Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([CH2:35][CH2:36][C:37](O)=[O:38])(=[O:34])=[O:33])[CH:26]=[CH:25]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([CH2:35][CH2:36][C:37]([N:4]1[CH2:5][CH2:6][N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][CH:3]1[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[O:38])(=[O:33])=[O:34])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1

Procedure:
Di-tert-butyl piperazine-1,3-dicarboxylate (Wu, Guosheng, et al., Enantiomer 6, pp. 343-345, (2001): 4.1 g) was dissolved in dichloromethane (50 mL), and triethylamine (4.0 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (4.3 g), HOBt (2.4 g) and WSC (3.0 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (5.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8](Cl)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)[CH:7]=1.[BH4-].[Na+].[OH-].[Na+].Cl>O.C1(C)C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:7]=1)[CH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=1
Reactant: Fc1ccc(Br)cc1C(Cl)c1cc2ccccc2s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(Br)cc1Cc1cc2ccccc2s1
Temperature: 56 °C
Reaction time: 39 h
Yield: 75 %

Procedure:
A dioxane (1.1 liters) solution of 2-[(5-bromo-2-fluorophenyl)(chloro)methyl]-1-benzothiophene (551 g) was added to a dioxane (3.3 liters)-water (1.6 liters) solution of sodium borohydride (410 g) and sodium hydroxide (31 g) at 60 to 66° C., followed by stirring at 52 to 60° C. for 39 hours. To the reaction mixture was added toluene (5.5 liter), water (3.8 liters) and 36% hydrochloric acid (620 ml) to conduct extraction. The organic layer was subjected to distillation under reduced pressure to distil off the solvent. The residue was dried under reduced pressure. The obtained crystals were dissolved in 2-propanol (1 liter) and methanol (1 liter) with heating, followed by stirring at 0° C. for 20.5 hours. The separated-out crystals were collected by filtration, washed with methanol (500 ml), and dried under reduced pressure to obtain 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene [373 g, yield: 75.0%, purity: 99% (HPLC)] as white crystals. Incidentally, the 2-[(5-bromo-2-fluorophenyl)(chloro)methyl]-1-benzothiophene is the same as the compound (5) obtained in the second step of the production method of the present invention.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:29][CH2:30]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2nc(N3CCN(CCCCn4cnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl) piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.9 g compound (I-17) with a yield of 59.6%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([OH:13])[CH:6]=1.C[O:16][C:17](=O)[CH2:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.N1CCCCC1>C(#N)C.C1C=CC=CC=1>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:18]1[C:17](=[O:16])[O:13][C:7]2[C:8]([CH:9]=1)=[CH:11][CH:12]=[C:5]([N:4]([CH2:3][CH2:2][F:1])[CH3:14])[CH:6]=2
Reactant: CN(CCF)c1ccc(C=O)c(O)c1
Reactant: COC(=O)Cc1nc2ccccc2s1
Solvent: c1ccccc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CN(CCF)c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
130 mg (ca. 0.65 mmol) crude 4-[(2-Fluoro-ethyl)-methyl-amino]-2-hydroxy-benzaldehyde and 202 mg (1.5 eq.) benzothiazol-2-yl-acetic acid methyl ester are dissolved in 3 mL acetonitrile and 6 mL benzene, treated with 0.14 mL (2 eq.) piperidine and heated to reflux for 45 minutes. After cooling to room temperature, the crude product is extracted with AcOEt/isopropanol 9:1 and saline, dried over sodium sulfate and evaporated. The crude product is dissolved in 20 mL methanol, and slowly concentrated down to 10 mL at 50° C. The orange crystals are filtered and dried under high vacuum to yield 110 mg (48%) desired product.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[CH:18][S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][S:19]([NH:8][C:1](=[NH:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([O-:12])=[O:11]
Reactant: N=C(N)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
Reaction of benzamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)BENZAMIDINE m.p. 173°-175° C., by triturating with methanol.
