Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][C:19]([O:21]CC)=O)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([NH:28][CH2:29][CH2:30][CH2:31][NH2:32])([CH3:27])([CH3:26])[CH3:25].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(NCCC#N)(C)(C)C>C1COCC1.C(Cl)Cl.O>[CH3:25][C:24]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:19](=[O:21])[CH2:18][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cn1cnc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)NCCCN
Agent: CC(C)(C)NCCC#N
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NCCCNC(=O)Cn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
A mixture of 7.0 g (23 mmol) of ethyl 4,5-diphenyl-1H-imidazole-1-acetate of example 1 and 4.5 g (34.6 mmol) of 3-(t-butylamino)propylamine, conveniently made by LAH reduction of 3-(t-butylamino)propionitrile in THF, was heated at 100° C. for 8 hr. The residue was distributed between water and methylene chloride, and the methylene chloride layer was dried over MgSO4 and stripped. The residue was recrystallized from ether and then cyclohexane to yield 4.5 g of product, mp 94°-96° C.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][C:22]1[N:27]=[C:26]([CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].CO>O>[ClH:1].[ClH:1].[CH3:21][C:22]1[N:27]=[C:26]([CH2:28][CH2:29][N:16]2[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=1
Reactant: C=Cc1cccc(C)n1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(CCN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Yield: 150.7 %

Procedure:
0.254 g (0.797 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 0.22 g (1.88 mmol) of 6-methyl-2-vinylpyridine and 0.15 g of sodium acetate were suspended in 3 ml of a mixture of methanol and water (1:1) and the suspension was refluxed for 2 h. The liquid reaction mixture was filtered and the filtrate was concentrated. The obtained residue was purified according to silica gel column chromatography (chloroform:methanol:aqueous ammonia=96:4:0.4). The purified product was converted into its hydrochloride with ethanolic hydrogen chloride and recrystallized from ethanol to obtain 0.285 g (yield: 81%) of the intended compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:28](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@H:9]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc2ccccc12)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2-tert-Butoxycarbonylamino-3-(1-naphthyl)propionic acid (5.0 g; 0.015 mol) was dissolved in tetrahydrofuran (40 mL). Iodomethane (7.6 mL; 0.12 mol) was added. The reaction mixture was cooled to 0° C. and sodium hydride was added. The reaction mixture was stirred for 48 hours. Ethyl acetate (50 mL) and water (20 mL) were added dropwise. The solvent was removed in vacuo and ether (30 mL) and water (20 mL) were added. The organic phase was washed with an aqueous solution of sodium hydrogen carbonate (pH 8 ; 30 mL). To the aqueous phases was added citric acid (5%) to pH 3. The aqueous phase was extrated with ethylacetate (3×30 mL). The combined organic phases were washed with water (2×40 mL), an aqueous solution of sodiumthiosulfate (5%; 40 mL) and water (40 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and ether (10 mL) and dicyclohexylamine (8.5 mL) were added. The precipitated crystals were filtered off and dissolved in water (20 mL). Hydrochloric acid was added to pH 2. The reaction mixture was extrated with ethyl acetate (4×40 mL), dried (magnesium sulfate) and evaporated in vacuo to afford 3.97 g of (2R)-2-(tert-butoxycarbonyl methylamino)-3-(1-naphthyl)propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10](OCC)[N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(OC)(C)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([CH2:25][CH:24]=[CH2:23])[N:9]1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: C=CCC1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 12.6 g of the α-methoxycarbamate 45 (40.0 mmol) and 16.0 ml of allyltrimethylsilane (100 mmol, 2.5 eq.) in 100 ml of anhydrous CH2Cl2 was cooled to −78° C. and added dropwise with 10.1 ml of BF3.OEt2 (80.0 mmol, 2 eq.). After completed addition, stirring was continued for 30 min, and completion of the reaction was checked by means of TLC (EE/CH 1:9). Thereafter, 10 ml of a saturated NaHCO3 solution was added, and the batch was allowed to come to RT. After transferring into a separating funnel together with 200 ml of MTBE, the phases were separated and the aqueous phase was extracted with 2×100 ml of MTBE. The combined organic phases were washed with 100 ml of half-conc. NaCl solution, dried over MgSO4 and concentrated. The residue was purified using silica gel column chromatography (EE/CH 1:9), thereby obtaining 9.62 g of allyl substitution product 46 (30.9 mmol, 77%) as a colorless oil (mixture of epimers, cis/trans 75:25).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 538.0 (M+); Rt: 1.84 min. δH (400 MHz; CDCl3) 2.27 (s, 3H), 3.15-3.30 (m, 2H), 3.45 (d, 2H), 3.99-4.06 (m, 2H), 4.13-4.22 (m, 4H), 4.73 (s, 2H), 4.96 (s, 2H), 6.57-6.60 (m, 1H), 6.74 (d, 1H), 6.76-6.81 (m, 2H), 7.25-7.31 (m, 4H), 7.32-7.36 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.Cl.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].OS(O)(=O)=O>C(O)(=O)C.O>[CH3:1][N:2]1[CH2:8][CH2:7]/[C:6](=[CH:18]\[C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)/[C:5](=[O:9])/[C:4](=[CH:18]/[C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)/[CH2:3]1
Reactant: CN1CCCC(=O)CC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CN1CC/C(=C\c2ccc([N+](=O)[O-])cc2)C(=O)/C(=C/c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h

