Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.OO.[OH2:20].C[OH:22]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][S:2]([C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])=[O:20]
Reactant: O
Reactant: CO
Reactant: COC(=O)C1=Cc2cccc(SC)c2CCC1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: COC(=O)C1=Cc2cccc(S(C)(=O)=O)c2CCC1

Procedure:
Methyl 4-methylthio-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (0.50 g, 2.01 mmol) was dissolved in methanol (10 ml), followed by adding thereto a 30% aqueous hydrogen peroxide solution (1.14 ml, 10.07 mmol) and sodium tungstate dihydrate (0.066 g, 0.201 mmol), and the resulting mixture was stirred at 70° C. for 5.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate (twice), and the extract solution was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.589 g of methyl 4-methylsulfonyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.C[C:22]([OH:25])(C)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CS(C)=[O:57]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:22]([OH:25])=[O:57])[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: CC(C)(C)O
Reactant: CS(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H]1C(=O)N(C)c2cnc(C(=O)O)nc2N1C1CCCC1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Intermediate B (10.0 g, 34.01 mmol) was dissolved in 15 mL of DMSO and 185 mL of tBuOH and Pd(OAc)2 (1.14 g, 5.1 mmol), DPPP (2.2 g, 5.1 mmol) and TEA (7.7 g, 76.5 mmol) were added. The solution was stirred at 80° C. for 10 h under CO (10 atm). The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with water and brine, dried with Na2SO4, purified by silica gel column (DCM:MeOH=20:1) to give (R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridine-2-carboxylic acid (compound I-245, 2.2 g) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]1.C(N(CC)CC)C>O>[CH2:29]1[N:28]([CH2:31][CH2:32][O:33][C:10]([CH:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[O:11])[CH2:27][CH2:26][O:25][CH2:30]1
Reactant: O=C(Cl)C1CC1(c1ccccc1)c1ccccc1
Reactant: OCCN1CCOCC1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCCN1CCOCC1)C1CC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.1 mol of 2,2-diphenyl-cyclopropane-carboxylic acid chloride in 30 ml. of anhydrous benzene is added dropwise to a mixture of 0.1 mol of β-morpholino-ethanol and 0.1 mol of triethylamine in 50 ml. of anhydrous benzene. The mixture is allowed to cool and then stirred for 2 hours at ambient temperature. 300 cc. of water are added, the mixture is extracted with diethyl ether, the extract dried over sodium sulphate, and the solvent removed in vacuo to yield the base.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[C:18](=[O:24])[NH:19][C:20](=S)[NH:21][CH:22]=1>C(O)C>[CH3:16][C:17]1[C:18](=[O:24])[N:19]=[C:20]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[NH:21][CH:22]=1
Reactant: Cc1c[nH]c(=S)[nH]c1=O
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CCO
Product: Cc1c[nH]c(Nc2ccc(C3=NNC(=O)CC3C)cc2)nc1=O
Temperature: 180 °C
Yield: 14.7 %

