:13]1[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([CH3:21])[N:14]=1)(=O)C.C(Cl)(Cl)Cl.Br.[Br:27][CH2:28][CH2:29][NH2:30].[O:31]1CC[CH2:33][CH2:32]1>>[Br:27][CH2:28][CH2:29][NH:30][C:32](=[O:31])[CH2:33][O:12][C:13]1[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([CH3:21])[N:14]=1
Reactant: CC(=O)OOc1nc(C)c(C)nc1C
Reactant: C1CCOC1
Reactant: NCCBr
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(OCC(=O)NCCBr)nc1C
Reaction time: 4 h

Procedure:
Triethylamine (7.0 ml, 50 mM) was added to compound 037 (9.80 g, 50 mM) dissolved in tetrahydrofuran (100 ml) and chloroform (100 ml) in solution with bromoethylamine hydrobromide (10.30 g, 50 mM) and triethylamine (7.7 ml, 55 mM) was added dropwise at -5° C., then the mixture was stirred for 4 hours with ice cooling. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (Chlodil, 250 g), and eluted successively with chloroform and chloroform-methanol (500:1) to obtain the product (6.92 g)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[C:19](Cl)=[C:18]([S:21]([CH3:24])(=O)=O)[N:17]([CH3:25])[N:16]=2)[C:7]=1[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])#[N:2].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[CH:19]=[C:18]([S:21][CH3:24])[N:17]([CH3:25])[N:16]=2)[C:7]=1[CH:8]([O:9][CH2:10][CH3:11])[O:12][CH2:13][CH3:14])#[N:2]
Reactant: CCOC(OCC)c1c(C#N)cnn1-c1nn(C)c(S(C)(=O)=O)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1c(C#N)cnn1-c1cc(SC)n(C)n1

Procedure:
0.6 g (1.5 mmol) of 4-cyano-5-diethoxymethyl-1-(4-chloro-1-methyl-5-methylsulfonyl-3-pyrazolyl)pyrazole (Example B.2) and 0.5 ml of ethylene glycol together with 10 mg of p-toluenesulfonic acid are heated under reflux in 20 ml of toluene for 3 hours. Shaking with sodium bicarbonate and water, drying (sodium sulfate) and concentration using a rotary evaporator gives, in crystalline form, the desired product which can be further purified, if required, by recrystallization or silica gel column chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[N:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O1CCOCC1>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:35][C:32]3[CH:33]=[CH:34][NH:30][N:31]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=Cc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(C2CCN(Cc3cc[nH]n3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.9 %

Procedure:
tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) and 1H-pyrazole-3-carbaldehyde (50.7 mg, 0.53 mmol) were stirred at ambient temperature in dichloromethane (5 ml) for 1 hour. Sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added and the mixture stirred at ambient temperature for 48 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give a foam. This was dissolved in 1,4-dioxane (2 ml), a 4M solution of hydrogen chloride in 1,4-dioxane (2 ml) was added and the solution stirred at ambient temperature for 48 hours. The product was filtered and washed with diethyl ether and air-dried. The resulting solid was dissolved in water, basified with 2N sodium hydroxide and the resulting solid filtered, washed with water and dried under vacuum to give the title compound (61 mg, 44%). NMR Spectrum: 1H NMR (DMSO d6) δ 1.71 (m, 4H), 2.07 (m, 2H), 2.56 (m, 1H), 2.95 (m, 2H), 3.53 (s, 2H), 4.86 (s, 2H), 6.16 (s, 1H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.18 (d, 1H), 7.37 (d, 2H), 7.64 (m, 1H), 7.91 (d, 2H), 9.55 (s, 1H), 12.59 (m, 1H); Mass Spectrum: M+H+ 376.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)c(I)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1ccc(C#N)cc1I
Yield: 94.7 %

