Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:27]=1[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][N:43]=2)[C:37](OC)=[O:38])[C:30]1=[O:44].FC1C=CC(CN)=CC=1>>[F:25][C:26]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:27]=1[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][N:43]=2)[C:37]([NH:7][CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:38])[C:30]1=[O:44]
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3F)C2=O)c1
Agent: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccc(F)cc3F)C2=O)c1
Yield: 55 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(2,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 4-fluorobenzylamine, 2-(3-(2,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 55% yield: mp 171-173° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.36 (dd, J=5.1, 0.6 Hz, 1H), 7.56-7.27 (m, 4H), 7.07-6.97 (m, 2H), 6.92-6.74 (m, 3H), 4.58 (d, J=6.0 Hz, 2H), 4.48 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H); MS (ES+) m/z 441.1 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Br-].[CH3:31][CH:32]([CH3:35])[CH2:33][CH3:34].O1CCOCCOCCOCCOCC1>C1(C)C=CC=CC=1>[CH3:31][CH:32]([CH3:35])[CH2:33][CH2:34][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: CCC(C)C
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)CCOCCCc1c[nH]cn1
Temperature: 70 °C

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate, 5 mmol of 3-methylbutane bromide and 0.5 mmol of 15-crown-15 (1, 4, 7, 10, 13-pentaoxacyclopentadecane) dissolved in 10 ml of anhydrous toluene are refluxed for 24 hours. The solvent is then evaporated off, and the residue dissolved in 10 ml THF and 30 ml 2N HCl and then heated at 70° C. for 2 hours. The THF is evaporated off under reduced pressure and triphenylmethanol is extracted with diethyl ether. The aqueous phase is neutralized with potassium carbonate and the product is extracted with diethyl ether. The organic extract is dried and evaporated, giving rise to an oil, which is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.80 g), 2-(4-chloro-2-fluorobenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 120° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 to 7:10 by volume) to afford title compound, 0.20 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH3:12])=[C:7]([CH2:9][NH2:10])[CH:8]=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:21].Cl>O1CCCC1>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:12])=[O:21])=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CSc1ccc(Cl)cc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)c1ccc(Cl)cc1CN
Reaction time: 2 h
Yield: 139.2 %

Procedure:
(Step 3) To a solution of 1-[5-chloro-2-(methylsulfanyl)phenyl]methanamine hydrochloride obtained in Step 2 (5.11 g) and triethylamine (4.61 g) in tetrahydrofuran (150 ml) was added di-t-butyl dicarbonate (6.47 g) at room temperature. The mixture was stirred at the same temperature for 2 hr, treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 ml), and m-chloroperbenzoic acid (5.62 g, containing water: Wako Pure Chemical Industries, Ltd.) was added at 0° C. The mixture was stirred at the same temperature for 2 hr, and treated with aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=2:1). The obtained residue was dissolved in methanol (100 ml), and 4N hydrogen chloride-ethyl acetate solution (10 ml) was added. The mixture was stirred at 60° C. for 30 min, and concentrated under reduced pressure to give 1-[5-chloro-2-(methylsulfinyl)phenyl]methanamine hydrochloride (3.81 g) as a solid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1.[N:33]1([C:38]2[N:42]=[C:41]([CH:43]=O)[N:40]([CH2:45][C:46]([F:49])([F:48])[F:47])[N:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH:12]=[CH:43][C:41]3[N:40]([CH2:45][C:46]([F:49])([F:47])[F:48])[N:39]=[C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[N:42]=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: O=Cc1nc(N2CCCC2)nn1CC(F)(F)F
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc12
Yield: 27.6 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (85 mg, 185 μmol, Eq: 1.00), 3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-5-carbaldehyde (50.6 mg, 204 μmol, Eq: 1.1) as starting materials. Chromatography afforded 5,8-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-a]pyrazine (20 mg/27.5%) as a white viscous oil. MS: m/e=393.5 (M+H+)
Reaction SMILES: [C:1]([C:5]1[C:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:11]=3)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C:41]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)=C1C=CC=C1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.C(OCC)C.C[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]>C1COCC1>[CH2:34]([C:41]([C:47]1[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=1)=[C:14]1[C:15]2[C:10]([CH:9]=[C:8]3[C:16]=2[CH:17]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:7]3)=[C:11]([CH:62]2[CH:61]=[CH:65][CH:64]=[CH:63]2)[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]1[C:18]([CH3:21])([CH3:20])[CH3:19])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCCC
Reactant: CC(C)(C)c1cc2c(cc1-c1ccccc1)Cc1cc(-c3ccccc3)c(C(C)(C)C)cc1-2
Reactant: Clc1ccc(C(Cc2ccccc2)=C2C=CC=C2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1cc2c(cc1-c1ccccc1)=Cc1c(C3C=CC=C3)c(-c3ccccc3)c(C(C)(C)C)c(=C(Cc3ccccc3)c3ccc(Cl)cc3)c1=2
Temperature: 25 °C
Yield: 73 %