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30]([F:34])([CH3:33])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:28][CH2:29][C:30]([F:34])([CH3:33])[CH2:31][CH2:32]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)(F)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(F)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
The 0.67 mL of benzo[d][1,3,2]dioxaborole (751 mg, 3.13 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (650 mg, 1.57 mmol) and 0.63 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (174 mg, 0.63 mmol) in toluene (15 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-fluoro-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 620 mg (95%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.88/5.86 (s, 1H), 4.95-4.93 (m, 1H), 3.85-3.81 (m, 1H), 3.56 (t, J=11.4 Hz, 1H), 3.23/3.03 (br. s, 1H), 2.76-2.74/2.65-2.62 (m, 1H), 2.53 (s, 3H), 2.39 (s, 3H), 1.91-1.71 (m, 4H), 1.39/1.35 (s, 3H), 1.14 (d, J=5.9 Hz, 3H), 1.07 (d, J=6.2 Hz, 3H). UPLC (M+H)=419.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[NH:4][C:5](=[O:20])[C:6](=[O:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].Br[CH2:27][CH:28]([OH:32])[CH2:29][CH2:30]Br>C(#N)C>[CH2:12]([N:7]1[CH:8]2[CH:3]([CH:2]([N:1]3[CH2:30][CH2:29][CH:28]([OH:32])[CH2:27]3)[CH2:11][CH2:10][CH2:9]2)[NH:4][C:5](=[O:20])[C:6]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC(CBr)CCBr
Reactant: NC1CCCC2C1NC(=O)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1NC2C(N3CCC(O)C3)CCCC2N(Cc2ccccc2)C1=O
Reaction time: 24 h

Procedure:
(4aRS,5SR,8aRS)-5-Amino-1-benzylperhydroquinoxaline-2,3-dione (144 mg, 0.53 mmol) was dissolved in acetonitrile (16 ml), and NaHCO3 (300 mg, 3.57 mmol) and racemic 1,4-dibromobutan-2-ol (purity 85%, 1.15 g, 4.20 mmol, 0.57 ml) were added. After 24 hours, NaHCO3 was separated off and the mixture was evaporated in vacuo. The solid was taken up in CH2Cl2 and the mixture was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography over silica gel 60 (40-63 μm, (Merck) Ø 2 cm, acetone/MeOH/Et2NH 9.5:0.5:0.1, l=17 cm, V=5 ml). A pale yellow solid was isolated.
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:5][O:6][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A solution of cyclobutanemethanol (4.0 g, 46.4 mmol) in dichloromethane (28 mL) at 25° C. was treated with 4-dimethylaminopyridine (6.23 g, 50.9 mmol). The reaction was then cooled to 0° C. and was treated with para-toluenesulfonylchloride (8.95 g, 46.94 mmol). The reaction was allowed to slowly warm to 25° C. and was allowed to stir overnight. After this time, the reaction was partitioned between water (200 mL) and methylene chloride (2×200 mL). The combined organics were washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution (1×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford toluene-4-sulfonic acid cyclobutylmethyl ester (10.87 g, 97%) as colorless oil which was used without further purification.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.C[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([CH3:32])[CH:24]=1>>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])=[C:25]([CH3:32])[CH:24]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Product: Cc1cc(O)ccc1-c1c(C=O)sc(-c2ccc(O)cc2)c1C
Yield: 57.5 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 4-methoxy-2-methylphenylboronic acid (0.55 g, 3.3 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.56 g, 90%, m.p. 244-47° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]=O.[CH:14](=[O:17])[CH2:15][CH3:16].[Cl-].[Na+]>O.C(O)(=O)C.CO>[CH3:16][C:15](=[CH:5][CH:4]([CH3:3])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=[O:17]
Reactant: CC(C=O)Cc1ccccc1
Reactant: CCC=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C=O)=CC(C)Cc1ccccc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
