Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([CH3:30])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: C[C@@H]1CCCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 239A (0.045 g, 0.10 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.075 mL, 0.15 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83 (m, 3 H) 1.22 (m, 3 H) 1.73 (m, 3 H) 2.99 (m, 1 H) 5.67 (d, J=4.04 Hz, 1 H) 7.04 (t, J=6.99 Hz, 1 H) 7.28 (t, J=8.27 Hz, 2 H) 7.53 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 8.06 (m, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [O:1]=[C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H][H]>C1COCC1>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(=O)Cc1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: COC(=O)C(O)Cc1ccccc1

Procedure:
Methyl 2-oxo-3-phenylpropionate (16d, R18=Ph, R19=methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 30% conversion to methyl 2-hydroxy-3-phenylpropionate (17d, R18=Ph, R19methyl) with 85.4% ee as determined by chiral GC analysis.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[CH2:20][N:21]1[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]1>CN(C)C=O.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:20][N:21]2[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: ClCn1cnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncn(COc2ccc(Oc3ccccc3)cc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.3 g of 4-phenoxyphenol is dissolved in 60 ml of anhydrous dimethylformamide. 1.58 g of 80% strength sodium hydride is added, and the mixture is heated at 60° C. until no more hydrogen evolves (about 1 hour). A solution of 9.28 g of N-(1-chloromethyl)-4,5-dichloroimidazole in 30 ml of dimethylformamide is then dripped in. The mixture is stirred overnight at room temperature, after which it is poured into 500 ml of water, followed by extraction three times with methyl tert-butyl ether. The combined organic phases are washed three times with water, dried over sodium sulfate, and freed from solvent under reduced pressure. The solid residue is recrystallized from n-pentane/ether (6:1) to give N-[(p-phenoxyphenoxy)methyl]-4,5-dichloroimidazole, m.p.: 82°-83° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([CH:13]=O)[N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[N:24]=[C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](=O)[CH3:27].O>C(O)(=O)C>[CH2:15]([N:22]1[C:26]([CH3:27])=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:24]=[C:13]1[C:8]1[N:9]=[C:10]([NH:11][CH3:12])[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)C(=NO)c1ccccc1
Reactant: CNc1nc(C=O)cn2c(C)nnc12
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CNc1nc(-c2nc(-c3ccccc3)c(C)n2Cc2ccccc2)cn2c(C)nnc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
3-Methyl-8-methylamino-[1,2,4]-triazolo[4,3-a]pyrazine-6-carbaldehyde (34 mg; 0.18 mmol), benzylamine (20 μl; 0.18 mmol) and 1-hydroxyimino-1-phenyl-propan-2-one (32 mg; 0.18 mmol) are dissolved in 0.6 ml acetic acid stirred for 2 h at 120° C. The reaction mixture is treated with water and extracted with DCM. The organic layer is dried over MgSO4 and evaporated to dryness. The crude intermediate is dissolved in 20 ml of THF and treated with Ra—Ni. The reaction mixture is stirred for 2 days at 25° C. and 4 bar hydrogen atmosphere. The solid materials are filtered off and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].CC1C=[CH:19][C:20](S(O)(=O)=O)=[CH:21][CH:22]=1.C1(=O)CCC1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][CH2:22]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C1CCC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC2(CCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 221.1 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (110 mg, 0.502 mmol), PTSA (9.5 mg, 0.050 mmol), cyclobutanone (1.0 mL, 13.3 mmol) and acetic acid (1 mL) was stirred at 80° C. for 16 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL). Extraction with EtOAc (100 mL), washing with brine, drying over MgSO4, filtration and concentration under reduced pressure gave a yellow solid. This residue was purified by column chromatography (Purif, silica gel, EtOAc to 95:5 EtOAc/MeOH) to afford yellow solid (30 mg). This solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (25.6 mg, 19%) as a yellow solid:
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]1[CH:15]2[CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:14]2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[ClH:26].C(N(CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:26][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:14][CH:15]1[NH:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOP(=O)(NC1CN(C(=O)OCc2ccccc2)CCC1Cl)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) and triethyl amine hydrochloride (4 equiv.) in DCM (0.1M) was added BF3.OEt2 (2.0 equiv.) and the reaction was allowed to stir at room temperature for 2 h under a nitrogen atmosphere. The solution was then quenched with water and extracted with DCM. The crude product was purified via silica gel column chromatography (ISCO eluting with EtOAc and Hexanes 50% to 100% EtOAc) to yield benzyl 4-chloro-3-(diethoxyphosphorylamino)piperidine-1-carboxylate in 89% yield. LCMS (m/z): 405.1 (MH+), Rt=2.73 min.
