Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[N:14]([C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:19][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][S:29]([O-:31])=[O:30].[Na+].CNCCNC>CS(C)=O.[Cl-].[NH4+].FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[CH3:28][S:29]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[N:14]([C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:19][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:31])=[O:30]
Reactant: CS(=O)[O-]
Reactant: O=C(NCc1ccc(Br)nc1)c1cccn2c(-c3ccc(F)cc3)ncc12
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccn3c(-c4ccc(F)cc4)ncc23)cn1
Temperature: 110 °C

Procedure:
To a solution of 3-(4-fluorophenyl)-imidazo[1,5-a]pyridine-8-carboxylic acid (6-bromopyridin-3-ylmethyl)-amide (133 mg, 0.313 mmol) in DMSO (2 mL) in a microwave tube is added sodium methanesulfinate (52.0 mg, 0.509 mmol), copper (II) trifluoromethanesulfonate (115 mg, 0.318 mmol) and N,N′-dimethylethylene diamine (0.100 mL, 0.939 mmol). The mixture is warmed at 110° C. for 35 minutes in a microwave reactor. The reaction is the diluted with saturated aqueous ammonium chloride (7 mL) and extracted with EtOAc (4×7 mL). The combined organic layers are washed with saturated aqueous ammonium chloride (3×7 mL) and brine (3×7 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0.5-3% methanol in dichloromethane. The resulting solid is triturated with dichloromethane-ether to afford the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.[C:24]([O:33][CH3:34])(=[O:32])[CH:25]=[CH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCCC1>[CH3:34][O:33][C:24]([C:25]1[C:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][NH:21][CH:20]=1)=[O:32]
Reactant: COC(=O)C=CCC(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1c[nH]cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a lithium bis(trimethylsilyl)amide (1M; tetrahydrofuran solution) (21 ml), a tetrahydrofuran (100 ml) solution of p-toluenesulfonylmethylisocyanide (4.04 g) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. Successively, a tetrahydrofuran (20 ml) solution of dimethyl glutaconate (3.78 g) was added dropwise thereto, followed by stirring while raising the temperature to room temperature for 2 hours. The reaction mixture was concentrated, and the residue was washed with water and 1N hydrochloric acid successively, followed by extraction with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:2) to give the title compound (2.11 g) having the following physical properties.
Reaction SMILES: [CH3:1][C@:2]([C:11](O)=[O:12])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].[BH4-].[Na+].II>C1COCC1>[NH2:3][C@:2]([CH3:1])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][OH:12]
Reactant: C[C@@](N)(Cc1ccccc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@](N)(CO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of alpha-methyl-D-phenylalanine (1.74 g, 9.71 mmol) in 30 mL THF at rt was added NaBH4 (0.92 g 24.27 mmol) in one portion. The solution was cooled to 0° C. Iodine (2.46 g, 9.71 mmol) in 5 mL THF was added dropwise over 30 min. After the addition was complete, the reaction was heated to reflux for 2 days. The reaction was then cooled to 0° C. and quenched by the addition of methanol until the bubbling subsided. The reaction mixture was acidified by the addition of 6N HCl until pH 1, stirred at 50° C. for 30 min and concentrated in vacuo. Purification using ion exchange chromatography (SCX cartridge) afforded (R)-2-amino-2-methyl-3-phenylpropan-1-ol as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.18 (m, 5H), 3.36 (A of AB, d, J=10.4 Hz, 1H), 3.31 (B of AB, d, J=10.4 Hz, 1H), 2.70 (s, 2H), 1.04 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[C:4]2[C:12]([CH3:18])([CH3:17])[CH:13]3[CH2:16][C:3]12[CH2:15][CH2:14]3.[CH2:20]1COCC1.[H-].[Na+].CI>CN(C=O)C>[CH3:20][O:10][CH2:9][CH:8]([C:5]1[CH2:6][CH2:7][C:2]([CH3:1])([CH3:19])[C:3]23[CH2:16][CH:13]([CH2:14][CH2:15]2)[C:12]([CH3:18])([CH3:17])[C:4]=13)[CH3:11]
Reactant: C1CCOC1
Reactant: CC(CO)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCC(C)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of 3b (1.0 g, 3.8×10−3 mol) in DMF (5 ml) was added to a THF (8 ml) suspension of sodium hydride (0.27 g of 50% dispersion in mineral oil, washed twice with hexane, 5.6×10−3 mol). After 3 h stirring at r. t., methyl iodide (1.6 g, 0.011 mol) was added under cooling and the reaction mixture was stirred at r. t. for additional 4 h, poured into ice-cold 2M HCl (100 ml) and extracted with MTBE (2×100 ml). The organic phase was washed with brine (2×50 ml), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (MTBE/hexane 1:20) to give 5-(1-methoxyprop-2-yl)-2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undec-5-ene (8b, 0.73 g, 69% yield, colourless oil).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:15]1=2)=O)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].B.C1COCC1>O1CCCC1>[CH2:1]([N:3]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:15]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH3:2]
Reactant: CCN(CC(=O)N1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CCN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A solution of tert-butyl ethyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (0.8 g, 2.097 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with borane-THF complex (1M in THF; 6.29 mL, 6.29 mmol) and stirred at room temperature for 3 hours. The reaction was quenched dropwise with methanol (10 mL) and then concentrated. The crude residue was diluted with methanol (25 mL) and refluxed for 10 minutes. The mixture was then concentrated, and the residue was subjected to column chromatography on silica gel (1:9-3:7 EtOAc:CH2Cl2) to give a yellow syrup (0.493 g, 64%). 1H-NMR (DMSO-d6) δ 7.85-7.78 (m, 2H), 6.94-6.85 (m, 1H), 3.76-3.79 (m, 2H), 3.62-3.57 (m, 2H), 3.37-3.33 (m, 2H), 3.22-3.19 (m, 2H), 3.08-3.04 (m, 2H), 1.35 and 1.30 (2×brs, 9H), 1.03 (t, J=6.9 Hz, 3H). ESI-MS (m/z, %): 390 (M+Na, 67%), 368 (MH+, 17%), 312 (83%), 268 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](OC)([O:17]C)[CH2:13][CH2:14][CH2:15]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:17]
Reactant: Cc1cc(Cl)ccc1Cl
Reactant: COC(CCCBr)(OC)OC
Product: COC(=O)CCCCc1cc(Cl)ccc1Cl

