Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[K+]>CO>[NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1Cc1ccc(CN)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NCc1ccc(Cc2ccccc2C(=O)O)cc1
Yield: 53.9 %

Procedure:
Methyl 2-(4-aminomethylbenzyl)benzoate (2.41 g, 0.01 moles) is dissolved in 50 mL methanol and 10 mL of 50% KOH is added. The mixture is heated at reflux for 6 hours, concentrated in vacuo and then acidified to yield 1.3 g (57%) of title compound as a precipitate. Mass Spec (DCl) m/z 228. Further purification is achieved by forming the HCl salt in isopropanol/saturated with HCl gas.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:9][C@@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@@H:4]1[OH:5].[OH-:12].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:14]([O:5][C@H:4]1[C@@H:6]([O:7][C:14](=[O:12])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:8]([CH2:10][O:11][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9][CH:3]1[O:2][CH3:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: COC1O[C@@H](CO)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
31.18 g of the crude 1-O-methyl-L-ribofuranose synthesized in (1) above, toluene (175 ml), a 25 wt. % sodium hydroxide aqueous solution (111 ml), and tetra-normal-butyl ammonium bromide (1.20 g; 5 molar % ratio) were added to a 1-L flask. The obtained mixture was cooled to an ice-cooled temperature, and benzoyl chloride (56.6 mol; 3.05 equivalents) was then slowly added dropwise thereto. The temperature was increased to room temperature, and the reaction was then carried out for 2 hours. The reaction product was again cooled to an ice-cooled temperature, and it was then diluted with toluene (200 ml) and a 1 N sodium hydroxide aqueous solution (100 ml). The temperature was increased to room temperature, and an organic layer was separated from an aqueous layer. The organic layer was washed with a 1 N sodium hydroxide aqueous solution (100 ml) 2 times, and was then washed with a 3 N hydrochloric acid aqueous solution (200 ml), so that the organic layer was concentrated. Thus, 62.69 g of crude 2,3,5-tri-O-benzoyl-1-O-methyl-L-ribofuranose was obtained in the form of a colorless oily liquid.
Reaction SMILES: Br[C:2]1[C:10]([CH2:11][OH:12])=[CH:9][C:5]2OCO[C:4]=2[CH:3]=1.[C:13]([C:15]1C=CC2OCOC=2[CH:16]=1)#N.O>CCOCC.C([Li])CCC.C(OCC)(=O)C>[O:12]1[CH:11]2[C:10]3[C:2]([CH:13]1[CH2:15][CH2:16]2)=[CH:3][CH:4]=[CH:5][CH:9]=3
Reactant: OCc1cc2c(cc1Br)OCO2
Reactant: N#Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)C1CCC2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of 5-bromo-6-hydroxymethyl-1,3-benzodioxol (5.0 g) in ether (100 ml), butyl lithium (1.6M solution in hexane, 30 ml) was added dropwise at −78° C. After stirring at 0° C. for 1 hour, the solution was again cooled to −78° C.; a solution of 5-cyano-1,3-benzodioxol (3.52 g) in ether (50 ml) was added dropwise. After stirring at room temperature for 3 hours, water was added, followed by extraction with ethyl acetate. After being washed with brine, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (100 ml); dimethyl fumarate (3.13 g) and trichloroacetic acid (0.83 g) were added. The mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. After being dried with magnesium sulfate, the mixture was concentrated under reduced pressure; the residue was purified by column chromatography (silica gel: 50 g, eluent: ethyl acetate−hexane=1:2) to yield a tetrahydro-1,4-epoxynaphthalene derivative (3.30 g) as a diastereomer mixture. This was dissolved in THF (15 ml) and methanol (15 ml); an aqueous solution (5 ml) of sodium hydroxide (1.24 g) was added, followed by overnight stirring. The reaction mixture was concentrated under reduced pressure and diluted with water, after which it was washed with ethyl acetate After concentrated hydrochloric acid was added to the water layer until the pH reached about 2, the product was extracted with ethyl acetate. The extract was washed with brine, after which it was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was dissolved in ether (10 ml); concentrated hydrochloric acid (0.5 ml) was added; followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, water was added; the resulting precipitate was washed with methanol and ether to yield the title compound (0.38 g).
Reaction SMILES: [Br:1][C:2]1[C:11](I)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Mg]Br)(C)C.[B:18](OC)([O:21]C)[O:19]C.Cl>C1COCC1>[Br:1][C:2]1[C:11]([B:18]([OH:21])[OH:19])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COB(OC)OC
Reactant: Brc1cc2ccccc2cc1I
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1cc2ccccc2cc1Br
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
On the other hand, to another 100 ml Schlenk reaction vessel were added under a nitrogen atmosphere 85 mg (0.255 mmol) of 2-bromo-3-iodonaphthalene synthesized in Synthetic Example 2 and 2.0 ml of THF. The solution was cooled to −65° C. and 0.34 ml (0.27 mmol) of a THF solution of isopropylmagnesium bromide (manufactured by Tokyo Chemical Industry Co. Ltd., 0.80M) was added dropwise. After 30 minutes of aging, 33 mg (0.32 mmol) of trimethyl borate (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise at the temperature. After the temperature was gradually raised to room temperature, 3N hydrochloric acid was added and phase separation was conducted. The organic phase was concentrated under reduced pressure to obtain 3-bromo-2-naphthylboronic acid as a residue. To the resulting white solid were added the intermediate obtained in the above, 15 mg (0.013 mmol) of tetrakis(triphenylphosphine)palladium (manufactured by Tokyo Chemical Industry Co. Ltd.), 2.2 ml of toluene, and 0.5 ml of ethanol. A solution composed of 148 mg (1.39 mmol) of sodium carbonate and 0.7 ml of water was further added and the mixture was subjected to a reaction at 85° C. for 5 hours. After cooling to room temperature, toluene and an aqueous sodium chloride solution were added and phase separation was conducted. The organic phase was washed with aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure and the solvent was removed by distillation, followed by further heating and drying under vacuum. The obtained residue was dissolved in toluene and a 70% tert-butyl hydroperoxide solution (manufactured by Wako Pure Chemical Industries, Ltd.) (0.04 ml) was added thereto, followed by 2 hours of stirring at room temperature. The solution was washed with water and then the organic phase was concentrated under reduced pressure. The residue was dissolved in hexane and chloroform and the solution was passed through a column packed with silica gel. The elute was concentrated under reduced pressure and the resulting crude solid was washed with hexane to obtain the objective compound (103 mg, yield 54.0%).
Reaction SMILES: [C:1]1([S:7]([C@@H:10]2[CH2:14][C@@H:13]([C:15]([OH:17])=O)[C@H:12]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][CH2:28][C:29]#[N:30].C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:28]([CH2:29][NH:30][C:15]([C@@H:13]1[CH2:14][C@@H:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH2:11][C@H:12]1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[O:17])#[N:27]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1
Reactant: N#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
A mixture of (1R,2R,4S)-4-benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid (0.1 mmol) and amino-acetonitrile hydrochloride (0.12 mmol) in dimethylformamide (0.5 ml) was subsequently treated with diisopropylethyl amine (0.5 mmol), 1-hydroxybenzotriazole hydrate (0.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.2 mmol) and stirring was continued at 22° C. overnight. The mixture was purified by preparative HPLC on a RP-18 column using a gradient of a mixture of acetonitrile and water to give (1R,2R,4R)-4-benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid cyanomethyl-amide as a white solid. MS: 406.5 (M+H)+.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH:5]([CH3:7])[CH3:6].[CH2:9]([Si:15](Cl)([Cl:17])[Cl:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)C.CCCCCC.O1CCCC1>[CH2:9]([Si:15]([CH2:4][CH:5]([CH3:7])[CH3:6])([Cl:17])[Cl:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)CBr
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CC(C)C

