Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+].[C:19](OC(=O)CCCC)(=O)[CH2:20]CCC>>[CH3:19][C:20]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[N:1]=1
Reactant: Nc1cccnc1Nc1ccc(O)cc1
Reactant: CCCCC(=O)OC(=O)CCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cccnc2n1-c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A mixture of (1.0 g, 4.97 mmol, 1.0 eq) 4-[(3-amino-2-pyridinyl)amino]phenol in 25 ml of valeric anhydride was heated to reflux for 8 hours. The reaction mixture was cooled, poured into 150 ml of 0.5N HCl, stirred 10 minutes, and extracted twice with ether. The ether extracts were combined, washed three times with saturated NaHCO3, once with H2O, once with brine, dried over MgSO4, and concentrated to give an oil. The oil was taken up in 100 ml CH3 OH and treated with 60 ml of 2N NaOH and allowed to stir at room temperature for 1 hour. The mixture was concentrated, poured into 200 ml of H2O and washed twice with ether. The aqueous layer was neutralized, and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed once with H2O, dried over MgSO4, and concentrated to give 0.7 g of a solid. Silica gel chromatography eluting with 10% CH3OH/CH2Cl2 gave 510 mg, 38%, of a solid. M.P.: 268°-2690° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2nnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
Sodium hydride (50.1 mg, 1.25 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (250 mg, 0.52 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (278 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-methylpyridin-2-yl)propanamide (335 mg, 91%). 1H NMR (400 MHz, CDCl3) δ0.97 (s, 9H), 2.28 (s, 3H), 3.67-3.84 (m, 4H), 4.26 (d, 2H), 6.15 (t, 1H), 7.30-7.41 (m, 5H), 7.48-7.71 (m, 10H), 8.06-8.14 (m, 2H), 8.68 (s, 1H), 8.76 (s, 1H); m/z (ES+), (M+H)+=708.65; HPLC tR=3.84 min
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](C)[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH2:13](O)C>[Pd]>[NH2:6][C:5]1[CH:7]=[C:8]([CH3:13])[C:2]([CH3:1])=[CH:3][C:4]=1[NH2:10]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: CCO
Agent: [Pd]
Product: Cc1cc(N)c(N)cc1C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (1.66 g, 10.0 mmole) and 10% Pd/C (200 mg) in ethanol (35 mL) was hydrogenated for 2 h at room temperature under 25 psi H2. The catalyst was removed by filtration with celite and the solvent was removed by rota-evaporation to give 1.300 g (96%) of 1,2-diamino-4,5-dimethylbenzene as a brown solid. 1H NMR (CDCl3): 6.449 (s, 1 H), 6.469 (s, 1 H), 3.327 (br, 2 H), 3.259 (br, 2 H), 2.190 (s, 3 H), 2.159 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20]Br.[CH3:23][O-:24].[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][O:24][CH3:23]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.401 g (1.072 mmol) of the above prepared 2-bromomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester, dissolved in 4.0 ml of abs. MeOH, was added 0.116 g (2.15 mmol) of sodium methoxide and the mixture stirred for 4 h at ambient temperature, when TLC indicated the complete disappearance of starting material. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), produced 0.279 g of pure title compound as white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]2[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Cc1c(CN2CCN(S(=O)(=O)C3CC3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: Nc1ncc(B(O)O)cn1
Product: Cc1c(CN2CCN(S(=O)(=O)C3CC3)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 271. NMR (CDCl3): 1.00-1.04 (2H, m), 1.18-1.22 (2H, m), 2.27-2.33 (1H, m), 2.45 (3H, s), 2.67-2.70 (4H, m), 3.38-3.41 (4H, m), 3.86 (2H, s), 3.39-3.41 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+ 531.29 (70%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])[CH:19]=[CH2:18]
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Reactant: C=CCBr
Product: C=CCOCCCc1cc(C(=O)O)cc(OC)c1OC

Procedure:
3-(3-Allyloxypropyl)-4,5-dimethoxybenzoic acid was prepared from 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (Example 10, Step 1) and allyl bromide in quantitative yield by following Method I and used without further purification.
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1>[C:23]([C:22](=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)#[N:24]
Reactant: CCOC1(OCC)CCCN1C
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CN1CCCC1=C(C#N)c1ccc([N+](=O)[O-])cc1