Procedure:
Under nitrogen flow, 200 mL of anhydrous THF was added to 4.3 g (10 mmol) of 3,6-di-tert-butyl-2,7-diphenylfluorene, they were stirred for dissolution and cooled in an ice bath, and then 11 mL (6.74 mmol) of a solution of 1.63-M n-butyllithium in hexane was added thereto. The product was stirred at room temperature for 1.5 hours, the obtained deep red solution was subsequently cooled in a dry ice-methanol bath, and a solution of 3.34 g (12 mmol) of 6-benzyl-6-(p-chlorophenyl)fulvene in THF (50 mL) was added thereto. The product was stirred for four hours while the temperature was gradually increased to room temperature, and then dilute hydrochloric acid was added to the resulting solution in an ice bath to terminate the reaction. Diethyl ether was added thereto for separation, the water layer was subjected to extraction twice with diethyl ether, and then the extract was combined with the organic layer. The resulting organic layer was washed twice with an aqueous solution of saturated sodium hydrogen carbonate, further twice with water, and further once with a saturated salt solution and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to produce an objective (amount: 5.2 g and yield: 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:3])=[O:2].C(Cl)Cl.ClC(OC)=O.[NH3:36]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([NH2:36])=[O:26])([O-:3])=[O:2]
Reactant: O=C(O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: N
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
88 g of N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-3-aminopropionic acid (compound 3) are added to 500 ml of methylene chloride with 34.3 ml of triethylamine at -25° C. With stirring, 22.8 ml of methyl chloroformate are run in over 30 minutes and stirring is continued at -10° to -20° C. After 2 hours, 40 ml of ammonia solution are added and the reaction mixture is warmed to room temperature. The mixture is then washed with water and the organic phase is concentrated. The residue is recrystallised from ethyl acetate/hexane. The product has a melting point of 137°-138° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:30])[CH2:13][CH:14]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[O:28][CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:10]>C(Cl)Cl>[CH2:9]([O:11][C:12](=[O:30])[CH2:13][CH:14]([C:20]1[CH:25]=[C:24]([C:5](=[O:7])[CH3:6])[CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[O:28][CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CCCCCC(CC(=O)OCC)c1cccc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(CC(=O)OCC)c1cc(C(C)=O)cc(OC)c1OC
Temperature: 0 °C
Yield: 85.6 %