Procedure:
Anhydrous diethyl ether (125 mL) was put into a reactor with magnesium (5.0 g, 0.21 mol) which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. i-Butylbromide (25 g, 0.18 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing n-hexyltrichlorosilane (64 g, 0.25 mol) in anhydrous diethyl ether (50 mL)/anhydrous tetrahydrofuran (50 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 50° C.-60° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1O[N:23]=[CH:22][CH:21]=1.[Na].Cl.[C:27]([CH2:30][C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32])(=[NH:29])[NH2:28].C(O)(=O)C>C(O)CC>[NH2:29][C:27]1[NH:28][C:20]([CH3:19])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:9]3)[C:30]=1[C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32]
Reactant: CCCOC(=O)CC(=N)N
Reactant: Cc1ccno1
Reactant: O=Cc1cccc2ncc(-c3ccccc3)cc12
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCCO
Product: CCCOC(=O)C1=C(N)NC(C)=C(C#N)C1c1cccc2ncc(-c3ccccc3)cc12
Reaction time: 20 h
Yield: 16.3 %

Procedure:
23.3 g (100 mmol) of 3-phenyl-quinoline-5-aldehyde are suspended in 200 ml of n-propanol and the suspension is stirred with 8.25 ml (100 mmol) of 5-methylisoxazole. A solution of 2.3 g of sodium in 100 ml of n-propanol is added dropwise and the mixture is stirred at 40°-50° C. for hours. A brown solution is obtained by this procedure. 8.04 g (100 mmol) of propyl amidinoacetate hydrochloride and 6 ml of acetic acid (100 mmol) are added and the mixture is boiled for 20 hours. It is concentrated, the residue is dissolved in ethyl acetate/water and the phases are separated. The ethyl acetate phase is washed with sodium bicarbonate solution and twice with water, dried and concentrated. The resulting residue is dissolved in 100 ml of hot acetonitrile and the product is left to crystallise. It is filtered off with suction and recrystallised from n-propanol and then from acetonitrile. 6.9 g of colourless crystals of melting point 237° C. are obtained.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Br:16][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>C1C=CC=CC=1.CCCCCC>[Br:16][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26]
Reactant: S=C=Nc1ccc(Br)cc1Br
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(Br)cc1Br