Procedure:
Stir 29.9 g of 2,2-diethoxy-1-methylpyrrolidine and 28 g of 4-nitrophenylacetonitrile in 80 ml of benzene for one hour at room temperature. Distil off the solvent from the resulting reaction mixture under a vacuum to produce a crystalline residue. Recrystallize this residue from ethanol/diethyl ether. Concentrate the mother liquor to obtain a total of 29.5 g (70% of theory) of the title compound as dark-brown shiny crystals of m.p. 67°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]=O)=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CCC=O)c1Cl
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(CCCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CC1
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(3-oxopropyl)phenyl)carbamate (113 mg, 0.366 mmol) was taken up in THF (2 mL) and 1-methylpiperazine (0.081 mL, 0.732 mmol) and acetic acid (0.042 mL, 0.732 mmol) were added. The reaction was stirred for 10 min, and then sodium triacetoxyborohydride (233 mg, 1.098 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-10% MeOHIDCM; 24 g column). Tert-butyl (2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)carbamate (120 mg) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][C:11]#[CH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]1)[C:11]#[CH:12]
Reactant: CN1CCCNCC1
Reactant: C#CCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Temperature: 120 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
A mixture of 2-chloro-1-[2-(propargyloxy)ethyl]-benzimidazole (3.70 g) and N-methylhomopiperazine (9.00 g) is stirred at 120° C. for 5 hours. A 5% aqueous sodium hydroxide (50 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue is dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (60 g), and then eluted with chloroform-methanol (10:1 by volume). The eluate is concentrated to give a pale yellow oily substance (1.90 g). The pale yellow oily substance is dissolved in ethanol (3 ml) and the solution is added to a solution of fumaric acid (1.50 g) in hot ethanol (18 ml). After the mixture is allowed to cool, the precipitated crystals are separated by filtration and recrystallized from ethyl acetate-ethanol to give 1-[2-(propargyloxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (2.14 g) as colorless needles, m.p. 122°-124.5° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]2.C[Si](Cl)(C)C>C(O)CCC>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:17][NH:16][C:11]=2[N:12]=[C:13]([NH:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]3)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(NCc4ccccc4)c4c(-c5ccncc5)c[nH]c4n3)ccc21
Temperature: 116 °C
Reaction time: 40 h

Procedure:
A solution of N-benzyl-2-chloro-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27 mg, 0.055 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (20 mg, 0.11 mmol) and trimethylsilyl chloride (0.070 mL, 0.553 mmol) in nBuOH (1.5 mL) was stirred at 116° C. for 20 h. More trimethylsilyl chloride (0.100 mL, 0.790 mmol) was added. It was stirred at 116° C. for another 40 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 476.4 (M+H); UV 200.3, 268.7, 309.3 nm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:27][C:25](=[NH:26])[CH2:24][O:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)=[O:6]
Reactant: CCc1cnc(Cl)c(C(=O)O)c1
Reactant: N=C(N)COCCc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cccc(Cl)c2)c1

Procedure:
In analogy to the procedure described in example 78.3, 2-chloro-5-ethyl-nicotinic acid (example 124.1) was reacted with 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride (example 79.2) in the presence of TBTU and DIPEA to give 2-chloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide as yellow oil. MS: m/e=380.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>CN1C(=O)CCC1.CO>[OH:21][CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:2]2[C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[N:5]=[CH:6][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:16][CH2:17]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: NC(=O)c1cnn2cccc2c1Cl
Solvent: CO
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnn2cccc2c1NC1CCC(O)CC1
Temperature: 80 °C
Yield: 85 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide, Preparation 3 (15 mg, 0.077 mmol) and (trans)-4-aminocyclohexanol (22.08 mg, 0.192 mmol) in NMP (0.3 ml) was heated at 80° C. for 1.5 h. The product mixture was diluted with methanol and purified by preparative HPLC (condition A) to afford the title compound as a white solid (17.8 mg, 85% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.44-1.56 (m, 4 H) 1.97-2.08 (m, 2 H) 2.17-2.28 (m, 2 H) 3.62-3.76 (m, 1 H) 4.03-4.19 (m, 1 H) 6.69 (dd, J=4.52, 2.76 Hz, 1 H) 6.91 (dd, J=4.77, 1.51 Hz, 1 H) 7.56 (dd, J=2.64, 1.63 Hz, 1 H) 8.10 (s, 1 H). HPLC (method F): ret. Time 2.105 min.; LC/MS [m/z, (M+H)] 275.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([NH:24]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[CH:10]=[CH:9]2>[Pd].CO>[CH3:1][O:2][C:3](=[O:35])[CH:4]([NH2:24])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[CH:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a flame dried 500 mL of round bottom flask was added 2-benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-acrylic acid methyl ester (2.24 h, 4.36 mmol), methanol (100 mL) and 10% palladium on charcoal (0.52 g). The mixture was degassed and purged with hydrogen five times. It was stirred at room temperature for 1 h and filtered through a pad of celite. Solvents were removed and the residue was subjected to flash chromatography using ethyl acetate/hexanes (1:1 and 2:1) containing 1% triethylamine to afford the tile compound as a colorless viscous liquid (1.27 g, 76%), which solidified upon cooling. 1H-NMR (CD3CN, 500 MHz) δ 7.82 (d, J=8.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.22 (dd, J=8.6, 1.5 Hz, 1H), 6.72 (d, J=3.7 Hz, 1H), 3.70 (dd, J=7.3, 6.1 Hz, 1H), 3.65 (s, 3H), 3.38-3.34 (m, 2H), 3.08 (dd, J=13.4, 5.8 Hz, 1H), 2.95 (dd, J=13.4, 7.3 Hz, 1H), 0.82-0.79 (m, 2H), −0.05 (s, 9H). 13C-NMR(CDCl3, 125 MHz) δ 176.0, 134.4, 133.4, 131.1, 127.9, 126.4, 122.4, 113.1, 107.7, 56.6, 51.7, 50.8, 41.3, 10.1, −2.7. Mass spec. 383.16 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9](O)[CH3:10])[CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[OH:8])[CH3:10])[CH:18]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(O)c1cc(Cl)ccc1O
Agent: Cl
Product: CC(c1cc(Cl)ccc1O)c1cc(Br)ccc1O
Yield: 43.5 %

