Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C>O1CCOCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1
Solvent: C1COCCO1
Product: O=C(O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1
Yield: 73.7 %

Procedure:
To (3-{[(4-chloro-benzenesulfonyl)-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (48 mg), of Step B, was added HCI in dioxane (4M, 3 mL) at room temperature for 24 h. The reaction was concentrated in vacuo, azeotroping with CH2Cl2 to provide the title compound (32 mg). 1H NMR (400 MHz, CDCl3) δ 8.20-6.80 (m, 11H), 6.75 (s, 1H), 6.65 (s, 1H), 6.38 (s, 1H), 4.50 (s, 2H), 4.23 (s, 2H), 4.16 (s, 2H); MS 526 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:27][O:28][Si](C(C)C)(C(C)C)C(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-].CCOCC>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:27][OH:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OCc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.4 %

Procedure:
To a solution of 0.93 g (1.66 mmol) of 2-(1-benzyl-2-triisopropylsilanyloxymethyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 10 mL of THF were added 1.66 mL (1.66 mmol) of a 1 M solution of tetrabutyl ammonium fluoride in THF. The mixture was stirred at RT for 1 h and poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.0 g (quantitative) of 2-(1-benzyl-2-hydroxymethyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow semisolid, MS: 402 (M−H)−.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(C)O)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
6.3 ml of a 2 molar solution of isopropylmagnesium chloride in THF (12 mmol) were added dropwise to a solution of 3 g methyl 4-iodobenzoate (11.5 mmol) in 30 ml THF at a temperature of −20° C. The reaction mixture was stirred for 1.5 h at −20° C., then 1.26 ml acetone (17 mmol) were added and the mixture was allowed to warm to rt. After 30 min at ambient temperature the reaction was quenched with methanol, poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. Chromatographic purification (silica gel; c-hexane/EtOAc 2:1) of the remaining residue yielded 1.64 g (74%) of 4-(1-hydroxy-1-methyl-ethyl)-benzoic acid methyl ester as a colorless liquid. 1H-NMR (CDCl3, 300 MHz): δ 1.60 (s, 6H), 3.91 (s, 3H), 7.56 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28]O)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2].[NH2:39][N:40]1[C:44]([N:45]2[C:49]([CH3:50])=[CH:48][C:47]([CH3:51])=[N:46]2)=[N:43][N:42]=[C:41]1[SH:52].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC(C)=O.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[C:21]([C:25]([OH:27])=[O:26])=[C:20]([CH2:28][S:52][C:41]4[N:40]([NH2:39])[C:44]([N:45]5[C:49]([CH3:50])=[CH:48][C:47]([CH3:51])=[N:46]5)=[N:43][N:42]=4)[CH2:19][S:18][C@H:17]23)=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CO)CSC23)c2ccc(O)cc2)C(=O)C1=O
Reactant: Cc1cc(C)n(-c2nnc(S)n2N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(-n5nc(C)cc5C)n4N)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Reaction time: 2 h

Procedure:
A suspension of 294.78 mg. of 7-[2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 3-acetate and 157.7 mg. of 4-amino-5-(3,5-dimethyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol in 10 ml. of water is adjusted to pH 6.5 with aqueous sodium carbonate. A 2 ml. portion of acetone is added producing solution. This solution is stirred at 60°-63° C. for 51/2 hours, then stripped free of acetone under reduced pressure and acidified to pH 2.0 with 2 N hydrochloric acid. The resulting solid is filtered, washed repeatedly with ethyl acetate, then with ether and dried, giving 190 mg. of the desired product as a yellow solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:33][C:34]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[C:35]=1[CH2:36][S:37]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1)(=[O:39])=[O:38].C(O)(=O)CC>C1COCC1.O.CCCCCC.C(OCC)(=O)C.CN1C(=O)N(C)CCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([S:37]([CH2:36][C:35]3[C:34]([Cl:33])=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:52])(=[O:39])=[O:38])=[CH:47][CH:46]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cc1c(Cl)cccc1Cl)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc2)C(=O)O1