Procedure:
N-methylazepan-4-one.HCl (50 mg, 0.30 mmol) and 4-nitrobenzaldehyde were dissolved in acetic acid (5 mL) and stirred for 10 min, then conc. H2SO4 (50 μL) was added slowly and the mixture was stirred at rt overnight. More concentrated H2SO4 (100 μL) was added and stirring was continued at rt for 6 h. Additional 500 μL of concentrated H2SO4 was added and the reaction stirred overnight. A further 350 μL of conc. H2SO4 was added and stirring continued for additional 5 h, during which period further H2SO4 was added in two portions (500 μL and 250 μL). Then water (3× reaction volume) was added and the mixture was stirred until rt was reached. The reaction mixture was extracted with ethyl acetate (3× reaction volume). The phases were separated and the organic phase concentrated to yield a dark yellow viscous oil. The crude product was purified by preparative HPLC, (XBridge column; eluents 50 mM ammonium carbonate buffer at pH 10 and methanol) giving the title product as a yellow solid (26.3 mg). LCMS System A: Rt 1.87 m/z [M+H]+ 394.1, System B: Rt 2.57.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3CCCC3)cc2)CC1
Temperature: 90 °C

Procedure:
A suspension of 4-(4-Bromophenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 5.79 mmol), palladium acetate (54 mg, 0.24 mmol), 2-(di-t-butylphosphino)biphenyl (154 mg, 0.52 mmol), and sodium t-butoxide (846 mg, 8.80 mmol), pyrrolidine (587 mg, 8.25 mmol) in toluene (80 mL) was heated at 90° C. for 3 h under nitrogen atmosphere. The resulting suspension was passed through a Celite column and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by HPLC afforded 4-(4-pyrrolidin-1-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a solid that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29]>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]([O:28][CH3:29])[CH3:26])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: CON(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (43 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 22 mg (25% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.55 (m, 4 H), 1.57 (s, 9 H), 2.26-2.40 (m, 1 H), 2.72 (s, 3 H), 3.30-3.37 (m, 2 H), 3.76 (s, 3 H), 3.86-3.95 (m, 2 H), 4.38 (d, J=7.42 Hz, 2 H), 7.73 (dd, J=8.6, 1.6 Hz, 1 H), 7.78 (d, J=8.2 Hz, 1 H), 8.10 (d, J=0.98 Hz, 1 H); MS (ESI) (M+H)+=396.0; Anal. Calcd for C19H29N3O4S+0.30 EtOAc (421.96): C, 57.50; H, 7.50; N, 9.96. Found: C, 57.88; H, 7.48; N, 9.95
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11](=[CH2:23])[CH:12](O)[CH:13]([NH:19][CH:20]=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].S(Br)([Br:26])=O.O>C(Cl)Cl>[Br:26][CH2:23][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:13]([NH:19][CH:20]=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=C(CCCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CBr
Reaction time: 0.17 h

