Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:12]1[OH:17].[NH3:18]>>[NH2:18][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:12]1[OH:17]
Reactant: O[C@@H]1[C@H](O)CC[C@H]1n1cnc2c(Cl)ncnc21
Reactant: N
Product: Nc1ncnc2c1ncn2[C@@H]1CC[C@@H](O)[C@H]1O

Procedure:
(±)-(1R*,2S*,3R*)-3-(6-Chloro-9H-purin-9-yl)-1,2-cyclopentanediol (4.00 g, 15.7 mmol) and ammonia (1, 100 ml) were stirred in a Parr bomb at 25° C. for 18 hours. Evaporation and neutralization with 1N NaOH (16 ml), followed by elution of a silica gel column with MeOH:CHCl3 /1:4 gave title compound as white crystals, recrystallized from 95% ethanol (3.54 g, 96%); mp 201°-202° C.; 1H-NMR (Me2SO-d6) δ8.19 and 8.12 (both s, 2, purine H-2, H-8), 7.18 (br s, 2, NH2), 4.98 (d, J=6.6, 1, 2-OH), 4.76-4.64 (m) overlapping 4.70 (d, J=3.4, 2, H-3 and 1-OH), 4.42-4.34 (m, 1, H-2), 4.04-3.97 (m, 1, H-1), 2.5-1.9 and 1.7-1.6 (both m, 4, two CH2).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:15][C:16](Cl)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[F:20][C:21]([F:46])([F:45])[C:22]1[CH:23]=[C:24]([S:32]([NH:35][C:36]2[S:37][C:38]3[CH2:39][NH2+:40][CH2:41][CH2:42][C:43]=3[N:44]=2)(=[O:34])=[O:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH:10]1([CH2:15][C:16]([N:40]2[CH2:41][CH2:42][C:43]3[N:44]=[C:36]([NH:35][S:32]([C:24]4[CH:23]=[C:22]([C:21]([F:20])([F:45])[F:46])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=4)(=[O:34])=[O:33])[S:37][C:38]=3[CH2:39]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=S(=O)(Nc1nc2c(s1)C[NH2+]CC2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)CC1CCCC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCCC1)N1CCc2nc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)sc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIEA and cyclopentyl-acetyl chloride are added at 0° to a mixture of 75 mg of 2-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-5-ium hydrochloride salt in CH2Cl2. The mixture obtained is stirred at RT for 4 hours, 2 ml of 1 M aqueous NaHSO4 solution are added and two phases formed are separated. The organic layer obtained is concentrated and subjected to preparative HPLC (RP-18). N-[5-(2-Cyclo-pentyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-3,5-bis-trifluoromethyl-benzene-sulfonamide is obtained.
Reaction SMILES: [CH3:1][PH:2](=[O:10])[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:11]I>>[CH3:1][P:2](=[O:10])([CH3:11])[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CCOC(OCC)[PH](C)=O
Reactant: CI
Product: CCOC(OCC)P(C)(C)=O

Procedure:
Following a procedure analogous to that of Example 12, but using methyl(diethoxymethyl)phosphine oxide instead of tert-butyl(diethoxymethyl)phosphine oxide and using methyl iodide instead of benzyl bromide, there is obtained dimethyl(diethoxymethyl)phosphine oxide.
Reaction SMILES: [C:1]([C:3]([CH2:15][Si:16]1([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C(OCC)=O)#[N:2].O.[Br-].[Li+]>CN(C)C=O>[CH3:21][Si:16]1([CH2:15][CH:3]([C:1]#[N:2])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(C#N)(C[Si]1(C)CCCC1)C(=O)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C#N)C[Si]1(C)CCCC1
Yield: 88.3 %

Procedure:
Diethyl 2-cyano-2-[(1-methyl-1-silacyclopentan-1-yl)methyl]succinate (1.943 g, 6.25 mmol) was treated with water and lithium bromide in dimethylformamide in the same manner as that of Example 15. The reaction mixture was treated in a conventional manner, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate (14:1)] to obtain ethyl 4-(1-methyl-1-silacyclopentan-1-yl)-3-cyanobutanoate (1.321 g, 88%) mentioned in the title was obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[O:13][CH:11]([CH3:12])[CH2:10]2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC(C)O)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: COc1cc2c(cc1Cl)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 21.16 g (105.4 mmol) of 1-(3-chloro-4-methoxyphenyl)-2-hydroxypropane in 106 ml of dry benzene is mixed with 15.93 g (105.4 mmol) of 4-nitrobenzaldehyde and 14.36 g (105.4 mmol) of freshly melted zinc chloride, and dry hydrogen chloride gas is introduced for 3 hours. Then, the mixture is heated to boiling for 30 minutes. Working-up is carried out according to the process that is described in Example 3, Step A. The 6-chloro-3-methyl-7-methoxy-1-(4-nitrophenyl)-isochroman that is obtained is first isolated as an oily crude product, which crystallizes during treatment, however, with 370 ml of hot ethanol: 15.79 g (50%, melting point 118-120° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:11])[CH3:10]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)cc1
Yield: 90.6 %

