Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: Cc1cccc(OC2CCN(c3ncc(Cl)cc3C(=O)O)C2)c1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4cccc(C)c4)C3)CC2)cc1
Yield: 5 %

Procedure:
The title compound (D198) (12 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(m-tolyloxy)pyrrolidin-1-yl)nicotinic acid (D141) (160 mg, 0.472 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (107.46 mg, 0.472 mmol). The residue (50 mg) obtained from SPE-Si cartridge purification (50 mg) dissolved in a mixture of chloroform/ethanol (1/1) (1 ml) was separated by chiral HPLC [Phenomenex Lux1 column (250×20 mm, 5 μm particle size). Mobile phase: isocratic premixed mixture of (hexane 80%, ethanol 20%) containing 0.1% of diethylamine. Flow rate=10 ml/min. UV detection: 245 nm]. Collected fractions, after solvent evaporation, afforded the title compound (D198) (12 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred solution of 8-methyl-6-(2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone (0.5 g) in concentrated sulphuric acid (4 cm3) at 0° was added concentrated nitric acid (1 cm3). The mixture was stirred for 1 hour, poured carefully onto ice (100 g), and the solution basified to pH8 with solid sodium carbonate. The resulting suspension was extracted with dichloromethane (3×100 cm3) and the combined organic phases were dried (MgSO4), filtered, and evaporated to yield a foam which was triturated with ethyl acetate/ether to afford 8-methyl-6-(2,4-dimethyl-5-nitro-imidazol-1-yl)-2-(1H)-quinolone, m.p. 244°-247°, (0.52 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>C(O)(=O)C>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(-c2nc3ccccc3n2-c2ccccc2)c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc(-c2nc3ccccc3n2-c2ccccc2)c1

Procedure:
A solution of 1-phenyl-2-(3-methoxyphenyl)benzimidazole (0.20 g, 0.67 mmol) and hydrobromic acid (4 ml) and acetic acid (4 ml) was refluxed for 48 hours. The reaction mixture was cooled and extracted with diethyl ether (5×150 ml) at pH 3-5. The organic fractions were discarded. The aqueous phase was alkalinized to pH 8-9 and extracted with ethyl acetate (5×150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo to yield a white solid. The solid was triturated with an ethyl acetate/diethyl ether mixture.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12]C)=[O:10])=C1.[C:30]1([S:36](CC2C(C(OC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1.CC1(C)C(C)(C)OB(C2SC=CC=2)O1>>[C:21]1([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[S:36][CH:30]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Agent: CC1(C)OB(c2cccs2)OC1(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cccs2)c1OC

Procedure:
Prepared by proceeding in a manner similar to Intermediate 28, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[CH:14]=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:16]=[C:17]([CH2:20][CH3:21])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)=O)(C)(C)C.[ClH:29].O1CCOCC1.C(OCC)C>CCO.[Pd]>[ClH:29].[CH2:20]([C:17]1[C:18]2[CH2:19][C@@H:10]3[CH2:9][NH:8][CH2:28][CH2:27][N:11]3[C:12](=[O:26])[C:13]=2[CH:14]=[C:15]([C:22]([F:23])([F:25])[F:24])[CH:16]=1)[CH3:21]
Reactant: CCc1cc(C(F)(F)F)cc2c1C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCc1cc(C(F)(F)F)cc2c1C[C@@H]1CNCCN1C2=O
Yield: 40 %

Procedure:
MS (ESI) 340 (M+H). Crude (R)-2-N-(t-butoxycarbonyl)-10-ethyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one was dissolved in EtOH (2 mL) and hydrogenated [10% Pd/C (50 mg), H2 (30 psi)]. The reaction mixture was filtered through diatomaceous earth, and then purified by flash column chromatography (silica gel, 4:1 hexanes/EtOAc). The resulting material was deprotected using 4 N HCl in 1,4-dioxane (200 μL, 0.8 mmol), followed by trituration with diethyl ether, to provide the desired product (18 mg, 40% over 3 steps) as a white solid. MS (ESI) 299 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:34][CH:33]=2)([OH:32])[CH2:27][CH2:28]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCCCOc1cccc(OCc2ccccc2)c1
Product: Cc1ccc(CC2(O)CCN(CCCOc3cccc(OCc4ccccc4)c3)CC2)cc1

