Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.CO.N1C(C)=CC(C)=CC=1C.C[CH2:22][O:23]CC>O1CCCC1>[CH3:22][O:23][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:9])[CH:5]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCOCC
Solvent: CO
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Cl)n1

Procedure:
A solution of 2,4,6-trichloropyrimidine (55 g), methanol (50 ml) and collidine (50 g) is heated in dry tetrahydrofuran (400 ml) for 48 hr. Ether is added and the precipitate is collected. The precipitate is column chromatographed on silica gel to give 6-methoxy-2,4-dichloropyrimidine. This product is mixed with morpholine in THF and stirred at 20°-25° to give 6-methoxy-2-morpholino-4-chloropyrimidine. The 6-methoxy-2-morpholino-4-chloropyrimidine is heated with piperazine in pyridine at 60° for 24 hr to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:51][O:52][CH2:53][CH2:54][CH2:55][NH2:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:56][CH2:55][CH2:54][CH2:53][O:52][CH3:51])=[O:28])=[CH:29][CH:30]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COCCCN
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCCNC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.7 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-methoxy-propylamine (10 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 100% ethyl acetate) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-methoxy-propyl)-benzamide (21 mg, 46%) as a white powder: ESI-LRMS m/e calcd for C30H37ClN4O5S [M+] 600.22, found 601.47 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.23 (m, 2H, CH2), 1.45-1.98 (m, 10H, 5×CH2), 2.12-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.39 (s, 3H, OCH3), 3.51-3.70 (m, 5H, 2×CH2 and CH), 5.20 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 6.97 (brm, 1H, NH), 7.18 (d, Jo=8.1 Hz, 2H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jo=8.1 Hz, 2H, Ar), 8.07 (d, Jo=8.1 Hz, 1H, Ar), 8.16 (s, 1H, NH).
Reaction SMILES: Br[CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:29][CH:28]=1
Reactant: CCCCCCCCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCCCCCCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[(2-Bromo-decyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03008, 607 mg, 1.5 mmol), 4-hydroxy-thiophenol (378 mg, 3.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) in DMF (10 mL) was stirred for 12 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.71). The resulting yellow solid was dissolved in acetone and precipitated by addition of hexane to give a light yellow powder. Yield: 401 mg (59%). 1H-NMR (400 MHz, d6-DMSO) δ=1.16-1.52 (m, 16H), 2.76 (t, J=7.2 Hz, 2H), 3.80 (t, J=7.2 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.97 (s, 2H), 9.53 (s, 1H, —OH). LRMS (FAB+): 450.2 (100, [M+H]+). HRMS (FAB+) 450.23208 C25H32N5OS requires 450.232758.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:15]=1
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3ccccc23)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(Br)ccc23)cc1
Yield: 33 %

Procedure:
A mixture of 4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.062 g 0.17 mmol) and bromine (0.03 g 0.17 mmol) in chloroform (3 ml) was heated under reflux for 24 hours. The reaction mixture was diluted with chloroform (20 ml), washed with M sodium thiosulphate (10 ml), water (10 ml) and dried. Removal of solvent gave a brown solid which was purified by SPE chromatography. Elution with cyclohexane/ethyl acetate (10/1) gave the title compound as a white solid (0.025 g 32%). MH+: 446, 448; NMR: (d6-acetone): δ 6.55 (2H, br) 7.05 (2H, t) 7.30 (1H, d) 7.45 (2H, d) 7.50 (2H, m) 7.55 (1H, d) 7.80 (2H, d) 8.80 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]([CH3:16])[C:6]1[S:7][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][N:10]=1)=[O:4].[OH:18]O>C(O)(=O)C>[CH3:1][N:2]([CH3:17])[C:3]([N:5]([CH3:16])[C:6]1[S:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[O:18])=[N:9][N:10]=1)=[O:4]
Reactant: CCCCSc1nnc(N(C)C(=O)N(C)C)s1
Reactant: OO
Solvent: CC(=O)O
Product: CCCCS(=O)c1nnc(N(C)C(=O)N(C)C)s1
Reaction time: 120 h