Procedure:
A mixture of 8.54 g (0.035 mole) of 4-amino-3-iodobenzonitrile (31), 16 mL (16.32 g, 0.16 mole) of acetic anhydride and five drops of concentrated sulfuric acid was heated at 700 under reflux for 10 minutes (the mixture became thick when the temperature reached 400 and some manual stirring was required). The reaction mixture was poured over 400 mL of cold water and stirred for 5 minutes to give a white solid which was filtered and dried, yielding 9.48 g (95%) of 32 as white powder, mp 176-181°. Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3276 (NH), 2230 (CN), 1663 (C=O), 1517, 1297 cm−1. 1H nmr (90 MHz, CDCI3):δ 8.73 (1H, br s, NH), 8.13-8.05 (2H, m, H-5 and H-2), 7.65 (1 H; dd, 3JH5-H6=8.4 Hz, 4JH2-H6=1.8 Hz; H-6), 2.25 (3H, s, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.C(=O)(O)[O-].[K+].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CCc2c(N)cccc2C1
Agent: O=C([O-])O
Agent: [K+]
Agent: c1ccc2c(c1)CCNC2
Solvent: c1ccccc1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2Cl)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (9.2 g) prepared as in Example 4 was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 2-chlorobenzoyl chloride was dissolved in dry benzene (100 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A white precipitate formed immediately and the mixture was then refluxed for 1 hour. The precipitate was collected by filtration and was washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining residue was recrystallized from ethanol to yield 12.6 g of the desired product as fluffly, crystalline plates, m.p., 189.5°-191.5° C.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([N:38]([CH2:65][CH2:66][CH2:67][CH3:68])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[C:41]([O:47][Si:48]([C:61]([CH3:64])([CH3:63])[CH3:62])([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:40]=1)[CH2:35][CH2:36][CH3:37].O>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:38]([CH2:65][CH2:66][CH2:67][CH3:68])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[C:41]([O:47][Si:48]([C:61]([CH3:62])([CH3:64])[CH3:63])([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.17 g of phenyllithium (19% solution in dibutylether) (7.16 mmol), and 2.57 g (6.5 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 3.17 g (6.5 mmol) of 4-dibutylamino-2-tert-butyldiphenylsiloxybenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 3 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.32 g of a yellowish brown oily matter (yield: 62.9%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[C:17]3[C:18]4[C:10](=[C:11]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[NH:12][C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:25][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI.O>O1CCCC1>[CH3:25][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[CH:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:8][CH2:9][C:10]([C:18]=23)=[C:11]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: c1ccc(-c2[nH]c3cccc4c3c2CCC4N2CCOCC2)cc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(N1CCOCC1)CC2
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A portion (55 mg) of the compound obtained in Example 226 was dissolved in anhydrous tetrahydrofuran (2 ml) and to the solution was added sodium hexamethyldisilazide (1.0 M tetrahydrofuran solution; 0.52 ml) under cooling with ice. After stirring for 30 minutes, methyl iodide (32.3 μl) was added to the mixture, followed by stirring for 15 minutes. After adding further sodium hexamethyldisilazide (1.0 M tetrahydrofuran solution; 0.35 ml), the mixture was stirred for 30 minutes. Then, methyl iodide (21.5 μl) was added and the mixture was stirred for additional 15 minutes. Water was added to the reaction mixture, followed by extraction with two portions of ethyl acetate. The organic layers were combined, washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by preparative TLC (ethyl acetate/hexane=1:2) to yield 35 mg (61%) of the titled compound as a pale yellow solid. Specific rotation: [α]D +21° (25° C., c0.75, chloroform)
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[CH3:27])[N:18]=[N:19][CH:20]=1>>[ClH:14].[CH3:27][C:23]1[N:22]([CH2:21][C:17]2[N:18]=[N:19][CH:20]=[C:15]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH:16]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1cccc2ccccc12
Product: Cc1nccn1Cc1cc(-c2cccc3ccccc23)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=301.3 (M+H+), was prepared from 1-naphtylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [OH:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([S:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:26][Mg]I.[Mg].CI>C(OCC)C>[OH:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([S:17][CH2:18][C:19]([OH:25])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCC(=O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)O
Reactant: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CCCCCC(C)(O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)O

Procedure:
Add dropwise 0.37 g. 9,11-dihydroxy-15-oxo-13-thia-5-prostenoic acid, dissolved in 10 ml. dry diethyl ether, to a methyl magnesium iodide solution, prepared from 0.024 g. magnesium shavings and 0.14 g. methyl iodide in 15 ml. dry diethyl ether, stir the reaction for one hour, pour into 50 ml. saturated aqueous NH4Cl solution, extract with diethyl ether, dry the organic phase over Na2SO4 and distill off the solvent to obtain, as the residue, 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=NC(OC)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC)nc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(NCC2CCCC2)cn1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cn1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(6-methoxy-pyridin-3-yl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(6-methoxy-pyridin-3-yl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: S(=O)(=O)(O)O.[CH:6](OC)(OC)OC.[CH3:13][C:14]1[C:15]([OH:23])=[C:16]([CH3:22])[C:17]([CH3:21])=[C:18]([CH:20]=1)[OH:19].[CH:24]([C:26]([CH3:28])=[O:27])=[CH2:25]>CO.C(OCC)C>[OH:23][C:15]1[C:14]([CH3:13])=[C:20]2[C:18](=[C:17]([CH3:21])[C:16]=1[CH3:22])[O:19][C:26]([O:27][CH3:6])([CH3:28])[CH2:24][CH2:25]2
Reactant: C=CC(C)=O
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CO
Product: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.5 %

Procedure:
Concentrated sulfuric acid (0.8 mL) was added dropwise to a solution of trimethyl orthoformate (Aldrich, 48.5 g, 457.0 mmol) and trimethyl hydroquinone (Aldrich, 50.0 g, 328.5 mol) in methanol (200 mL), cooled by a water/ice bath. Methyl vinyl ketone (Aldrich, 46.05 g, 657.0 mmol) was added slowly (1.5 h) to the reaction mixture while the reaction mixture was cooled by an ice/water bath. A pasty slurry formed. The reaction mixture was allowed to come to ambient temperature and was stirred at ambient temperature for 48 h. The reaction mixture was diluted with diethyl ether (600 mL) and the resulting solution was extracted with water (2×200 mL) and saturated aqueous sodium bicarbonate (2×100 mL). The organic solution was dried (sodium sulfate) and concentrated in vacuo to give a tan solid. The solid was recrystallized from methanol to give 71.8 g (92.6%) of the desired product as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][O:18][CH3:19].Cl.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[O:15])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Yield: 87 %

Procedure:
To a solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added N,O-dimethylhydroxylamine×HCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0° C. and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10% citric acid (aq) and saturated NaHCO3(aq) solution. The organic phase was dried with Na2SO4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1:1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87% yield.