Procedure:
Into a reaction flask equipped with a stirrer and thermometer was charged 216 grams (2.0 moles) of p-cresol, 225 grams (2.2 moles) of acetic anhydride and 500 milliliters of pyridine and the resulting reaction mixture was then heated to a temperature of 50° C.-55° C. After completion of the reaction, work-up and distillation at reduced pressure, 272 grams of p-methylphenyl acetate was obtained (91 percent of theoretical). The nuclear magnetic resonance (NMR) spectrum was consistent with the chemical structure.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][N:14](CC4C=CC=CC=4)[CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[CH2:9]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(OCC2CC3CN(Cc4ccccc4)CCN3C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 1.20 g (3.53 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 2), 30 mL of methanol and 2.5 mL of 5.0 M ammonium formate was treated with an aqueous slurry of 0.15 g of 10% palladium on carbon. The mixture was heated at reflux for 48 hours, cooled to ambient temperature, filtered through Celite, and the filtrate was evaporated. The residue was taken up in dilute aqueous ammonium hydroxide and extracted with chloroform (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated to give 0.874 g (99%) of the title compound. 13C NMR (CDCl3): δ 32.0, 34.5, 45.2, 50.9, 53.4, 57.0, 63.7, 72.6, 115.4, 115.5, 115.8, 155.1, 155.6, 158.7. HRMS calc'd for C14H20FN2O (MH+): 251.156, found: 251.155.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:22]1
Reactant: Nc1ccn(Cc2cccc(Cl)c2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4cccc(Cl)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3-chloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=56%). MS ISP (m/e): 389.2 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]=2)[CH:3]=1.[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26](B(O)O)[CH:27]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH2:12][CH2:11][C@:10]4([CH2:16][CH2:15][N:14]([CH3:17])[C:13]4=[O:18])[N:9]=3)[CH:3]=2)[CH:27]=1)[CH3:20]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CN1CC[C@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(F)c(-c2ccnc(C3=N[C@]4(CC3)CCN(C)C4=O)c2)c1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a solution of (5R)-2-(4-bromo-pyridin-2-yl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 3) (0.1670 g, 0.5419 mmol) in MeCN (2 mL) and water (0.3000 mL) in a Smith microwave vessel was added (5-ethoxy-2-fluoro-phenyl)boronic acid (0.1097 g, 0.5961 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.0114 g, 0.0163 mmol) and sodium carbonate (0.1149 g, 1.0838 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 40 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvents gave an amber oil, which was further purified by silica gel chromatography to give the desired product (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (0.2000 g, 0.5443 mmol) (D55) as an amber oil;
Reaction SMILES: C([N:8]([CH2:30][C@@H:31]([C:33]1[CH:42]=[CH:41][C:40]([O:43]CC2C=CC=CC=2)=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[OH:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.[C:52]([O:55]CC)(=[O:54])[CH3:53].C(O)(=O)C>C(O)C.[Pd].[OH-].[OH-].[Pd+2]>[C:52]([OH:55])(=[O:54])[CH3:53].[OH:32][C@H:31]([C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1cccc(CCCOCCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(CCCOCCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)c1

Procedure:
A solution of 3-(3-{[7-(benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)heptyl]oxy}propyl)benzenesulfonamide (36 mg) in ethanol (10 ml) with ethyl acetate (2 ml) and glacial acetic acid (1 ml) was hydrogenated using 10% palladium on carbon (50% water by weight, 10 mg) and 20% palladium hydroxide on carbon (10 mg) for 19 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified on an aminopropyl SPE cartridge (2 g), eluting with methanol-dichloromethane mixtures. Evaporation of the appropriate fractions with glacial acetic acid gave the title compound (15 mg). LCMS RT=2.26 min ES+ve m/z 532 (MH)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:12]=[O:13])=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:21]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:21])=[O:13])=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1cc(C=O)sc1C(=O)OC
Reactant: C1COCCO1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C(=O)O)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-Ethyl-5-formyl-thiophene-2-carboxylic acid methyl ester (1.22 g, 6.15 mmol) in dioxane (30 ml) was added 2-methyl-2-butene (8 ml) and a solution of Na2ClO2 (3.42 g, 37.8 mmol) and NaH2PO4 (3.25 g) in water (8 ml). The mixture was stirred at rt for 2 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (1.48 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH2:25])=[N:22][C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:22][C:21]=2[CH:26]=1
Reactant: Nc1nc2cc(Cl)ccc2o1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc(Cl)ccc3o2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzooxazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH3:18][C:19]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:20]=1[O:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1.Cl>[CH3:12][N:13]1[C:17]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][O:21][C:20]2[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:19]=2[CH3:18])=[O:26])=[CH:16][CH:15]=[N:14]1
Reactant: Cn1cccn1
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and N,N,-dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at -70 to -60° C. over 15 minutes, and then the mixture was stirred at -70° C. to room temperature for 1 hour. The reaction mixture was cooled to -70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at -70° C. for 1 hour. After completion of the reaction, IN hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]([C:6]1([OH:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH2:3][CH2:4]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>ClCCl>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[O:19][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(O)CCO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OCCC2O
Reaction time: 12 h