Procedure:
To a solution of 300 g of 1,1,3-trimethyl-3-(5-butylthio-1,3,4-thiadiazol-2-yl) urea in 1.9 ltr glacial acetic acid there are added in drops at room temperature and with agitation 136 g of perhydrol. The temperature then rises to 28° C. After standing for 5 days, the perhydrol excess is destroyed with manganese dioxide, the glacial acetic acid is vacuum-distilled to a very large extent, and the residue taken up in methylene chloride, is treated twice with active carbon, the solvent distilled, and the remaining oil dried in high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18](=[O:20])[CH3:19])[C:13](=[O:21])[CH2:12]3)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24].[H-].[Na+].Br[CH2:30][CH2:31]Br.Cl>CS(C)=O.CCOCC.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18](=[O:20])[CH3:19])[C:13](=[O:21])[C:12]23[CH2:31][CH2:30]2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: BrCCBr
Reactant: CC(=O)N1C(=O)Cc2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N1C(=O)C2(CC2)c2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Temperature: 25 °C

Procedure:
A solution of 5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-1-acetyl-2-indolinone (5.1 g, 12.7 mmol) in dimethylsulfoxide is treated with sodium hydride (1.12 g, 27.9 mmol) portionwise over a 30 minute period, treated dropwise with a solution of 1,2-dibromoethane (2.62 g, 14.0 mmol) in dimethylsulfoxide over a 1 hour period and stirred at room temperature until reaction is complete by thin layer chromatography. The reaction mixture is poured into a mixture of water and ether, treated with 10% HCl and separated. The organic phase is washed with water, dried (MgSO4) and concentrated in vacuo to give a residue. The residue is chromatographed on silica gel using 5-10% ethyl acetate in hexane to give the title product as a pale yellow solid, 1.1 g, (20%), mp 118.5°-121° C., identified by 1HNMR.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[CH3:9][CH:10]([NH2:13])[C:11]#[CH:12].C(N(CC)CC)C>C(O)C>[CH3:9][CH:10]([NH:13][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[C:11]#[CH:12]
Reactant: C#CC(C)N
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CC(C)NC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (2 g) in ethanol (35 mL) were added but-3-yn-2-amine hydrochloride (2.38 g) and triethylamine (3.14 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.42 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:38])(=[O:37])[NH:32]C(C)(C)C)=[CH:21][CH:20]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[CH2:1]([N:5]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:37])(=[O:38])[NH2:32])=[CH:23][CH:24]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 1-[N-butyl-N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step A) and TFA in the presence of anisole, according to the procedure of Example 4, Step B, to give a 97% yield of the desired material after flash chromatography as a foam, homogeneous by TLC in 95:5 CH2Cl2 --MeOH; FAB-MS m/e 478 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[N:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[N:12][CH:11]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:8][C:6]1[N:7]=[C:2]([C:14]2[CH:15]=[N:10][CH:11]=[N:12][CH:13]=2)[CH:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)cc(-c2cncnc2)n1
Temperature: 160 °C

Procedure:
To a microwave vial were added 6-chloro-2-methylpyrimidin-4-amine (700 mg, 4.88 mmol), pyrimidin-5-ylboronic acid (725 mg, 5.86 mmol), PdCl2(PPh3)2 (684 mg, 0.97 mmol), dioxane (10 mL) and Na2CO3 (2 M, 7 mL, 14 mmol) under Argon. The vial was microwave heated for 1 h at 160° C. Water was added, and extracted with 10% MeOH/CHCl3 (3*50 mL). The organic layers were combined and concentrated under reduced pressure and the crude was purified by silica gel chromatography to yield the title compound as a white solid; MS (m/z): [M+H]+188.2.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=1)[O:12][C:13]1[CH:44]=[CH:43][C:16]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:42])([CH3:41])[C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=4)=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O.P(=O)(O)(O)O>[C:1]1(=[O:7])[N:40]([C:36]2[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=2)[O:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]([CH3:19])([CH3:18])[C:16]4[CH:15]=[CH:14][C:13]([O:12][C:11]5[CH:45]=[CH:46][CH:47]=[C:9]([N:8]6[C:1](=[O:7])[CH:2]=[CH:3][C:4]6=[O:5])[CH:10]=5)=[CH:44][CH:43]=4)=[CH:25][CH:24]=3)([CH3:42])[CH3:41])=[CH:28][CH:29]=2)[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: CC(C)(c1ccc(Oc2cccc(N)c2)cc1)c1ccc(C(C)(C)c2ccc(Oc3cccc(N)c3)cc2)cc1
Reactant: O=C1C=CC(=O)O1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CC(C)(c1ccc(Oc2cccc(N3C(=O)C=CC3=O)c2)cc1)c1ccc(C(C)(C)c2ccc(Oc3cccc(N4C(=O)C=CC4=O)c3)cc2)cc1
Yield: 97.4 %