Procedure:
To a solution of 800 mg (6.00 mmol) of anhydrous aluminum chloride in 5 ml of methylene chloride were added 0.43 g (6.05 mmol) of acetyl chloride with stirring and ice cooling and then dropwise a solution of 925 mg (3.00 mmol) of 3-(2, 3-dimethoxyphenyl)octanoic acid ethyl ester in 3 ml of methylene chloride. The resultant mixture was allowed to react under ice cooling for 20 minutes and added portionwise into ice water. The organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with water and aqueous saturated sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) to give 900 mg of 3-(5-acetyl-2, 3-dimethoxyphenyl)octanoic acid ethyl ester as a colorless oil. Yield, 86%.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][OH:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C(N(CC)CC)C.CO>[C].[Pd].O1CCCC1>[C:8]1([C:5]2[N:4]=[C:3]([CH2:14][OH:15])[CH:2]=[CH:7][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1nc(-c2ccccc2)ccc1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 3-chloro-6-phenyl-2-pyridylmethanol (2.20 g), 5% palladium-carbon (1.10 g), triethylamine (1.4 ml), methanol (20 ml) and tetrahydrofuran (20 ml) was stirred at room temperature under a hydrogen atmosphere. After palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-phenyl-2-pyridylmethanol (1.76 g, yield 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2](C)=[O:3].[N+:9]([O-:12])(O)=O.[OH2:13]>>[CH3:7][C:6]1[O:12][N:9]=[C:1]([C:2]([OH:13])=[O:3])[CH:5]=1
Reactant: O
Reactant: CC(=O)CCC(C)=O
Reactant: O=[N+]([O-])O
Product: Cc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetonylacetone (10 g, 88 mmol) and nitric acid (sp. gr. 1.42)/water (2:3) (50 ml) was cautiously brought to reflux under a stream of nitrogen and boiled for 1 h. The solution was cooled to room temperature and aged overnight. The resultant solid was collected by filtration, washed with chilled water (2×7 ml) and hexane, and dried in vacuo to give the title-acid (4.4 g, 40%), 1H NMR (CDCl3) δ 2.50 (3H, d, J=0.8 Hz, Me), 6.41 (1H, d, J=0.8 Hz, Ar—H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22](I)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[C-:31]#[N:32].[K+].C([Sn](Cl)(CCCC)CCCC)CCC>C(#N)C.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:31]([C:22]1[CH:21]=[N:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:7]3[C:8]4[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=4)[C:4](=[O:30])[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:6]3)=[CH:14][CH:15]=2)[CH:23]=1)#[N:32]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cc(I)cn3)cc2)c2cccc(F)c2c1=O
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(-n3cc(C#N)cn3)cc2)c2cccc(F)c2c1=O
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 5-fluoro-1-[4-(4-iodo-1H-pyrazol-1-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.100 g, 0.193 mmol), potassium cyanide (0.038 g, 0.52 mmol), and tributyltin chloride (0.68 mg, 1.9 μmol) in 2 mL of acetonitrile under nitrogen was added bis(tri-tert-butylphosphoranyl)palladium (10 mol %). The reaction mixture was stirred at 120° C. for 48 hours, cooled to room temperature, and purified via reverse phase HPLC to provide the title compound which gave a proton NMR spectrum consistent with theory. This compound could be further hydrolyzed to the corresponding carboxylic acid, as described in Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[CH:2].[CH3:11][NH:12][CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCCl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]([CH3:13])[CH3:11])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
Glacial acetic acid (3 drops) was added to a mixture of 4-ethynylbenzaldehyde (250.7 mg, 1.93 mmol), dimethylamine (2M in THF, 1.5 mL, 3.0 mmol) and NaBH(OAc)3 (617 mg, 2.91 mmol) in DCE (6.5 mL). The resulting mixture was stirred for 2.5 h at rt. The reaction was quenched with saturated aqueous NaHCO3 (˜40 mL). The product was extracted into CH2Cl2 (100 mL, then 2×50 mL), and the combined organic layer was washed with brine (25 mL), dried (Na2SO4) and evaporated in vacuo. Purification on Biotage Isolera (silica, 0-3% 2M NH3— methanol/CH2Cl2) gave 1-(4-ethynylphenyl)-N,N-dimethylmethanamine (280.1 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 3.42 (s, 2H), 3.07 (s, 1H), 2.24 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]2[CH2:17][CH2:16][C:15]3([CH3:18])[C:13]2([C:19](O)=[O:20])[CH2:14]3)[N:4]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[NH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>ClCCl>[CH3:39][O:38][C:36]([CH2:35][NH:34][C:19]([C:13]12[CH2:14][C:15]1([CH3:18])[CH2:16][CH2:17][CH:12]2[O:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)=[O:20])=[O:37]
Reactant: COC(=O)CN
Reactant: COc1cc(OC)nc(OC2CCC3(C)CC23C(=O)O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)C12CC1(C)CCC2Oc1nc(OC)cc(OC)n1
Reaction time: 0.08 h

Procedure:
1 g (3.4 mmol) of 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-5-methyl-bicyclo[3.1.0]hexane-1-carboxylic acid is dissolved in 50 ml of dichloromethane and mixed with 2.1 g of triethylamine. 0.53 g (3.4 mmol) of phosphorus oxychloride, dissolved in 5 ml of dichloromethane, is added dropwise at -5° C. and the mixture is subsequently stirred for 5 minutes. A solution of 0.9 g (7.1 mmol) of methyl aminoacetate (glycine methyl ester) in 5 ml of dichloromethane is then added, with continued stirring, to the solution of the acid chloride. The reaction mixture is then allowed to reach room temperature within the space of 15 minutes. Subsequently, the organic phase is separated off, washed three times with water, dried over magnesium sulphate and evaporated. The remaining residue is purified by means of (flash) chromatography. 2-(4,6-Dimethoxy-pyrimidin-2-yl-oxy)-5-methyl-bicyclo-[3.1.0]hexane-1-carboxylic acid N-(methoxycarbonyl-methyl)-amide is obtained in the form of an oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18](=[O:28])[NH:17][CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)(=O)C.[H-].[Na+].Br[CH2:32][CH2:33][OH:34]>CN(C=O)C.C(OCC)(=O)C.O>[OH:34][CH2:33][CH2:32][N:17]1[CH:16]=[CH:15][C:14]2[N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=3)[C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][C:19]=2[C:18]1=[O:28]
Reactant: CC(=O)OCc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2ccn1CCO
Reaction time: 24 h