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (3.25 g) and 5-methylthiouracil (2.5 g) was heated at 180° C. for 11/2 hours. The residual gum was dissolved in hot aqueous ethanol and the solution was evaporated. Trituration of the residue with chloroform:methanol (10:1) gave the crude product as a solid (0.78 g), m.p. 260°-270° C. The filtrate was evaporated and the residue was heated at 180° C. for one hour. Purification of the residue by column chromatography (silica gel, chloroform:methanol, 25:1) gave a further amount of product (0.73 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].CCCCCC.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]([OH:26])[C:3]2[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1C(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(pyridin-2-yl)pivalamide (1.84 g, 10 mmol) in tetrahydrofurane (100 mL) was added at −78° C. under an atmosphere of nitrogen 1.6 M butyl lithium in hexane (13.1 mL, 21 mmol). The reaction is slighly exothermic and a yellow color appears. The reaction is warmed to 0° C. within 15 minutes and stirred at 0° C. for 2 hours. A white suspension is formed. The reaction is cooled to −78° C. and 4-fluorobenzaldehyde (1.52 g, 1.29 mL, 12.0 mmol) was added in tetrahydrofurane (6.55 mL). The reaction was warmed to room temperature over night to yield an orange suspension. Saturated aqueous ammonium chloride solution was added and the reaction was extracted twice with ethyl acetate and once with methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow viscous oil (1.058 g, 35%) after purification by column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. MS ISP (m/e): 303.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](I)=[CH:9][CH:8]=[C:7]([CH3:12])[N:6]=1)=[O:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:12][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1nc(C)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1nc(C)ccc1-c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
To a suspension of methyl-3-iodo-6-methylpyridine-2-carboxylate (1 g, 3.6 mmol; prepared according to WO2010063663), Phenyl Boronic Acid (440 mg, 3.6 mmol) and Pd Tetrakistriphenylphospine (417 mg; 0.36 mmol) in dry toluene (12 ml) was added K2CO3 1M aq solution (3.6 ml, 3.6 mmol). The mixture was heated in a microwave oven for 5 min at 120° C. (procedure was repeated for 4 times). To promote the reaction further Tetrakistriphenylphospine palladium (208.5 mg; 0.18 mmol)) and phenyl boronic acid (220 mg, 0.18 mmol) were added. The mixture was subject to 2 cycles of microwave heating at 140° C. for 10 min. The reaction mixture was diluted with AcOEt (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried with Na2SO4 and filtrated. The solvent was evaporated under reduced pressure and the crude mixture purified on silica gel column (Cyclohexane to Cyclohexane/AcOEt 9:1) to obtain 506 mg of the title compound as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[Li+].[OH-:16]>C1COCC1.CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]=[CH:7][C:5]([O:6][CH2:2][CH3:1])=[O:16]
Reactant: [OH-]
Reactant: Cc1oc(-c2ccccc2)nc1C=O
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
5-Methyl-2-phenyloxazole-4-carbaldehyde [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] (5.62 g, 30 mmol), triethylphosphonoacetate (6.55 mL, 33 mmol), and LiOH (1.38 g, 33 mmol) were dissolved in anhydrous THF (150 mL) and stirred for 18 h at ambient temperature under an atmosphere of nitrogen. The reaction mixture was then diluted with ether (100 mL) and washed with saturated NH4Cl solution (100 mL), then water (100 mL). The aqueous layers were back-extracted with ether (100 mL) and the combined organic layers were again washed with water (100 mL). The ether layer was dried over MgSO4 and concentrated. The resultant residual solids were purified by column chromatography (250 mg silica, 100% hexanes to 10% EtOAc/hexanes) to provide a white crystalline solid (3.46 g, 45%): Rf=0.55 (50% hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.97-8.05 (m, 2H), 7.50 (d, 1H), 7.40-7.44 (m, 3H), 6.63 (d, 2H) 4.26 (q, 2H), 2.43 (s, 3H), 1.33 (t, 3H); MS(EI): 258 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1)C1CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and cyclopropyl carboxylic acid; MS: m/e=362.2 (M+H+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:47][N:48]([CH3:52])[CH2:49][CH2:50]O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:30].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:50][CH2:49][N:48]([CH3:52])[CH3:47])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CN(C)CCO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCN(C)C)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Product: Cl
Reaction time: 0.08 h

Procedure:
4-{(2S,4R)-1-Acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see Intermediate 18 ((100 mg, 0.230 mmol) was suspended in DCM (1 mL). DMAP (33.7 mg, 0.276 mmol) and DCC (52.2 mg, 0.253 mmol) were added and the mixture was stirred for 5 min producing a clear yellow solution. 2-(Dimethylamino)ethanol (20.5 mg, 0.230 mmol) in DCM (0.5 mL) was subsequently added and the reaction stirred at room temperature overnight. The reaction was diluted with DCM (8.5 ml) and washed with NaOH (2N), water and brine (10 ml each) then dried with Na2SO4, filtered and concentrated in vacuo to yield an off-white semi-solid. The crude product dissolved in a minimal volume of DCM (with a few drops of MeOH to aid solubility) and applied to a 25 g cartridge. The cartridge was dried under vacuum at 40° C. for 1 h then eluted with 1% 2M NH3 in methanol/DCM for 2 CV then 1-5% 2M NH3 in methanol in DCM over 10 CV then held at 5% for 5 CV. The appropriate fractions were concentrated in vacuo to yield the free amine product (18.8 mg) as a clear oil. The latter was taken up in the minimum of DCM and HCl in Et2O (1N, 0.19 mL, 0.190 mmol) added and the solvent evaporated under a stream of nitrogen. A small amount of Et2O was added (˜1 mL) and evaporated under nitrogen to yield 2-(dimethylamino)ethyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate hydrochloride (76.7 mg, 0.135 mmol, 58.6% yield) as a white solid. LCMS (Formate, 2 min), Rt=0.91 min, MH+=506.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH3:10][N:5]1[C:4]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:3]=2[C:2]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=2)=[N:8][CH2:7][C:6]1=[O:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2cc(-c3ccccc3)ccc21
Yield: 20 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-trifluoromethylphenyl boronic acid. The title compound (30 mg) was obtained as a beige solid, (yield=20%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C(Cl)Cl.O>[CH3:20][O:24][N:25]([CH3:26])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (10 g, 43 mmol) in DCM (60 mL) was added HATU (19 g, 50 mmol) in portions, The mixture was stirred at room temperature for 0.5 h. Then DIPEA (12.9 g, 100 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.5 mmol) were added in the mixture. The mixture was stirred at room temperature overnight. Water (40 mL) was added and the mixture was extracted by DCM (100 mL*3). The organic layer was washed with brine (5 mL) and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-10/1) to give tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (10 g, 84%).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:32]4[CH:33]=[N:34][CH:35]=[CH:36][C:31]=4[N:30]=[CH:29]3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([SH:45])[CH:42]=[CH:43][CH:44]=1>CN(C)C=O.O1CCCC1>[N:30]1[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[N:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:14]3[C:13]([S:45][C:41]4[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH3:37])[CH:40]=4)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=3[CH:23]=2)[CH:29]=1
Reactant: CCOC(=O)c1sc2cc(Cn3cnc4ccncc43)ccc2c1Cl
Reactant: COc1cccc(S)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cc(Cn3cnc4ccncc43)ccc2c1Sc1cccc(OC)c1
Temperature: 60 °C
Yield: 81.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.07 ml, 0.48 mmol) was added to a mixture of ethyl 3-(chloro)-6-(3H-imidazo[4,5-c]pyridin-3-ylmethyl)benzo[b]thiophene-2 carboxylate (Preparation 12, 150 mg, 0.4 mmol) and 3-methoxybenzenethiol (0.07 ml, 0.6 mmol) in a mixture of dimethylformamide (1 ml) and tetrahydrofuran (1 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 6 hours and then partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was triturated with diethyl ether and hexane mixture to give the title compound as a colourless solid (155 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br-:14].[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Product: [Br-]
Temperature: 70 °C