Procedure:
The title compound, MS: m/e=446.5(M+H+), was prepared from 1-(3-bromopropoxy)-3-(phenylmethoxy)-benzene and 4-(4-methyl-benzyl)-piperidin-4-ol.
Reaction SMILES: [Cl:1][CH:2]([Cl:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24]O)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].CCN(C(C)C)C(C)C.CS([Cl:42])(=O)=O>C(Cl)Cl>[Cl:28][CH:2]([Cl:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24][Cl:42])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.5 %

Procedure:
To a cooled (ice-water) solution of the product of step 1 (800 mg, 1.87 mmol) and DIPEA (0.675 mL, 3.75 mmol) in DCM (10 mL) is slowly added methanesulfonyl chloride (0.150 mL, 1.87 mmol). The reaction mixture is stirred at room temperature for 6 hours. The reaction is diluted with DCM (10 mL), washed with water (2×10 mL) dried over Na2SO4 and concentrated under reduced pressure to give the title compound (813 mg): LCMS m/z (Cl): 445 [M+H].
Reaction SMILES: [OH-].[Mn+2:2].[OH-].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][C:8]([OH:10])=[O:9].CCCCCC>O>[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][C:8]([O-:10])=[O:9].[Mn+2:2]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Mn+2]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Reaction time: 3 h

Procedure:
The recovered manganese hydroxide was than placed into a beaker provided with a reflux condenser and Dean Stark water trap. 15.5 grams (0.105 Mole) glutamic acid was added. 100 ml hexane was thereafter added and stirred and boiled at atmospheric pressure for 3 hours. During the course of the reaction about 3.6-3.8 ml water was removed from the reaction media and acquired in the Dean Stark apparatus. The reaction mixture was then cooled and filtered yielding 21 grams of manganese glutamate. The product, manganese glutamate, was hygroscopic and requires handling in conditions to avoid absorption of moisture from the air by methods known for those skilled in the art.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(O)[CH2:17][CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH2:17][CH2:18][OH:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: OCCCO
Reactant: C=CCNc1ccc(CC(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCNc1ccc(CC(=O)OCCCO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(allylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 4-(allylamino)phenylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(OCC)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]=[C:12]=[O:14])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 203.7 %