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:12][CH2:11]2)=O)C=CC=CC=1.C(O)C.[OH-].[K+].[ClH:30]>CCOCC.O>[ClH:30].[NH:10]1[CH2:11][CH2:12][CH:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:14][CH2:15]1
Reactant: O=C(Oc1ccccc1)N1CCC(c2noc3ccccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: c1ccc2c(C3CCNCC3)noc2c1
Reaction time: 16 h
Yield: 57 %

Procedure:
A mixture of 5.0 g of 4-(1,2-benzisoxazole-3-yl)-1-piperidine carboxylic acid phenyl ester, 100 ml of ethanol, 50 g of (85%) potassium hydroxide and 50 ml of water was heated under reflux, with stirring, under nitrogen for 16 hrs. Most of the ethanol was removed in vacuo and the resultant aqueous suspension was extracted with ether (3×50 ml). The ether extracts were combined, washed with water, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure to give an oil. The oil was dissolved in anhydrous ether and hydrogen chloride was introduced to precipitate a 3.0 g of a hydrochloride salt. Recrystallization from methanol-ether gave 2.0 g (57%) of product as the hydrochloride, mp, 313°-315° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cccc(Cl)c2Cl)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)OCC
Yield: 79.9 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (0.293 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)=[C:8]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2]>CCOC(C)=O.C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)=[C:8]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)c[nH]2)c1
Yield: 91 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [5-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 200 mg, 0.406 mmol). Silica gel chromatography (5-15% EtOAc/DCM) afforded the title compound (134 mg, 91%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.85 (s, 1H), 9.75 (s, 1H), 9.13 (d, 1H, J=1.8 Hz), 8.18 (d, 1H, J=2.5 Hz), 7.75 (dd, 1H, J=8.1, 1.8 Hz), 7.32 (d, 1H, J=8.1 Hz), 5.86 (m, 1H), 2.67 (s, 3H), 2.28-2.35 (m, 2H), 2.08-2.19 (m, 2H), 1.62 (t, 2H, J=6.3 Hz), 1.13 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O2, 363.2 (M+H), found 363.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a suspension of 4-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and dimethylformamide (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture was diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium hydrogen sulfate and saturated brine. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the subtitle compound as a solid (4.28 g).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C@@H:14]([CH2:19][C:20]([F:29])([F:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([O:17]C)=[O:16])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH2:4]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([NH:13][C@@H:14]([CH2:19][C:20]([F:29])([F:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([OH:17])=[O:16])=[O:12])[CH2:9][CH2:10]2)[CH2:1][CH2:2][CH2:3]1
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (S)-2-[(8-azaspiro[4.5]decane-8-carbonyl)amino]-4,4-difluoro-5-phenylpentanoate (240 mg, 0.59 mmol) was dissolved in a mixture of 15 ml of THF and 5 ml of methanol. A solution of 42 mg of LiOH (1.76 mmol, 3 eq.) in 5 ml of water was added and the mixture was stirred at RT for 3 h. After the reaction had ended, the reaction mixture was acidified to pH=3 by adding a 2 M HCl solution. The organic solvent was removed under reduced pressure and the remaining aqueous phase was extracted with ethyl acetate. Subsequently, the organic phase was washed another three times with water and once with saturated NaCl solution, dried over MgSO4 and freed from the solvent under reduced pressure. The product was obtained in the form of a yellow solid which was used in the reaction which followed without further purification.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C(OO)=O.ClC1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=1.S1(OSO1)(=O)=O.[Na].[C:27](=[O:30])(O)[O-].[Na+]>ClCCl>[Cl:1][C:15]1[N:14]=[C:27]([OH:30])[C:18]([F:19])=[CH:17][CH:16]=1
Reactant: O=C([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccnc1Cl
Agent: O=S1(=O)OSO1
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: Oc1nc(Cl)ccc1F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
3-chloroperoxybenzoic acid (21 g) was added to a dichloromethane (200 ml) solution of 2-chloro-3-fluoropyridine (10 g), and the obtained mixture was stirred at 65° C. for 8 hours. The reaction solution was cooled on ice. A saturated sodium thio sulfate aqueous solution was added to the reaction solution, and the obtained mixture was stirred for 20 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was washed with t-butyl methyl ether/n-heptane (1/1), and the solid was collected by filtration. The obtained solid was dissolved in THF (150 ml). Triethylamine (13.2 ml) and trifluoroacetic acid anhydride (33.2 ml) were added to the solution, while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 5 hours. A small amount of water was added to the reaction solution. Thereafter, a 5 N sodium hydroxide aqueous solution was added to the mixture, while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. The reaction solution was converted to the mild acidic range by addition of acetic acid, and it was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 1:1). The obtained solid was washed with t-butyl methyl ether/n-heptane (1/1) and then collected by filtration, so as to obtain the title compound (2.6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7](Br)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:18]/[C:19](/[CH3:28])=[C:20](/[O:26][CH3:27])\[O:21][Si](C)(C)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:27][O:26][C:20](=[O:21])[C:19]([CH3:28])([CH3:18])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)(C)OC(=O)NC(Br)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 12.9 %