Procedure:
5 g (15.1 mmol) of ethyl 7-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-heptanoate are dissolved in 50 ml of CH2Cl2 and 1.4 ml (18.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours 50 ml of water are added and the batch is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted once with CH2Cl2. The combined phases are dried over Na2SO4, filtered, and the filtrate is concentrated by evaporation giving ethyl 4-bromomethyl-7-ethoxycarbonylmethoxy-2-formylamino-hept-3-enoate as a yellow oil which is further reacted without purification. 6.4 g (15 mmol) of ethyl 4-bromomethyl-7-ethoxycarbonylmethoxy-2-formylamino-hept-3-enoate and 14.8 ml (60 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred for 18 hours under a pressure of 100 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is chromatographed over silica gel with hexane/ethyl acetate (1:2:5%) to give ethyl 7-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@H:9](O)[CH2:8]2)[CH:2]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([N:17]3[C:16](=[O:18])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:23])[CH2:8]2)[CH:2]=1
Reactant: O[C@H]1CC[C@@H](c2cccnc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of (1S,3R)-3-(3-pyridyl)cyclopentanol (3.95 g, 24.2 mmol) in THF (80 mL) was cooled to 4° C. and treated with phthalimide (3.91 g, 26.6 mmol), Diisopropylazodicarboxylate (5.24 mL, 26.6 mmol) and triphenylphosphine (6.98 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (Hexane/EtOAc=4/1) to yield (1R,3R)-N-[3-(3-pyridyl)cyclopentyl]phthalimide (6.27 g, 89%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[S:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:26])=[O:25].Cl>C(N(CC)CC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[S:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:26])=[O:25])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: COC(=O)CS(=O)(=O)C1CCCCC1Cl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CS(=O)(=O)C1CCCCC1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (3.2 g, 0.013 mole) was added to a solution of methyl [(2-chlorocyclohexyl)sulfonyl]acetate (0.85 g, 0.0033 mole) in triethylamine (13 ml) and the reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and poured into 1 N hydrochloric acid (150 ml). The mixture was extracted twice with 50 ml of diethyl ether, then washed twice with 20 ml of 1.5 N hydrochloric acid and once with brine (10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in a rotary evaporator to give the crude product as an oil. The product was purified by silica gel chromatography to give a solid m.p. ca. 105° C. The structure was supported by NMR, and infrared spectroscopy and elemental analysis.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: NCC1CC1
Product: O=[N+]([O-])c1ccc(NCC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1A from 4-fluoro-1-nitro-2-(trifluoromethyl)benzene and (cyclopropylmethyl)amine: MS (APCI) m/z 261 (M+1).
Reaction SMILES: C(Cl)(Cl)=O.NC1C=CC2N(C)[C:14](=[O:17])[C@H:13](C)[N:12]=C(C3C=CC=CC=3F)C=2C=1Cl.[Cl:28][C:29]1[C:34]2[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[N:36][C@@H:37]([CH3:42])[C:38](=[O:41])[N:39]([CH3:40])[C:33]=2[CH:32]=[CH:31][C:30]=1[N:50]=[C:51]=[O:52].NCCO>ClCCCl.C(N(CC)CC)C>[Cl:28][C:29]1[C:34]2[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])=[N:36][C@@H:37]([CH3:42])[C:38](=[O:41])[N:39]([CH3:40])[C:33]=2[CH:32]=[CH:31][C:30]=1[NH:50][C:51]([NH:12][CH2:13][CH2:14][OH:17])=[O:52]
Reactant: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N=C=O)c2Cl)N(C)C1=O
Reactant: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O
Agent: O=C(Cl)Cl
Solvent: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(NC(=O)NCCO)c2Cl)N(C)C1=O
Temperature: 0 °C