Procedure:
To 5-bromomethylthiophene-2-carboxylic acid tert-butyl ester (14.9 mmol, 43.8 mmol) was added toluene (300 mL) and triphenylphosphine (14.1 g, 53.8 mmol). The mixture was heated to 70° C. overnight. The solvent was remove in vacuo to give (5-tert-Butoxycarbonyl-thiophen-2-ylmethyl)-triphenylphosphonium bromide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].C[K].N1CCCC[CH2:23]1.C(=O)=O.Cl>C(O)(=O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][C:15]([O:17][CH3:23])=[O:16]
Reactant: C1CCNCC1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: O=C(O)CC(=O)O
Agent: C[K]
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COC(=O)C=Cc1ccc(OC)cc1OC
Temperature: 0 °C

Procedure:
A mixture of 105.6 g of 2,4-dimethoxybenzaldehyde, 93.6 g of methyl potassium malonate, 200 ml of pyridine (dried over KOH), 1.2 ml of piperidine, 36 ml of acetic acid and 48 g of 3A molecular sieves is heated at 150° C. until evolution of CO2 has ceased. The solution is poured onto ice while hot, and the mixture is acidified to pH 1-2 with concentrated hydrochloric acid and then stirred in the ice bath for 20 minutes. The precipitate is filtered off with suction, washed with 1N HCl and water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.[Na+].[Cl-].O>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)c1cc(N)ccc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
A solution of methyl 5-amino-2-fluorobenzoate (1.20 g, 7.1 mmol, described in J. Chem. Soc. Perkin Trans. I, 1975, 1283-1284 and J. Org. Chem., 1990, 2034-2044) and 4-[(4-butylphenyl)ethynyl]benzaldehyde (1.95 g, 7.4 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) in toluene (30 ml) was heated under reflux for 2.5 hrs with azeotropic removal of water. The reaction mixture was cooled down to 0° C., then MeOH (30 mL) and sodium borohydride (540 mg, 14.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min, then at rt for 1 hr. The reaction mixture was diluted with a saturated aqueous solution of NaCl (100 mL) and water (30 mL) and then extracted with Et2O (300 mL+50 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. The residual brown gummy oil was taken up in MeOH (10 mL) and a white solid precipitated out. Filtration and washing with MeOH (2×) gave 2.23 g (76%) of the title compound as a white powder. HPLC, Rt: 5.8 min (purity: 98.2%). LC/MS, M−(ESI): 414.0. 1H NMR (CDCl3) δ: 7.51 (d, J=7.9 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 3H), 6.97 (m, 1H), 6.76 (m, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 2.63 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22]([O:29][C@@H:30]3[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])[C@@H:47]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]3[O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:23][NH:24][C:25]=2[CH:26]([CH3:28])[CH3:27])=[C:16]([CH3:65])[CH:15]=1)=[O:9])([CH3:6])[CH3:5])(O)=[O:2].[OH:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[OH:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][N:72]([C:1]([C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[C:22]([O:29][C@@H:30]4[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])[C@@H:47]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C@H:31]4[O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])=[N:23][NH:24][C:25]=3[CH:26]([CH3:27])[CH3:28])=[C:16]([CH3:65])[CH:15]=2)=[O:9])([CH3:5])[CH3:6])=[O:2])[CH2:71][CH2:70]1
Reactant: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (40 mg) in N,N-dimethylformamide (2 mL) were added 1-(2-hydroxyethyl)piperazine (7 mg), 1-hydroxybenzotriazole (7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg) and triethylamine (0.018 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=15/1) to give 4-[(4-{3-[1-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (27 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.015 mL), and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (12 mg).