Procedure:
In analogy with Example 5d), 5.0 g (16.34 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one, dissolved in 24 ml of abs. THF and 2.7 ml of DMPU, are deprotonated, at -75° C., with 32.7 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated, at -75° C., with 9.67 g (24.5 mmol) of p-(2,6-dichlorobenzylsulfonyl)benzyl bromide (Maybridge; Tintagel/UK) in 50 ml of abs. THF. Protonation, at -75° C., with 6.1 ml (81.7 mmol) of propionic acid and 6.1 ml of water, extraction and column chromatography (SiO2, hexane/ethyl acetate, 2:1) of the crude product, and crystallization from DIPE, affords the title compound: TLC Rf (D)=0.30; tRet (II)=17.3 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[C:28]([CH3:33])=[CH:29][O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[C:28]([CH3:33])=[CH:29][O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1coc2cc(O)ccc2c1=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1coc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.23 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 120 mg of 7-hydroxy-3-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 183 mg of the above compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19]C)=O)=[CH:4][CH:3]=1.[NH3:21]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:21])=[O:19])=[CH:6][CH:7]=1
Reactant: COC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 260 mg of methyl 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate in 30 mL of a 7N solution of ammonia in methanol are added 5 mL of 22% aqueous ammonia solution. The reaction mixture is then stirred for 20 hours in an autoclave at 80° C. (12.6 bar) and then concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica (eluent: 9/1 dichloromethane/methanol by volume). The fractions containing the expected product are concentrated under reduced pressure. 140 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are obtained in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C([O-])([O-])=O.[K+].[K+].O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH2:2]([NH:6][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH2:3][C:4]#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: C#CCCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of but-3-yn-1-amine hydrochloride (26.4 g, 0.25 mol), K2CO3 (17.4 g, 0.13 mol), and tert-butyl 4-oxopiperidine-1-carboxylate (41.8 g, 0.21 mol) in MeOH (500 mL) was stirred at rt for 5 hrs. Then, NaBH(OAc)3 (133.6 g, 0.63 mol) was added and the suspension was stirred at rt for 17 hrs. The crude reaction mixture was used directly in the next step. ESI-MS (EI+, m/z): 253.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.CN(C)C=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Clc1nc2c(c(-c3ccccc3)n1)CCC2
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a round bottomed flask containing 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.85 g, 10.5 mmol) was added phenylboronic acid (1.43 g, 11.8 mmol), dichloro-((bis-diphenylphosphino)ferrocenyl)-palladium (II) (complex with methylene chloride), (800 mg, 0.98 mmol), triethylamine (4.1 mL, 29 mmol), dimethylformamide (30 mL), and water (2 mL). The reaction mixture was heated to 80° C. for 14 h, then cooled to rt and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The material was purified by flash column chromatography to afford 2-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.25 g, 52%) as an off-white solid.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[C:24]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36](O)=[O:37])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36]([NH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:37])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CCNC(=O)c2ccnc(NC(=O)c3ccccc3)c2)cc1
Yield: 48 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(4-methoxyphenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(4-methoxyphenyl)ethyl]isonicotinamide was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 7.91 (d, J=5.6 Hz, 2H), 7.62-7.43 (m, 4H), 7.19-7.15 (m, 4H), 6.90-6.87 (m, 2H), 6.45-6.43 (m, 1H), 3.79 (s, 3H), 3.71-3.65 (m, 2H), 2.89 (t, J=7.2 Hz, 2H); MS (ES+) m/z 376.5 (M+1).
Reaction SMILES: [C:1]([N:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([N:8]1[CH2:9][CH2:10][O:11][C:23](=[O:25])[O:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CCO)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-boc diethanolamine (3 g, 14.6 mmol), triethylamine (4.1 mL, 29.2 mmol), dry dichloromethane (100 mL) and triphosgene (1.4 g, 4.9 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=O)[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=[S:24])[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 159.8 %

Procedure:
To a suspension of (1-carbamoyl-cyclopropyl)-carbamic acid tert-butyl ester (1.00 g, 4.99 mmol) in 6 mL of THF was added Lawesson's reagent (1.01 g, 2.50 mmol). The pale yellow cloudy reaction mixture was stirred at room temperature for 6 h and then partitioned between 40 mL of ethyl acetate and 15 mL of 0.5 M NaOH solution. The organic phase was washed with 15 mL each of water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel, eluting with 20-60% EtOAc/hexanes, to give 864 mg (80%) of (1-thiocarbamoyl-cyclopropyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:2]1[N:7]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)n1
Product: CC(C)(C)Nc1nccc(C#C[Si](C)(C)C)n1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-4-[trimethylsilylethynyl]pyrimidine (25 g, 0.12 mol) and tert-butylamine (100 mL) was heated to 80° C. for 2 d in a sealed tube. The mixture was cooled to rt and triturated with hexanes (100 mL). The resulting white precipitate was filtered and washed with hexanes. The filtrate was concentrated to give the crude product as a brown oil, which was used in the following reaction without further purification. TLC: Rf=0.40. mp 71-73° C. IR: 3293 (br, w), 2962 (w), 1569 (s). 1H NMR: 8.22 (d, J=5.0 Hz, 1H), 6.57 (d, J=5.0 Hz, 1H), 5.19 (s, 1H), 1.42 (s, 9H), 0.26 (s, 9H). 13C NMR: 162.38, 158.15, 150.95, 112.94, 102.77, 97.62, 51.41, 29.25, −0.11. Anal. Calcd for C13H21N3Si: C, 63.11; H, 8.56; N, 16.98. Found: C, 63.20; H, 8.52; N, 16.70.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C(C)C)=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)(C)C=O.C(Cl)Cl.CCOCC>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:10]([NH:12][CH:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH2:16])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)NC(Cc1c[nH]cn1)C(N)=O
Reaction time: 24 h