Procedure:
In the same reactor used in Example 2D, there were placed 26.5 g (0.27 mole) of maleic anhydride, 0.7 g of phosphoric acid and 150 ml of mixed xylene. A solution was then added dropwise thereto, the solution having been prepared by thermally dissolving 52.8 g (0.1 mole) of 1,4-bis[4-(3-aminophenoxy)-α,α-dimethylbenzyl]benzene obtained in Example 1D in a mixture of 100 ml of mixed xylene and 50 ml of N,N-dimethylformamide. A dropping time of 5 hours and an aging time of 2 hours were used in order to carry out the reaction. The reaction solution was concentrated to about 1/2 the original amount and then cooled. When a temperature of 80° C. had been reached, 50 g of water was added thereto. Afterward, the solution was slowly cooled, so that crystals precipitated. The precipitated crystals were then cooled to room temperatures filtered; and washed with cold methanol. 67.1 g of desired crude 1,4-bis[4-(3 -maleimidophenoxy)-α,α-dimethylbenzyl]benzene was obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:19])[CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH:14]([CH3:15])[CH2:13][NH:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].CC(C)=O.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][CH:14]([CH3:15])[C:10]([CH2:9][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:19])([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1CNCC1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 0.5 °C
Yield: 95.1 %

Procedure:
A 2 N aqueous sodium hydroxide solution (20.2 ml) was added to a mixture of (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Reference Example 1a (9.84 g, 40.5 mmol), acetone (39 ml) and water (49 ml) with stirring under ice-cooling (0 to 1° C.), and the reaction mixture was dissolved by stirring for 45 minutes. Benzyl chloroformate (6.35 ml, 44.5 mmol) and a 2 N aqueous sodium hydroxide solution (22.3 ml) were simultaneously added dropwise to the reaction mixture at an internal temperature of 3.5° C. or lower with stirring under ice-cooling (0 to 1° C.) over 20 minutes. The reaction liquid was stirred in an ice bath and gradually returned to mom temperature. This was stirred at mom temperature overnight. A 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction liquid with stirring under ice-cooling (internal temperature: about 15° C.), and the mixture was adjusted to pH 12. This reaction liquid was returned to room temperature and washed three times by adding ethyl ether. The aqueous layer was adjusted to pH 2 to 3 by sequentially adding a 2 N aqueous hydrochloric acid solution (20.2 ml) and a 1N aqueous hydrochloric acid solution (13 ml) with stirring under ice-cooling (internal temperature: 5° C. or lower). The aqueous layer was returned to mom temperature and extracted with ethyl acetate three times. The organic layer was washed with brine, and then dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water four times and then with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (14.53 g, yield: 95.1%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].O.[NH3+:14]N>O.[Ni]>[NH2:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: N[NH3+]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Solvent: O
Product: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 14 h

Procedure:
Glucose (0.55 mol; 100 g) was dissolved in 500 ml of H2O, and 40 ml of an 80% hydrazinium hydrate solution (1 mol) were added. The mixture was stirred slowly for 14 h and filled into a high pressure autoclave. Freshly activated Raney nickel (20 g) was added and the mixture was hydrogenated for 3 h at 50° C. while stirring with about 1000 r.p.m. The autoclave was depressurized and the product-catalyst mixture was filtered. The blue filtrate was treated with diacetyldioxime (2,3-butanedionedioxime) to remove the dissolved nickel. The product was concentrated to a clear yellowish syrup and was crystallized in the refrigerator. The white crystals were filtered off and washed with MeOH. If necessary the product was purified using the oxalate method of J. W. Long, G. N. Bollenbach in "Methods of Carbohydrate Chemistry" ed. by R. L. Whistler and M. L. Wolfrom, Academic Press N.Y. 1963, Vol. 2, P. 79). Yield: 80 g ( 80%), m.p.: 127° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[F:18][C:15]([F:16])([F:17])[CH2:14][S:13][C:12]1[NH:8][N:9]=[N:10][C:11]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1SCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn[nH]c1SCC(F)(F)F
Temperature: 65 °C
Yield: 99.6 %