Procedure:
The anion of 2,5-dichlorotoluene was reacted with trimethyl 4-bromoorthobutyrate to produce methyl 5-(2,5-dichlorophenyl)pentanoate after mild hydrolytic work-up. Competitor A was prepared by LiOH hydrolysis of the methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:28])=[CH:4][N:3]=1.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:28][C:5]1[C:6]([N:8]([CH3:27])[CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a suspension of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (241 mg, 0.56 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (172.32 mg, 1.29 mmol) in butan-1-ol (5 mL) was added DIPEA (217.14 mg, 1.68 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a white solid (198 mg, 72%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][CH3:17])[C:3]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7]O)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:9]([N:5]1[CH2:6][CH2:7][NH:1][C@@H:2]([CH2:16][CH3:17])[C:3]1=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@H](N)C(=O)N(CCO)Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H]1NCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 47 %

Procedure:
Diisopropylazidodicarboxylate (1.82 g, 9.3 mmol) was added to solution of (S)-2-amino-N-benzyl-N-(2-hydroxyethyl)butanamide (1.84 g, 7.8 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 7 d. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 10% CH3OH in EtOAc) to afford (S)-1-benzyl-3-ethylpiperazine-2-one (0.8 g, 47%) as clear oil. 1H NMR consistent.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](O)=[O:35])[CH2:9]1)=O)(C)(C)C.CN.C[C:40]#[N:41].O>CC#N>[CH3:40][NH:41][C:34]([C@H:10]1[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12][NH:8][CH2:9]1)=[O:35]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Reactant: CC#N
Agent: CN
Solvent: O
Product: CNC(=O)[C@@H]1CNC[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C