Procedure:
A solution of 2 g of phosgene in 20 ml of ice-cold 1,2-dichloroethane is placed in a sulphonation flask. There is added dropwise thereto a solution of 4 g (0.012 M) of (S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one in 40 ml of 1,2-dichloroethane while cooling with ice and stirring in such a manner that the temperature does not exceed 10° C. The mixture is then stirred at room temperature for 45 minutes. The resulting solution of (S)-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate is cooled with ice and slowly made alkaline with 6 ml of triethylamine. A solution of 2 ml of 2-aminoethanol in 20 ml of 1,2-dichloroethane is treated with the foregoing pre-prepared solution, the mixture is stirred at room temperature for 30 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then methylene chloride/ethanol (20:1) as the eluting agent and crystallised from a small amount of ethyl acetate/n-hexane. There is obtained (S)-1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which melts above 147° C. with decomposition; [α]25D =+192.2° (in dioxan; 1%).
Reaction SMILES: Cl[C:2]([CH3:5])([CH3:4])[CH3:3].[Mg].C([Mg]Cl)(C)(C)C.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C(=O)=O>[CH3:3][C:2]([CH3:5])([C:18](=[O:19])[CH2:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:4]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)(C)Cl
Agent: CC(C)(C)[Mg]Cl
Agent: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
2-chloro-2-methylpropane (75 g, 0.8 mol) was slowly added to magnesium pellets (19.5 g, 0.8 mol) in 800 mL of THF to make the Grignard reagent, tBuMgCl. This was added slowly to a mixture of cuprous chloride (49.5 g, 0.50 mol) and tertbutylacetylchloride (67.25 g, 0.50 mol), cooled to −50° C. in dry ice. After addition, the mixture was allowed to warm up to room temperature overnight. Most of the THF was removed by decreased pressure, followed by the addition of 500 mL of hexanes and 200 mL of 2M HCl. This mixture was filtered to remove the solid byproducts. The aqueous layer was washed 3× with 100 mL of hexanes, the hexanes layer washed 3× with 200 mL of 2M HCl, 2× with 200 mL of NaHCO3/water, 1× with 200 mL of water, and finally 1× with 200 mL of NaCl/water. The product mixture was then dried for an hour in MgSO4, which was subsequently removed by filtration. The hexane was then removed by atmospheric distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([Cl:18])=[O:15]
Reactant: O=C(O)c1c(Cl)ccc2cc(Cl)cnc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(Cl)ccc2cc(Cl)cnc12
Yield: 95.7 %

Procedure:
3,7-Dichloro-8-quinolinecarboxylic acid(20 g, 82 mmol) was added to thionyl chloride(80 ml), and the mixture refluxed for 3 hours and concentrated under reduced pressure to afford the desired product(20.6 g, yield=95.7%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]([Cl:49])([Cl:48])[CH2:3][O:4][C:5]([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][CH:24]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:34][CH2:33]3)[C:25]([O:27]C(C)(C)C)=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].CO>ClCCl>[Cl:49][C:2]([Cl:1])([Cl:48])[CH2:3][O:4][C:5]([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][CH:24]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:36][CH2:37]3)[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.4 %

Procedure:
Prepared from 2-[2-(1-benzyloxycarbonyl-piperidin-4-yl)-2-tert butoxy carbonyl-ethanesulfonyl]-1,2,3,4-tetrahydro-β-carboline-9-carboxylic acid 2,2,2-trichloro-ethyl ester (600 mg) to give, after chromatography (SiO2, 2.5% methanol in dichloromethane), the title compound (530 mg, 94%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][CH2:10]2)[CH:15]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
41.2 mg of the target compound (0.12 mmol, 14.7%) was obtained using 1-(2-methylphenyl)piperazine (289 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.