Procedure:
4-Chloro-2-(1-hydroxyethyl)phenol (4 g) was added slowly to a melt of 4-bromophenol (7.9 g) and concentrated hydrochloric acid (3 drops) at 100° C. The melt was heated at this temperature for 3 hr and then cooled and the product crystallised from benzene/hexane to give 1-(5-bromo-2-hydroxyphenyl)-1-(5-chloro-2-hydroxyphenyl)ethane (3.3 g); m.p. 167° C.
Reaction SMILES: [C:1]1([CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C)C=O.O>[CH:20]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:12][CH2:11][CH2:10][C:1]1[CH:2]=[C:3]([CH2:7][CH2:8][OH:9])[CH:4]=[CH:5][CH:6]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCc1cccc(CCO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCc1cccc(CCO)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
2,2′-(1,3-Phenylene)diethanol (0.430 g, 2.59 mmol) and imidazole (0.176 g, 2.59 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL) and cooled to 0° C. in an ice bath. Chlorotriisopropylsilane (0.22 mL) was slowly added and the reaction mixture was kept stirring at 0° C. for 3 h, and then diluted with water (5 mL), extracted with ethyl acetate (15 mL×2), and washed with brine (10 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue so obtained was purified by column chromatography eluting with 1:10 of ethyl acetate-hexanes to give the desired compound as a colorless oil. Yield 35%.
Reaction SMILES: Cl[C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:25]1([N:22]2[CH2:21][CH2:20][CH:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([C:7]4[N:8]([CH3:11])[C:9](=[O:10])[C:4]5[CH:3]=[CH:2][N:31]=[CH:30][C:5]=5[N:6]=4)=[CH:17][CH:16]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: [H][H]
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnccc2c1=O
Yield: 72.2 %

Procedure:
6-Chloro-2-{4-[(1-cyclopentylpiperidin-4-yl)oxy]phenyl}-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (11 mg, 0.025 mmol) produced in Example 30 and triethylamine (17 μL, 0.15 mmol) were dissolved in ethyl acetate (0.5 mL), and 10% palladium-carbon (3 mg) was added thereto and stirred in a hydrogen atmosphere at room temperature for 15 hours. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the entitled compound (7.3 mg, 71%) as a pale brown solid.
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:18][CH:19](Cl)[C:20](=O)[CH3:21]>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([S:2]([F:14])([F:15])([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[O:12][CH:21]=1
Reactant: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.10 g (15.0 mmol) 3-(4-pentafluorosulfanyl-phenyl)-acrylamide, 2.37 g (18.7 mmol) dichloro acetone and 25.0 ml toluene were kept at reflux temperature for 12 h with continuous removal of water by use of a Dean-Stark trap (a water separator used in chemical reactions). The reaction mixture was evaporated and purified by chromatography on silica gel (eluent:heptane/ethyl acetate 5:1). All fractions containing the product were evaporated and the residue stirred with 10 ml isohexane, the crystallized material isolated by filtration dried. 4.40 g (85%) 4-Chloromethyl-2-[2-(4-pentafluoromsulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:28]O>Cl.O1CCOCC1.ClCCl>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][CH:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:28])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CO
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of the lithocholic acid 1 (25.1 g, 66.4 mmol) in anhydrous methanol (100 mL), 4M HCl in 1,4-dioxane (100 mL) was added and the reaction mixture stirred at ambient temperature overnight. The reaction mixture became heterogeneous. The reaction mixture was diluted with dichloromethane (300 mL) and the organic layer was washed with saturated NaHCO3 (2×200 mL). The organic layer was concentrated and dried under high vacuum overnight to provide the pure ester as a white solid (25.7 g, 97%). The analytical and spectral data were consistent with that of reported values (Rensen, Patrick C. N.; van Leeuwen, Steven H.; Sliedregt, Leo A. J. M.; Van Berkel, Theo J. C.; Biessen, Erik A. L. Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asialoglycoprotein Receptor. Journal of Medicinal Chemistry (2004), 47(23), 5798-5808.).