Into a 2 L Morton flask equipped with a mechanical air stirrer, temperature probe, Nitrogen inlet, autojack, and cooling bath was placed methanol (350 mL) and NaOH (31.25 g, 0.78 mol) dissolved in water (93.75 mL). 2-Methyl-3-phenyl-propanal (100 g, 0.68 mol) was added to the resulting mixture with stirring at 20° C. Over a period of 5 hours at an exponentially decreasing rate, propionaldehyde (48.82 mL, 39.25 g, 0.68 mol) was added to the mixture via a syringe pump while maintaining the reaction temperature at 14-20° C. The following propionaldehyde addition rate profile was used: 0.179 mL/min for two hours; 0.162 mL/min for one hour; and 0.147 mL/min for two hours. The reaction mixture was stirred for an additional 20 min at 14-20 ° C. Acetic acid (47 mL) was then added to the reaction mass followed by 100 mL of a saturated aqueous solution of sodium chloride. The mixture was extracted with two 100 mL portions of MTBE. The organic layers were combined and washed with two 100 mL portions of a saturated aqueous solution of sodium bicarbonate solution then with a saturated aqueous solution of.sodium chloride, dried (MgSO4), filtered, and roto-evaporated to give 2, 4-dimethyl-5-phenylpent-2-enal as a yellow liquid isomeric mixture (118.9 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)[CH:3]=1.N1C=CC=CC=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C=O)C>[Cl:33][CH2:34][C:35]([NH:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:10]=2)[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of Example 150b (0.262 g, 0.681 mmol) in DMF (6 mL) was added pyridine (0.11 mL, 1.36 mmol) and 2-chloroacetyl chloride (0.060 mL, 0.749 mmol). After 2 hours, the suspension was filtered. The filtrate was treated with water slowly. The precipitate formed was filtered, washed with water, and oven-dried to give 0.289 g of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH2:16]C)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)C1C=CC=CC=1.C([C@H](N)C1C=CC=CC=1)C>>[CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](NCc1ccccc1)c1ccccc1
Agent: CC[C@H](N)c1ccccc1
Solvent: O=Cc1ccccc1
Product: C[C@H](NCc1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
Prepared as described earlier for N-benzyl-(R)-α-ethylbenzylamine from benzaldehyde (3.94 mL, 38.8 mmol) and (S)-α-ethylbenzylamine (5.0 mL, 38.8 mmol, 96% ee.) to afford 7.88 g (96%) of N-benzyl-(S)-α-methylbenzylamine as an oil contaminated with ~ 5% of benzyl alcohol and (S)-a-methylbenzylamine: 1H NMR (DMSO-d6, 250 MHz) δ 7.15-7.45 (m, 10 H, Ar), 3.69 (q, 1 H, J=6.5 Hz), 3.48 (dd, 2 H, J1 =13.6 Hz, J2 =20.9 Hz), 2.45 (br s, 1 H, NH), 1.26 (d, 3 H, J=6.5 Hz, CH3); 13C NMR (DMSO-d6) δ 146.0, 141.0, 128.1, 128.0, 127.8, 126.4, 126.3, 56.7, 50.6, 24.5. This mixture was directly used in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2.[C:22]1([S:28]([N:31]=C=O)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-2-benzoyl-1,4-dihydroquinolin-4-one (0.57 g, 1.8 mmol) and benzenesulfonyl isocyanate (0.26 mL, 2.0 mmol) in acetonitrile (9 mL) and heat at reflux for 18 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a residue. Chromatograph the residue on a column of silica gel eluting with dichloromethane to obtain a solid. Recrystallize the solid from ethyl acetate/hexane to give the title compound; mp, 186°-187° C. Rf =0.37 TLC/silica gel/dichloromethane. Elem. Anal. Calcd. for C22H14Cl2 N2O3S: C, 57.77; H, 3.09; N, 6.13. Found: C, 57.76; H, 3.22; N, 5.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11](C)[C:10](=[O:13])[O:9][C:8](=O)[C:7]=2[CH:15]=1.COC1C(OC)=CC2[NH:28][C:27](=O)OC(=O)C=2C=1>>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[NH:11][C:10](=[O:13])[CH2:27][NH:28][C:8](=[O:9])[C:7]=2[CH:15]=1
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Product: COc1cc2c(cc1OC)C(=O)NCC(=O)N2
Yield: 54 %

Procedure:
By replacing 6,7-dimethoxy-1-methyl-11,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XVI) in example XVIIaa by 6,7-dimethoxy-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XV) and proceeding in the same manner, the abovenamed product is obtained. Yield: 54%. 1H-NMR (DMSO, 300 MHz): d 3.55 (d, J=5.3, 2H, CH2), 3.77 (s, 6H, 2×OCH3), 6.16 (s, 1H Ar), 6.67 (s, 1H Ar), 8.34 (t, J=5.3, 1H, NH), 10.07 (s, 1H, NH).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:10]2[C@@H:6]([CH2:7][N:8]([C:11](=[O:22])[CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]([CH3:15])[CH3:14])[CH2:9]2)[CH2:5][CH2:4]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:23]([NH:2][C@@H:3]1[C@@H:10]2[C@@H:6]([CH2:7][N:8]([C:11](=[O:22])[CH:12]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:13]([CH3:15])[CH3:14])[CH2:9]2)[CH2:5][CH2:4]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C(C(=O)N1C[C@H]2CC[C@H](N)[C@H]2C1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NCc3ccccc3)[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-((3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methyl-2-phenylbutan-1-one hydrochloric acid salt (49 