Procedure:
To a solution of 5-aminoindane (25 g) in anhydrous diethyl ether (1250 ml), under an atmosphere of nitrogen, at 0° C. was added triphosgene (18.3 g). The mixture was stirred at 0° C. for 2 min then triethylamine (64.7 ml) was added until pH8. The mixture was stirred at 0° C. for 10 min then at. 10° C. for 10 min. The undissolved solids were filtered off and the filtrate evaporated in vacuo. The residue was distilled at 100° C./1 mbar to afford the title compound (20 g). 1H NMR (360 MHz, CDCl3) δ2.07 (2H, quin, J=7.5 Hz), 2.86 (4H, m), 6.84 (1H, dd, J=7.9 and 2.0 Hz), 6.94 (1H, s), 7.13 (1H, d, J=7.9 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:7]=2[N:8]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2c(n1)CN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc2c(n1)CNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 2-(methylthio)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.43 g, 5.36 mmol) in dichloromethane (10 mL) was added a solution of trifluoroacetic acid (4.0 mL, 52 mmol) in dichloromethane (5 mL). The solution was stirred at room temperature for 3 hours. The dichloromethane was removed in vacuo. The residue was dissolved in water, treated with 5M sodium hydroxide to pH=14 and extracted with dichloromethane (5×10 mL). The organic layer was dried (MgSO4) filtered and evaporated to give the title compound (870 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19]([OH:21])=O)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19]([Cl:30])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1ncc2cc(C(=O)O)n(-c3ccc(F)cc3)c2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, 24, (4.7 g, 15.5 mmol) in dichloromethane (100 mL) is added DMF (0.5 mL) followed by dropwise addition of oxalyl chloride (2.7 mL, 31.1 mmol). The mixture is allowed to slowly warm to room temperature over a period of 3 hours. The reaction mixture is concentrated in vacuo and can be dried azeotropically with toluene to afford 4.7 g of the desired product, which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 9.38 (s, 1H), 8.04 (s, 1H), 7.40-7.20 (m, 4H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 322.0 (100, M++H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1>CC#N>[Br:8][C:6]1[N:7]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Clc1ncc(Br)nc1Br
Reactant: NCC1CCOCC1
Solvent: CC#N
Product: Clc1ncc(Br)nc1NCC1CCOCC1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a scintillation vial containing 3,5-dibromo-2-chloropyrazine (1 g, 3.67 mmol) and TEA (1.024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4-yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80° C. in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHCO3, and sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (20% EtOAc/Hexane) to yield 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61.1% yield), yield), LCMS (m/z): 308.0 (MH+), retention time=0.94 min, and 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89% yield), LCMS (m/z): 308.0 (MH+), retention time=0.91 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[H-].[Na+].[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29](SC)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29]([NH:6][C:5]4[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1cccc2c1CCc1cnc(SC)nc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCc1cnc(Nc3cc(OC)c(OC)c(OC)c3)nc1-2
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
To a solution of 3,4,5-trimethoxyaniline (0.401 g) in tetrahydrofuran at room temperature under nitrogen was added sodium hydride (60% oil dispersion, 0.16 g) in portions over 2-3 minutes. The mixture was stirred for 15 minutes, and then 7-methoxy-2-methylthio-5,6-dihydrobenzo[h]quinazoline (0.258 g) was added, and the mixture was refluxed for 4 hours. The reaction mixture was poured into 300 ml of water, and the resulting yellow precipitate filtered off, washed with pentane, and dried under vacuum, giving 7-methoxy-2-(3,4,5-trimethoxyanilino)-5,6-dihydrobenzo[h]quinazoline (0.3042 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.C(=O)=O.CO.CCCCCC.C([Li])CCC.CN1CCN(C)C1=O.[CH3:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=O)=[CH:38][CH:37]=1.Cl>C1COCC1>[C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[C:6](=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[C:39]2[CH:49]=[CH:50][C:36]([CH3:35])=[CH:37][CH:38]=2)[CH:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: CC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
To a 300 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 4.5 g (33.0 mmol) of 1-methyl-3-tert-butyl-cyclopentadiene and 150 ml of THF were charged under a nitrogen atmosphere. In the dry ice/methanol bath, 22.5 ml (34.7 mmol) of 1.54M n-butyllithium hexane solution was gradually added dropwise and then stirred at room temperature for 20 hours. To the obtained reaction solution, 4.3 ml (39.6 mmol) of 1,3-di-methyl-2-imidazolidinone was added, subsequently 8.3 g (39.6 mmol) of 4,4′-di-methylbenzophenone were changed, and the resultant solution was stirred for 120 hours under reflux. The reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of hexane. The separated organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous solution of sodium chloride, and dried over magnesium sulfate and the solvent was distilled off. Thereafter, the resulting product was purified by column chromatography to obtain 6.2 g of an orange solid. The yield was 56%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [Na].N.[C:3]([O:7][C:8](=[O:33])[N:9]([CH3:32])[C@:10]12[CH2:15][C@H:14]1[CH2:13][N:12](S(C1C=CC(C)=CC=1)(=O)=O)[C@H:11]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>C1COCC1>[C:3]([O:7][C:8](=[O:33])[N:9]([CH3:32])[C@:10]12[CH2:15][C@H:14]1[CH2:13][NH:12][C@H:11]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@]3(N(C)C(=O)OC(C)(C)C)[C@@H]2c2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@]12C[C@H]1CN[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a flame dried 125 mL rbf equipped with a dry ice condenser was added fresh sodium metal (0.32 g, 14.0 mmol). The flask was immersed in a −78° C. bath and ammonia gas was condensed into the flask until it was about a third full. Racemic Intermediate 11, one enantiomer being methyl-[(1R,2S,5S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (0.62 g, 1.4 mmol) in THF (10 mL) was added to the flask in a thin constant stream and the mixture was stirred for 10 minutes until the reaction was complete. Solid ammonium chloride was added and the reaction was warmed to room temperature. The volatile solvents were allowed to evaporate and the residue was partitioned between 1N NaOH and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as an oil (0.40 g, quantitative yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:7])=[O:5])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN1CCOCC1>CN(C=O)C>[CH2:39]([NH:47][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C@@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:7])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)O
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
N[1-(R)-Ethoxycarbonylethyl]-L-leucine (1.39 g, 6 mM), N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.16 g, 6 mM), 1-hydroxybenzotriazole (0.93 g, 6 mM) and phenethylamine (0.7 g, 6 mM) were dissolved in DMF (50 ml) at -6°. N-Methyl-morpholine (0.62 g, 6.2 mM) was added and the reaction mixture allowed to warm to room temperature. After 12 h the solvent was removed in vacuo. The residue in EtOAc (150 ml) was washed with H2O (2×100 ml), dried and evaporated in vacuo to yield an oil which was purified by chromatography on SiO2 in EtOAc to give N[1-(R)-ethoxycarbonylethyl]-L-leucine N-phenethylamide as an oil (1.84 g). For analysis, a portion of this material was dissolved in MeOH, treated with anhydrous HCl in Et2O and evaporated in vacuo to yield the corresponding hydrochloride as a foam; (Found: C,60.28; H,8.54; N,7.35; C19H30N2O3.HCl.0.4H2O (requires C,60.35; H,8.48; N,7.41%); [α]D20 =+9.4° (c=0.2, MeOH); νmax (Nujol) 3400 (br), 3100 (br), 2510 (br), 2400 (br), 1740, 1670 and 1550 cm-1 ; δ(CDCl3) 0.92 and 0.95 (6H, each d, each J=7 Hz, (CH3)2CH), 1.27 (3H, t, J=6.5 Hz, CH3CH2), 1.28 (3H,d,J=7 Hz, CH3CH), 1.3-1.7 (3H,m,CH2CH), 2.85 (2H,t,J=6 Hz,CH2CH2C6H5), 3.21 (1H,dd,J=10 Hz and 4 Hz, α--CH), 3.27 (3H,q,J=6.5 Hz, CH3CH), 3.54 (2H,q,J=7 Hz, NHCH2CH2), 4.16 and 4.18 (2H, each q, each J=6.5 Hz, OCH2CH3) and 7.25 (6H,m,C6H5 and NHCO).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([NH:23][C:24](=O)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH2:16]([N:23]1[C:11](=[O:13])[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:24]1[C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(OC)c1OC
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4)cc(OC)c1OC
Temperature: 0 °C
Yield: 68 %