Procedure:
130 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S, 2R, 3S )-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide and 130 mg of p-toluenesulphonic acid in 1 ml of trimethylacetaldehyde and 10 ml of methylene chloride are left to stand at room temperature for 24 hours. Thereafter, the reaction mixture is taken up in ether and the organic phase is washed in succession with 2N sodium bicarbonate solution and water, dried and evaporated. Chromatography of the residue on 30 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia yields (S)-N-[(S)-1-[(2R or S,4R,5S)-2-t-butyl-5-isopropyl-1,3-dioxolan-4-yl]-2-cyclohexylethyl]-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide as a foam, MS: 701 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[H][H]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:12][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: [H][H]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A repeat of the above experiment using the same type of catalyst and a feed comprising 50% aqueous glucose solution with a pressure of 2000 psi of hydrogen resulted in a 98% conversion of glucose with a 98% selectivity to sorbitol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].I[CH3:14]>C(#N)C.[Ag]=O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([O:11][CH3:14])[CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: CI
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Agent: O=[Ag]
Solvent: CC#N
Product: CO[C@@H](C)CNC(=O)OC(C)(C)C
Yield: 31.4 %

Procedure:
((S)-2-Hydroxy-propyl)-carbamic acid tert-butyl ester (0.25 g, 1.43 mmol) was dissolved in acetonitrile (14 ml) and iodomethane (1.78 ml, 28.5 mmol), and then silver oxide (0.53 g, 2.28 mmol; prepared as in Org. Syn. Coll. Vol. VII, p. 386) were added. The reaction flask was covered to protect from light and the reaction was heated at reflux for 24 h. Additional iodomethane (1.8 ml) and silver oxide (0.26 g) were added and heating was continued until the reaction was judged to be complete by standard reverse phase LC/MS. The reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 85 mg (32%) of ((S)-2-methoxy-propyl)-carbamic acid tert-butyl ester. (M+Na)+=212.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH:21]=[C:14]3[C:15](Cl)=[N:16][CH:17]=[C:18]([F:19])[C:13]3=[N:12]2)=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:3]([N:11]2[CH:21]=[C:14]3[C:15]([NH:29][C:25]4[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=4)=[N:16][CH:17]=[C:18]([F:19])[C:13]3=[N:12]2)=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(N)ncn1
Reactant: N#Cc1cc(F)cc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(F)cc4C#N)cc23)ncn1
Temperature: 150 °C
Yield: 32.6 %

Procedure:
A mixture of 3-chloro-2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-fluorobenzonitrile (80 mg, 0.28 mmol), 6-methylpyrimidin-4-ylamine (30 mg, 0.27 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos (14 mg, 0.028 mmol) and cesium carbonate (160 mg, 0.49 mmol) in dioxane (1.8 mL) was de-gassed and purged with nitrogen. The reaction mixture was heated at 150° C. in the microwave for 30 minutes. The resultant mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound (35 mg, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.44 (d, J=2.6 Hz, 1H), 8.69 (d, J=1.2 Hz, 1H), 8.37-8.30 (m, 3H), 8.01 (d, J=3.5 Hz, 1H), 2.44 (s, 3H). LCMS (Method B): RT=3.20 min, m/z: 398 [M+H+].
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO)N2
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a solution of (2S,5S,7R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 19, 80 mg, 0.136 mmol) in dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (88 mg) that was used in the next step without further purifications.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCC2)cc1
Temperature: 120 °C

Procedure:
The mixture of 2.50 g (14.5 mmol) of 4-bromophenol, 2.04 ml (21.7 mmol) of cyclobutyl bromide and 7.99 g (57.8 mmol) of K2CO3 in 25 ml DMF is stirred at 120° C. over night. The reaction mixture is extracted with water and EtOAc. The organic layer is dried, filtered and the solvent is removed in vacuo.