Procedure:
Ethyl 1-(4-methoxybenzyl)-5-[(2,2,2-trifluoroethyl)thio]-1H-1,2,3-triazole-4-carboxylate (0.127 g) was dissolved in trifluoroacetic acid (2 mL) and heated at 65° C. for 4 h. The trifluoroacetic acid was evaporated in vacuo and the residue was azeotroped with toluene (3×10 mL) then dried under vacuum to afford the subtitle compound (0.086 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:26]2[CH:31]=[CH:30][C:29](C3OCC(C)(C)N=3)=[CH:28][CH:27]=2)([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)(C)(C)C.C[C:41]([OH:43])=[O:42]>CO.C(Cl)(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:41]([OH:43])=[O:42])=[CH:28][CH:27]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc2)=N1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1
Temperature: 75 °C
Yield: 96 %

Procedure:
In a 50 mL round bottomed flask placed with [3-(3-{[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-hydroxy-phenyl-methyl}-phenoxy)-propyl]-carbamic acid tert-butyl ester (3, 220 mg) was added 3 mL of 80% aqueous AcOH and the reaction mixture was heated 75° C. for overnight. Then the reaction mixture was concentrated and dried and added 3 mL of 20% NaOH/EtOH (1:1, v/v) and refluxed for 3 h. Residue obtained on evaporation of the solvent was dissolved in CH3OH/CHCl3 mixture and adsorbed with silica gel and dried. The dried silica gel with compound was purified by silica gel column already flashed with 1% NH4OH in Et2O solution. Elution of the column at 50% CH3OH/CH2Cl2 gave 4-{[3-(3-Amino-propoxy)-phenyl]-hydroxy-phenyl-methyl}-benzoic acid, 4 as a colorless gelly solid. Yield: 96%. Mass: 378 (MH+), 376 (M-H), 360 (M-OH).
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(Br)cccc2s1
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Brc1cccc2sccc12
Temperature: 185 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of 4-bromobenzo[b]thiophene-2-carboxylic acid (21.05 g), copper powder (7.0 g) and quinoline (170 ml) was stirred at 180-190° C. for 1 hour, allowed to cool to ambient temperature and poured into 2M hydrochloric acid (900 ml). Ethyl acetate (500 ml) was added, the mixture was stirred for 15 minutes, then it was filtered through Celite. The aqueous phase was separated and shaken with ethyl acetate (200 ml), then the combined ethyl acetate solutions were washed with water (500 ml) and saturated aqueous sodium chloride solution (500 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 4-bromobenzo[b]thiophene (9.55 g) as a colourless oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:10]1[S:14][C:13]([Br:15])=[N:12][CH:11]=1)[CH2:8]C)([CH3:4])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:10]1[S:14][C:13]([Br:15])=[N:12][C:11]=1[Cl:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)c1cnc(Br)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(Br)nc1Cl
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of (2-bromo-thiazol-5-yl)-ethyl-carbamic acid tert-butyl ester (4.0 g, 13 mmol) in acetonitrile (75 mL) was added N-chlorosuccinimide (3.48 g, 26 mmol) in one portion and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a grey solid (4.2 g, 95%): IR (KBr) 1738 cm−1; 1H NMR (300 MHz, CDCl3) δ 3.61 (q, J=7.1 Hz, 2H), 1.43 (s, 9H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:20])[CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8][CH2:9]2)=[CH:14][C:15]=1[F:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)c(F)c2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1

Procedure:
4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-2-fluoro-phenylamine (0.85 g, 2.4 mmol) was dissolved in DCM (20 mL). To this solution was transferred a solution of CbzCl (560 mg, 3.28 mmol, 1.3 equiv.) in 5 mL of DCM, followed by addition of powder anhydrous K2CO3 (0.99 g, 7.2 mmol, 3 equiv.). The reaction mixture was stirred at 0° C. to rt. overnight. The reaction was quenched by dilution with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered and the filtrate was concentrated in vacuo to obtain the title compound.