Procedure:
Commercially available ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b)-thiophene-3-carboxylate (6.0 g, 26.6 mmol, 100 mol-%) and N-benzyl-3,4,5-trimethoxybenzamide (10.4 g, 34.6 mmol, 130 mol-%) were dissolved in dry 1,2-dichloroethane. The reaction mixture was cooled with an ice-salt-bath and POCl3 (1.7 ml, 24.6 mmol, 130 mol-%) was added. The reaction mixture was refluxed for 24 hours. During refluxing POCl3 (340 μl) was added twice. The reaction mixture was poured into ice-water and after neutralization with sodium acetate the product was extracted into dichloromethane. The organic phases combined were washed with sodium bicarbonate sat. (3×50 ml) and dried with MgSO4. The yield after recrystallization from i-propanol was 8.3 g (yield 68%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 69 %

Procedure:
A mixture of 9 g (0.020 mol) of 4-(4-chloro-3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained as described in A) in 72 g (0.060 mol) of pyridinium chlorochromate adsorbed on alumina, were suspended on 200 ml of CH2C12 then, the mixture was maintained with stirring at room temperature for 9 hours. The remaining solid was filtered, and the filtrate was washed with water (3×200 ml), dried with anh. Na2SO4, and the solvent evaporated under reduced pressure. The product was isolated as an oil, which was purified by column chromatography (Silicagel, n-hexane:EtAcO, 8:2) with a yield of 69%.