Procedure:
To a solution of 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzyl acetate (see preparation of 3-4 for this intermediate) (74 mg, 0.20 mmol) in dry DMF (1 mL) was added 60% sodium hydride in mineral oil (57 mg, 1.4 mmol). After 10 minutes 2-bromoethanol (50 μL, 0.71 mmol) was added to the reaction which was monitored over 24 hours by LC/MS. Two more portions of 2-bromoethanol were added during this period. The reaction was diluted with ethyl acetate and water. After stirring for 0.5 hour, the organic layer was isolated and washed with aqueous NaHCO3, dried (anhydrous Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with 30-100% ethyl acetate and then 0.25-1.5% methanol/ethyl acetate (sat'd with NH3) to give the title compound. 1H-NMR (500 MHz, CDCl3): δ 8.68 (1H, s), 7.47 (1H, d, J=7.8 Hz), 7.39 (2H, d, J=8 Hz), 7.27-7.31 (5H, m), 7.20-7.22 (2H, m), 6.89 (1H, d, J=7.5 Hz), 4.65 (2H, s) 4.19 (2H, t, J=5.3 Hz), 3.94 (2H, t, J=5.3 Hz) m/e (m+1): 373.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride ((for a preparation see Intermediate 4) 51 mg, 0.10 mmol) in dry DCM (3 mL) was added methanesulfonyl chloride (8 μL, 0.1 mmol), followed by pyridine (1 mL). The resultant pale yellow solution was stirred at room temperature overnight. LCMS showed only 19% of required product. Triethylamine (14 μL, 0.10 mmol), followed by more methanesulfonyl chloride (8 μL, 0.1 mmol) were added and stirring was continued for a further 30 min. The reaction mixture was then concentrated in vacuo and the residue dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title product (10.7 mg, 19%) as a white solid. LCMS (System A) RT=1.13 min, ES+ve m/z 541/543 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][Sn:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: C[Sn](C)(C)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Sn](C)(C)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a suspension of NaH (140 mg, 5.83 mmol) in anhydrous THF (150 mL) under N2 at RT was added dropwise 4-chlorophenol (738 mg, 5.74 mmol). After stirring the mixture at RT for 15 min, (chloromethyl)trimethylstannane (350 mg, 1.64 mmol) in anhydrous THF (5 mL) was added and the reaction was stirred at RT for 18 hours. The mixture was diluted with EtOAc (50 mL) and was washed with aqueous 1.0 N NaOH (3×60 mL). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica gel/hexane, using LC-MS to identify fractions containing the desire product) to afford ((4-chlorophenoxy)methyl)-trimethylstannane 8A (457 mg, 87% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 7.03 (2H, d, J=8.78 Hz), 6.67 (2H, d, J=9.03 Hz), 3.94 (2H, s), 0.00 (9H, s).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10](O)[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1)([OH:3])=[O:2].C(O)=[O:18].C([O-])=O.[Na+].C1(C=CC(O)=CC=1)O>O1CCOCC1.O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:11]([OH:15])[CH:12]=[CH:13][C:14]1=[O:18])([OH:3])=[O:2]
Reactant: O=CO
Reactant: O=C(O)CCCCCCC(O)c1ccco1
Agent: O=C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCC1C(=O)C=CC1O

Procedure:
A stirred mixture of 65.0g (0.287 mol) of α-(6-carboxyhexyl)furfuryl alcohol (Example 6), 113 ml of 97% formic acid, 4.95g of sodium formate, 100 mg of hydroquinone, and 1430 ml of 3:2 dioxane-water is heated at reflux temperature for 19 hr. The solution is concentrated to volume of about 750 ml, diluted with water, saturated with salt, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated with toluene chaser to give an amber solid.