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 300 ml. dry acetone, 16.5 g. heptanamidine hydrochloride, and 29.3 g. 2,4-dibromophenyl isothiocyanate (m.p. 68°-70° C.; prepared from 2,4-dibromoaniline) in 100 ml. dry acetone there was obtained 1-(2,4-dibromophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 86°-88° C. (from benzene-n-hexane); hydrochloride (14 g.), m.p. 164°-165° C. (from acetonitrile).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([C:11](CC)(CC)[C:12]([O-:15])([O-])[O-])C.[C:20](O)(=O)[CH3:21]>>[C:1]([C:3](=[C:20]([O:15][CH2:12][CH3:11])[CH3:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC#N
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(=O)C(C#N)=C(C)OCC
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-cyanoacetate (120 g, 1.06 mol) and triethylorthoacetate (354 g, 2.12 mol) in glacial acetic acid (33 g, 0.53 mol) was stirred at 120˜130° C. overnight. The mixture was concentrated under vacuum to provide crude ethyl 2-cyano-3-ethoxybut-2-enoate and carried into the next reaction without further purification assuming 100% conversion.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.[CH3:14]CN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3][N:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cncc2ccccc12
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a stirred solution of isoquinolin-4-carboxylic acid (Intermediate-14) (1.2 g, 6.9 mmol) in CH2Cl2 (10 mL) was added, EDCI (1.3 g, 8.3 mmol), HOBt (1.12 g, 8.3 mmol), DMAP (84 mg, 0.7 mmol) and the mixture was stirred at RT for 20 min. To this, MeOH (0.33 g, 10.4 mmol) was added and the reaction mixture was further stirred at RT for overnight. It was diluted with CH2Cl2 (100 mL) and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude product that was purified by flash column chromatography (10% EtOAc:Hexanes) to give the desired product (700 mg, 54%) as pale yellow solid.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH2:18]OS(C)(=O)=O)[C:10](=[O:17])[N:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:12]=2)=[CH:3][CH:2]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH2:18][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[C:10](=[O:17])[N:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:12]=2)=[CH:3][CH:2]=1
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 68.2 %

Procedure:
Following the procedure of Example 1(10), 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CCOC(=O)N1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Ethyl-4-{[4-({4-[(3-fluoro-5-morpholin-4-ylbenzoyl)amino]-1-naphthyl}oxy)pyrimidin-2-yl]amino}piperidine-1-carboxylate (Compound B341) Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 4-amino-piperidine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. Mp: 122-124° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.14 (t, J=6.9 Hz, 3 H), 1.17-1.26 (m, 2 H), 1.73 (bs, 2 H), 2.82 (bs, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.34 (bs, 1 H), 3.77 (t, J=4.8 Hz, 4 H), 3.89 (bs, 1 H), 3.96-4.01 (m, 2 H), 6.36 (bd, 1 H), 7.04 (d, J=12.4 Hz, 1 H), 7.12 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.56-7.62 (m, 3 H), 7.82 (d, J=7.6 Hz, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: C([C:7]1[O:8][C:9]2[CH:17]=[CH:16][C:15](OCC3C=CC=C(OCC4C=CC5C(=CC=CC=5)N=4)C=3)=[CH:14][C:10]=2[C:11](=[O:13])[CH:12]=1)(OCCC)=O.C(=O)(O)[O-].[Na+]>C(O)C.O>[O:13]=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH:7]=[CH:12]1
Reactant: CCCOC(=O)c1cc(=O)c2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1ccoc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.71 g of 2-carbopropoxy-6-(3-(quinolin-2-yl-methoxy)benzyloxy)-4-oxo-4H-1-benzopyran and 0.45 g of sodium bicarbonate in 20 ml of ethanol in 20 ml of water is refluxed for 1.5 hours, then stirred at room temperature overnight. The mixture was neutralized and the resulting solid is filtered off, washed with water and dried in vacuo to give 0.55 g of 2-carboxy-6-(3-quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a light yellow solid having an m.p. of 253°-54° C.
Reaction SMILES: [F:1][C:2]([F:20])([C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10](OC)=[O:11])[C:3](OC)=[O:4].C(=O)=[O:22].CC(C)=O.COCCO[AlH2-]OCCOC.[Na+].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[OH2:4].[OH2:22].[F:1][C:2]([F:20])([C:7]([F:18])([F:19])[C:8]([F:17])([F:16])[C:9]([F:14])([F:15])[CH:10]=[O:11])[CH:3]=[O:4]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(=O)OC
Reactant: O=C=O
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O
Product: O=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C=O
Temperature: -70 °C