Procedure:
tert-Butyl 4-(1,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (from step (ii) above; 480 mg) was dissolved in dichloromethane and p-toluenesulfonyl chloride was added followed by triethylamine (0.49 mL) and the mixture was stirred for 12 h. An additional aliquot of triethylamine was added (0.49 mL) and the mixture stirred for 48 h. This mixture was concentrated in vacuo. The crude product was purified by chromatography on silica using 50-95% ethyl acetate in iso-hexane as eluant to afford the product (300 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])(C)(C)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH:26]1[CH3:32])=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28]([OH:31])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[C:3]=2[F:12])[CH2:27][CH:26]1[CH3:32])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: Fc1cc2ccoc2c(Br)c1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1CC(O)(c2c(F)c(F)cc3ccoc23)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.28 gm (9.8 mMol) 5,6-difluoro-7-bromobenzofuran in 30 mL tetrahydrofuran was cooled to −78° C. and then 9.8 mL (19.6 mMol) tert-butyllithium (1.7M in tetrahydrofuran) were added. After stirring for 30 minutes, a solution of 1.9 gm (8.9 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxo-piperidine in 20 mL tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature over 16 hours and was then concentrated under reduced pressure. The residue was dissolved in 200 mL ethyl acetate and extracted sequentially with 50 mL 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure to provide 1-(tert-butoxycarbonyl)-2-methyl-4-hydroxy-4-(5,6-difluorobenzofur-7-yl)piperidine. This alcohol was converted to a mixture of the title compounds essentially as described in EXAMPLE 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][S:37][CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:45]([NH2:47])=[NH:46])[S:42][CH:43]=1)OC1C=CC=CC=1)#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:26]([NH:25][C:23]#[N:24])=[N:34][CH2:35][CH2:36][S:37][CH2:38][C:39]2[N:40]=[C:41]([NH:44][C:45]([NH2:47])=[NH:46])[S:42][CH:43]=2)[CH3:16])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Product: CN(CCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine and 0.94 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=599 ([M+H]+,7), 230 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 160° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:9]2[S:10][C:11]([C:14](O)=[O:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:27][CH2:28][N:29](CC)[CH2:30][CH3:31]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:17]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[S:10][C:11]([C:14]([N:29]2[CH2:30][CH2:31][CH2:27][CH2:28]2)=[O:15])=[CH:12][N:13]=1)=[O:26]
Reactant: O=C(O)c1cnc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)s1
Reactant: CCN(CC)CC
Product: O=C(c1cnc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)s1)N1CCCC1

Procedure:
According to the procedure described fort he synthesis of Example 136 further derivatives have been synthesised from 2-[(4-Chloro-phenyl)-(2,4-dichloro-benzoyl)-amino]-thiazole-5-carboxylic acid and various commercially available amines and comprise Examples 137-Example 146 below. In cases of Example 143 additionally 2 eq. NEt3 were added to the reaction mixture as the amine hydochloride was used as starting material.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:41][O:42][CH2:43]Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][O:29][CH2:41][O:42][CH3:43])[C:17]=1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: COCCl
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(CO)nn(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(COCOC)nn(C)c1=O
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.40 g, 5.45 mmol) and diisopropylethylamine (10 ml, 57.4 mmol) in THF (20 ml) was added chloromethyl methyl ether (2.4 ml, 31.6 mmol), and refluxed for 4 hours. After the reaction solution was cooled to room temperature, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2.11 g of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (yield: 80%) as solid.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[S:13][C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOC(C)=O>[C:1]1([C:7]([C:9]2[S:13][C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of phenyl-(2-phenylethynyl-thiazol-5-yl)-methanol (Example 234, 157 mg, 0.539 mmol) in dichloromethane (5.0 mL) was added pyridinium dichromate (243 mg, 0.647 mmol) and the reaction was stirred at room temperature for about 18 hours. The mixture was then diluted with EtOAc (15 mL), filtered over Celite® and washed with EtOAc. The solution was concentrated under reduced pressure and purified by preparative TLC, eluting with 20% EtOAc in hexanes, to afford the titled compound, phenyl-(2-phenylethynyl-thiazol-5-yl)-methanone (135 mg, 87%) as pale yellow oil.