Procedure:
The title compound is prepared analogously as described for the title compound Example 1, starting from (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester and methylamine. MS (LC-MS): 422.1 [MH]+; tR (HPLC, nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 3.83 min.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N+:2]([O-:1])=[N:3]3)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCc1ccc(-c2ccc(C(=O)n3n[n+]([O-])c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-hydroxybenzotriazole (501 mg) and 4-(4-heptylphenyl)benzoic acid (1 g) in dichloromethane (30 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (839 mg), and stirred for 3 hours at ambient temperature. The reaction mixture was added to water. The organic layer was separated, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-(4-heptylphenyl)benzoyl]benzotriazole 3-oxide. To a solution of The Starting Compound (2.49 g) and 1-[4-(4-heptylphenyl)benzoyl]benzotriazole 3-oxide in N,N-dimethylformamide (25 ml) was added 4-(N,N-dimethylamino)pyridine (381 mg), and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The residue was dissolved in water, and subjected to column chromatography on ion exchange resin (DOWEX-5WX4) eluting with water. The fraction containing the object compound were combined, and subjected to column chromatography on ODSD (YMC-gel.ODS-AM.S-50) eluting with 30% acetonitrile aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give The Object Compound (32) (1.99 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[N+:15]([O-])=O)[CH3:2]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[NH:15][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]#[N:14])[CH:9]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a suspension of 3-(4-cyano-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (1.21 g, 4.62 mmol) in acetic acid (50 mL) and water (8 mL) add zinc powder (1.81 g, 27.7 mmol) portionwise over 2 h. Stir at rt for 3 h then filter to remove the solids. Concentrate the filtrate to a volume of 10 mL, dilute with EtOAc (40 mL), and filter again to remove insoluble material. Concentrate the filtrate to give the desired product 6-cyano-1H-indole-2-carboxylic acid ethyl ester as a solid (670 mg, 3.13 mmol).
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5].CN(C=O)C.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:26])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5]
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-β-Ala-Ile-Ala-Leu SEQ ID NO: 117 (24.34 g, 0.04 mol) is added into a round bottom flask with DMF (350 mL) and a magnetic stirrer. After the tetrapeptide is dissolved, benzyl bromide (4.76 mL, 0.04 mol), followed by cesium carbonate (13.04 g, 0.04 mol), is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then the reaction mixture is slowly poured into a flask with 450 mL of iced water. A large amount of white solid precipitates out which is collected by suction filtration. The product is washed with water (2×200 mL) and placed in a vacuum desiccator.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([CH3:12])=[CH:4][C:3]=1[OH:13].C=O.S(=O)(=O)(O)O.[O:21]1[CH2:26]COC[CH2:22]1>>[CH3:12][C:5]1[C:4]2[CH2:26][O:21][CH2:22][O:13][C:3]=2[C:2]([CH3:1])=[CH:7][C:6]=1[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: Cc1cc(C(C)(C)C)c(C)cc1O
Reactant: C1COCCO1
Agent: C=O
Agent: O=S(=O)(O)O
Product: Cc1cc(C(C)(C)C)c(C)c2c1OCOC2
Yield: 59 %

Procedure:
Reaction of 2,5-dimethyl-4-(1,1-dimethylethyl)-phenol (20.2 g, GLC purity 88%, 0.1 mol, which may be prepared as described by W. Weinrich, Ind. Eng. Chem. (1943) 35, 264-272), 40% formaldehyde solution (80 mL, 1.07 mol), p-dioxane (170 mL) and sulfuric acid (10 mL) according to the procedure described in Example 2, provided after distillation 13.05 g (59% yield, GLC purity 97%) of 5,8-dimethyl-6-(1,1-dimethylethyl)-4H-1,3-benzodioxin, bp 139° C., 3 mm; 1H-NMR (CDCl3)δ 1.40 (9H, s), 2.21 (6H, s), 4.79 (2H, s), 5.14 (2H, s); 7.01 (1H, s); IR (film)νmax 2940, 1580, 1475 cm-1 ; MS m/e 220, 205, 190, 185, 147; UVλmax (ethanol) 225 nm (ε=4270), 281 nm (ε=1490).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(C)C=CC(C=[O:17])=CC=1.O=O.C=C.C1OC1>CC1C=CC(C)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:17])=[O:7])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccc(CO)cc1
Agent: C=C
Agent: O=O
Solvent: C1CO1
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C(=O)O)cc1
Temperature: 190 °C

Procedure:
Into a pressure vessel equipped with magnetic agitation is placed a liquid charge of 92% p-xylene and 4.0% each of p-methyl benzyl alcohol and p-tolualdehyde which are obtainable from recycling streams and is then pressurized with 45 p.s.i.a. oxygen and then pressurized with ethylene. The reaction mixture is heated to 190° C. and reacted for 30 min. with agitation at a system pressure of 1420 p.s.i.g. The liquid phase effluent is found to contain 1.52% ethylene oxide, 4.5% p-methyl benzyl alcohol and 4.4% p-tolualdehyde. The amount of p-toluic acid formed was not determined.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH:20]=[O:21])[CH2:14]2)([CH3:10])([CH3:9])[CH3:8].CI>CCOCC>[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:1])([CH:20]=[O:21])[CH2:14]2)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: CC1(C=O)Cc2ccc(C(C)(C)C)cc2C1
Yield: 6.6 %