Procedure:
In a 3 liter three neck round bottom flask fitted with a mechanical stirrer, dropping funnel equipped with a drying tube, and low temperature thermometer was placed a solution of 50.0 g. (0.158 mol) of dimethyl perfluoroadipate in 450 ml. of dry tetrahydrofuran (THF). The reaction mixture was cooled to -70° C. (dry ice-acetone) and 67.5 ml. (0.238 mol.) of Vitride (70% in benzene) diluted with 50 ml. of THF was added dropwise over 30 min. with vigorous stirring. The temperature of the reaction was maintained at ≤-70° C. during the addition and at -70° C. for 2.5 hours after addition was complete. To the viscous mixture 500 ml. of 20% sulfuric acid previously chilled at 5° C. was added dropwise. The temperature of the reaction was allowed to rise to -50° C. and maintained until the excess Vitride had been decomposed. The mixture was then allowed to warm spontaneously to room temperature. Ether (400-600 ml.) was added with vigorous stirring until a homogeneous two-phase system was obtained. The layers were separated and the aqueous phase extracted with an additional 200-300 ml. of ether. The combined ether extracts were washed to neutrality with brine, dried over MgSO4, and evaporated under reduced pressure. The title compound was left as a thick syrup, 45.2 g. (96% by weight), νmaxneat 3600-2000 (bd) cm-1.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:7][CH2:6][CH:5]=[CH:4]1.[CH:8](=[O:14])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[C:5]1([C:9]2([CH2:8][OH:14])[CH2:10][CH:11]=[CH:12][O:13]2)[CH2:6][CH2:7][CH2:3][CH:4]=1
Reactant: O=Cc1ccco1
Reactant: ClC1C=CCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC1(C2=CCCC2)CC=CO1
Temperature: 20 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Magnesium (36 g, 1.5 mole) and tetrahydrofuran (THF) (300 ml) were added to a reactor, and a solution of 3-chloro-1-cyclopentene (184.5 g, 1.8 mole) in THF (200 ml) was added dropwise at 0° to 10° C. to prepare a Grignard reagent. Thereafter, to this THF solution of the Grignard reagent was added dropwise a solution of furfural (106 g, 1.1 mole) in THF (150 ml) at 0° to 10° C. over about 1 hour, followed by stirring at 20° C. for further 2 hours. After completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution (about 1 liter), followed by extraction with ether. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 135 g (yield, 75%) of pure 2-cyclopentenyl-2-furyl methanol having a boiling point of 80°-86° C./3 mmHg.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][CH:9]=[CH:10][C:11]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:12]>C1(C)C=CC=CC=1>[CH3:6][O:5][C:1]([CH:2]1[CH2:3][CH2:12][C:11]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]1[O:8][CH3:7])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=C(C=COC)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(O[Si](C)(C)C)=CC1OC
Temperature: 80 °C

Procedure:
A mixture of methyl acrylate (5.23 mL, 58.0 mmol) and 1-methoxy-3-(trimethylsiloxy)-1,3-butadiene (from Aldrich, 10.0 g, 58.0 mmol) in toluene (100 mL) was heated at 80° C. for 2 d. The reaction solution was concentrated and purified on silica gel column to give the desired product as a mixture of trans- and cis-isomers (8.3 g, 55%). 1H NMR (500 MHz, CDCl3) δ 5.16 (1H, m), 4.97 (1H, m), 4.22 (1H, m), 4.08 (1H, m), 3.68 (3H, s), 3.67 (3H, s), 3.32 (3H, s), 3.24 (3H, s), 2.59 (1H, m), 2.51 (1H, m), 1.80-2.14 (8H, m), 0.18 (18H, s) ppm.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:23][C:24]([NH2:26])=[S:25]>>[BrH:1].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:23][C:24]1[S:25][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:26]=1
Reactant: NC(=S)Nc1cccc(Cl)c1Cl
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3cccc(Cl)c3Cl)n2)c(C)s1
Yield: 64.2 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2,3-dichlorophenylthiourea (42 mg) as described in Example 154, step (a) to give 60.5 mg (62% yield) methyl 4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ2.66 (s, 3H), 3.82 (s, 3H), 7.27 (dd, 1H, J=1.5, 6.5 Hz), 7.36 (d, 1H, J=8.2 Hz), 7.43 (s, 1H), 8.14 (s, 1H), 8.62 (dd, 1H, J=1.5, 8.4 Hz), 9.95 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C16H12Cl2N2O2S3, 431.38 (M+H), found 431.1, 433.0.