Procedure:
Bromo-tert-butoxycarbonylamino-acetic acid tert-butyl ester (1.5 g, 4.8 mmol) was dissolved in 40 mL of dichloromethane and then cooled in a dry ice/acetone bath. A solution of methyl trimethylsilyl dimethylketene acetal (1.9 mL, 9.6 mmol) in dichloromethane (5 mL) was added, followed by slow addition of a solution of titanium (IV) chloride (0.57 mL, 5.28 mmol) in dichloromethane (5 mL), and then a solution of triethylamine (0.73 mL, 5.28 mmol) in dichloromethane (10 mL). The reaction mixture was warned to room temperature with stirring over 16 h. An aqueous solution of citric acid (˜11 g/100 mL) was added and the reaction mixture briefly stirred. The layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined dichloromethane layers were washed with sodium bicarbonate solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 206 mg (13%) of 3-tert-butoxycarbonylamino-2,2-dimethyl-succinic acid 4-tert-butyl ester 1-methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][CH2:18][C:19]([OH:21])=O)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:37]([NH2:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:44]([O:45][CH3:46])=[C:41]([O:42][CH3:43])[CH:40]=1>O1CCCC1>[CH3:43][O:42][C:41]1[CH:40]=[C:39]([CH:48]=[CH:47][C:44]=1[O:45][CH3:46])[CH2:38][CH2:37][NH:49][C:19](=[O:21])[CH2:18][CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:12][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
13.2 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran are cooled to 0° C. and treated dropwise within 10 minutes with 5.44 g of chloroformic acid isobutyl ester in 80 ml of tetrahydrofuran. The mixture is then held at room temperature for 3 hours and treated at 0° C. with 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran. The suspension is left to stand at 3° C. for 48 hours, then evaporated, treated with water and extracted with ether/methylene chloride (3:1). The ethereal extracts are washed with water, sodium bicarbonate solution, 1-N tartaric acid and water. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized from methylene chloride/ether at 0° C. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionamide of melting point 135°-136° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[CH2:9]Cl.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[CH2:9][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cn1cnc(CCl)c1Cl
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2ncn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 246.2 %

Procedure:
A mixture of 5-chloro-4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (463 mg, 2.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (213 mg, 1.5 mmol), and potassium carbonate (1.1 g, 8.0 mmol) in acetone (15 mL) was stirred at room temperature overnight. The solid material was removed by filtration and washed with 50% acetone/MeOH (2×15 mL). The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/DCM and 0-6% MeOH/DCM), affording 2-{[(5-chloro-1-methyl-1H-imidazol-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.0 g, 93% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 3.53 (s, 3H), 4.25 (s, 2H), 5.97 (s, 1H), 7.70 (s, 1H); M+271. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>>[OH2:16].[NH2:5][C:4]1[C:3]2[C:2]([N:1]=[C:10]3[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccccc1N
Agent: Cl
Product: Nc1c2c(nc3ccccc13)CCCC2
Product: O
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 2-aminobenzonitrile (120 g), cyclohexanone (115.8 ml), conc hydrochloric acid (9.2 ml), and cuprous chloride (1.21 g) was heated under reflux for 3 days, with stirring. At the end of each 24 hr period, additional cuprous chloride (1.21 g) was added. At the end of the 3rd day, additional conc hydrochloric acid (47.3 ml) was added, and the mixture was cooled to ambient temperature. The precipitate was collected and washed with 10% hydrochloric acid to provide 160 g (67.0%) of 9-amino-1,2,3,4-tetrahydroacridine hydrate, mp 180°-185°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.O.[C:22](OC(C)=O)([CH3:25])([CH3:24])[CH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromophenylacetic acid (5.00 g, 23.2 mmol) in tBuOAc (75 mL) was added BF3.OEt2 (2.95 mL, 23.2 mmol). The mixture was allowed to stir overnight at room temperature and poured into H2O. The aqueous phase was extracted with EtOAc. The organic phase was washed with sat. aq NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by flash chromatography on silica gel (0% to 100% EtOAc in hexanes) provided the title compound. 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J=8.0 Hz, 2 H), 7.19 (d, J=8.0 Hz, 2 H), 3.52 (s, 2 H), 1.48 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1cccc2[nH]ccc12
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a suspension of 4-aminoindole (1.0 g, 7.57 mmol), triethylamine (1.07 mL, 7.57 mmol) in methylene chloride (50 mL) at 0° C., was added dropwise a solution of chloroacetyl chloride (0.615 mL, 7.57 mmol) in methylene chloride (5 mL). After 30 minutes, the solution was washed with water (2×100 mL) and dried over anhydrous magnesium sulfate. Purification by chromatography over silica gel (60 g, 40% ethyl acetate-hexane) and crystallization form hexane-ethyl acetate afforded the title compound as a white solid (1.17 g, 74.1%), mp 114-116° C.; MS EI m/e 208/210 (M+).