Procedure:
To a solution of potassium tert-butoxide (Fluka, 0.45 g, 4 mmole) and of 5-tert-butyl-2-indancarbaldehyde (ex. 4; 0.71 g, 3.5 mmole), there was added at room temperature and under N2, methyl iodide (0.56 g, 4 mmole) and reaction was allowed at room temperature, under stirring. The mixture was taken in ether and washed with NH4Cl and brine, dried over Na2SO4 and concentrated (0,9 g). Chromatography on SiO2 (30 g), with toluene as eluting agent, provided 50 mg (purity>99%, yield 7%) of the desired aldehyde.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH3:10])[N:4]=1.S(Cl)([Cl:13])=O>>[Cl:13][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH3:10])[N:4]=1
Reactant: CCCn1ncc(CO)n1
Reactant: O=S(Cl)Cl
Product: CCCn1ncc(CCl)n1
Temperature: 25 °C

Procedure:
To a solution of aluminum lithium hydride (1.57 g) in THF (140 ml) was added dropwise methyl 2-propyl-1,2,3-triazole-4-carboxylate (7.0 g) in. THF (70 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-hydroxymethyl-2-propyl-1,2,3-triazole (5.9 g). To 4-hydroxymethyl-2-propyl-1,2,3-triazole (4.0 g), thionyl chloride (32 ml) was added to the mixture at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, to give 4-chloromethyl-2-propyl-1,2,3-triazole (4.2 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C@@H:10]([CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.C(Cl)Cl.CO.O>[CH2:20]([C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[CH:27]([CH3:29])[CH3:28])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cccc(Cc2ccccc2)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1CNCCN1c1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.9 %

Procedure:
275.6 mg (0.70 mmol) 4-(3′-Benzylphenyl)-3-(S)-iso-propyl-piperazine-1-carboxylic acid tert-butyl ester (88) were dissolved in 8 ml dry CH2Cl2 and treated with 8 ml TFA, 0.42 ml H2O and 0.42 ml Et3SiH. The resulting mixture was then stirred at r.t. for 3.5 h before it was poured slowly into sat. aq. NaHCO3-solution. After adding 10% NaOH-solution to the mixture until it became alkaline the solution was extracted with CH2Cl2. The comb. org. fractions were dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2/MeOH (4+1)) yielded 191.1 mg (0.65 mmol, 92.92%) 4-(3′-Benzylphenyl)-3-(S)-isopropyl-piperazine (88a) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][Si:13]([CH2:16][CH2:17][O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:15])[CH3:14].CCOC(C)=O.CCCCCC>C(Cl)Cl.CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([CH:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[C:19]([O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[O:20])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C[Si](C)(C)CCOC(=O)N1CCNCC1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)N1CCNCC1c1nc(Cl)nc2nc[nH]c12
Yield: 71 %

Procedure:
To 2,6-dichloropurine (8.86 g, 57.73 mmol) dissolved in a mixture of CH2Cl2 (200 mL), MeOH (50 mL) and DPEA (7.71 mL, 63.50 mmol) was added N1-(trimethylsilylethoxycarbonyl) piperazine (13.30 g, 57.73 mmol) as a solid. The reaction progress was monitored by thin layer chromatography MeOH:EtOAc:hexane (1/49/50, v/v/v) which showed disappearance of starting material and formation of a new product spot after 15 hours. The solvent was removed in vacuo and the residue left behind was partitioned between water (100 mL) and CH2Cl2 (100 mL). The water layer was separated and extracted twice with CH2Cl2 (50 mL). The CH2Cl2 fractions were combined and washed with brine (100 mL), dried (MgSO4), filtered and evaporated. The residue was purified by silica gel flash column chromatography using MeOH:EtOAc:CH2Cl2 (1/49/50, v/v/v) as the eluent. The appropriate fractions were pooled and evaporated to give 15.70 g (71%) of the title compound. 1H NMR (CDCl3): δ 0.02 (s, 9H), 1.04 (t, 2H), 3.69 (t, 4H), 4.25 (t, 2H), 4.40 (bs, 4AH), 7.99 (s, 1H), 13.5 (bs, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[C:4]([OH:11])[CH:3]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:10]2)=[C:4]([OH:11])[CH:3]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccc(Cl)cc1O
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(Cl)cc2O)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of (4-chloro-2-hydroxyphenyl)boronic acid (Preparation 15, 200 mg, 1.16 mmol) in dichloromethane (15 mL) was added pinacol (274 mg, 2.32 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with water (10 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid, 280 mg, in a 95% yield.