mg, 0.152 mmol) and benzaldehyde (0.023 mL, 0.228 mmol) were combined in dichloromethane (1.5 mL). Acetic acid (1.5 mL) was added. The reaction was stirred at room temperature for 30 minutes, then PS-cyanoborohydride (64.9 mg, 0.152 mmol) was added. After 72 hours, 1 cms of the reaction showed no more starting material. The reaction mixture was filtered, and the solvent was removed under a stream of nitrogen. The crude material was purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.69-7.60 (m, 2H), 7.54-7.44 (m, 2H), 7.44-7.34 (m, 5H), 7.29 (tdd, J=4.8, 7.8, 13.0, 2H), 3.90-3.36 (m, 4H), 3.29 (dd, J=3.8, 10.6, 0.5H), 2.99 (dd, J=5.7, 11.4, 0.5H), 2.93 (dd, J=6.0, 11.3, 0.5H), 2.75-2.63 (m, 1H), 2.59-2.48 (m, 1H), 2.46-2.31 (m, 1H), 2.25 (dt, J=4.1, 8.7, 0.5H), 1.97 (dt, J=9.3, 11.6, 1H), 1.93-1.85 (m, 0.5H), 1.84-1.74 (m, 1H), 1.65-1.55 (m, 0.5H), 1.51-1.35 (m, 1H), 1.33-1.21 (m, 1H), 1.18-1.10 (m, 3H), 1.01 (td, J=7.7, 13.1, 0.5H), 0.87 (dt, J=6.6, 12.9, 0.5H), 0.75 (t, J=7.2, 3H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH2:6][CH3:7].[C:15](Cl)(=[O:18])[CH2:16][CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:14][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:13][C:8]=1[CH2:5][CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: CCCc1ccccc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCc1cc(C(=O)CC)ccc1O
Temperature: 70 °C
Reaction time: 48 h
Yield: 35 %

Procedure:
7.1 g (53 mmol) of aluminum chloride are placed in 70 ml of nitrobenzene in a round-bottomed flask and under a stream of nitrogen. The mixture is heated at 70° C. until dilution is complete. It is then cooled to 0° C. and 7.2 ml (52 mmol) of 2-propylphenol are added. The mixture is allowed to warm to room temperature and is then heated to 40° C. 4.6 ml (52 mmol) of propionyl chloride are then added dropwise. The reaction medium is heated at 40° C. for 2 hours and then stirred for 48 hours at room temperature. It is then poured into ice with 20 ml of concentrated hydrochloric acid. After extraction with ethyl ether, the organic phase is washed with 2N sodium hydroxide. The aqueous phases are acidified with hydrochloric acid and extracted with ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The black solid obtained is triturated in heptane, filtered off and dried. 3.5 g (35%) of the expected product are obtained in the form of a black powder.
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Tl+3].COC([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[NH:29][CH:28]=1)=O.[I-:37].[K+].ClCCl>C(O)(C(F)(F)F)=O.O.CO>[F:36][C:33]1[C:34]([I:37])=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2
Reactant: [I-]
Reactant: COC(=O)c1c[nH]c2ccc(F)cc12
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Agent: [Tl+3]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]ccc2c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A solution of thallium tris(trifluoroacetate) (8.45 g, 15.6 mmol) in TFA (35 mL) was added to a solution of 5-fluoro-1H-indole-3-carboxylic acid methyl ester (2 g, 10.4 mmol) in TFA (10 mL) at room temperature and stirred for 2 h. The reaction mixture was evaporated in vacuo and the resulting residue suspended in water (25 mL) before being treated with a solution of potassium iodide (5.2 g, 31.3 mmol) in water (50 mL). The reaction mixture was treated with dichloromethane (100 mL) and methanol (5 mL) and the resulting precipitate removed by filtration through celite. The organic layer was separated, washed successively with sodium thiosulfate solution and brine, then dried (MgSO4) and evaporated in vacuo. The resultant material was dissolved in methanol (60 mL) and treated with 40% aqueous NaOH solution (60 mL) then refluxed for 2 h. The reaction mixture was cooled to RT and extracted with DCM/MeOH (ratio 95:5). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide 5-fluoro-4-iodo-1H-indole as a pale brown solid (1.05 g, 39%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)(=[O:13])[C:10]([Cl:12])=[O:11]>>[C:10]([Cl:12])(=[O:11])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCc1ccccc1
Product: O=C(Cl)C(=O)OCc1ccccc1
Yield: 92.1 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step benzyl alcohol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce benzyl chlorooxalate having an assay of 96.6% and in a corrected yield of 92.1%. In the second step benzyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below: