Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[C:3]([C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([O:15][CH3:16])=[C:11]([S:13][CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C(C1C=C([N+]([O-])=O)C([O:31]C)=C(C=1)N)(C)(C)C>C(O)(C(F)(F)F)C(F)(F)F>[C:3]([C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([O:15][CH3:16])=[C:11]([S:13]([CH3:14])=[O:31])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: COc1c(SC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At ambient temperature 1.1 ml of a 35% aqueous hydrogen peroxide solution are added to a solution of 500 mg 5-tert-butyl-2-methoxy-1-methylsulphanyl-3-nitro-benzene (may be obtained starting from 5-tert-butyl-2-methoxy-3-nitro-aniline analogously to the method described in Syn. Commun. 1984, 14, 215-8 or in Syn. Commun. 2001, 31, 1857-62) in 15 ml of 1,1,1,3,3,3-hexafluoroisopropanol. The solution is stirred for 5 h at ambient temperature and then quenched with 10% aqueous Na2S2O3 solution. The resulting mixture is extracted with ethyl acetate, and the combined extracts are washed with saturated aqueous NaHCO3 solution and saturated aqueous saline solution. The organic phase is dried (Na2SO4) and the solvent is distilled off. The residue is chromatographed on silica gel with petroleum ether/ethyl acetate (20:1) as eluant.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A room temperature solution of 2.53 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (10 mL) is treated with 2.44 gms. 1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath. The reaction mixture is stirred in the ice bath for 30 minutes then it is allowed to warm to room temperature. Once at room temperature the reaction mixture is treated with 1.21 mL piperidine, and then is stirred overnight at room temperature. The reaction is then made basic with the addition of saturated aqueous sodium bicarbonate, and the resulting mixture is extracted with ethyl acetate. The organics are separated, dried over anhydrous sodium sulfate, filtered, and subsequently evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 50% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 2-(4-nitro-phenyl)-1-piperidin-1-yl-ethanone is isolated as a white solid in the amount of 3.18 gms.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[CH3:14]B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:14]
Reactant: CB(O)O
Reactant: N#Cc1cc(I)c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1O
Temperature: 130 °C
Yield: 41.1 %

Procedure:
To a solution of 4.0 g of 4-hydroxy-3-iodo-5-nitrobenzonitrile in 240 ml dimethylformamide was added 4.13 g of methyl boronic acid, and 8.99 g of cesium carbonate. The mixture was then degassed by bubbling argon gas through it for 30 min. Tris(dibenzylidineacetone)dipalladium (1.38 g) was added, and the mixture was then heated to 130° C. for 15 h. Analysis of the crude mixture via LC/MS showed complete formation of the desired product with ca. 14% reduction of the iodide. The mixture was cooled to room temperature, diluted with water (300 ml) and acetic acid (˜50 ml), and then extracted with ethyl acetate (5×300 ml). The organic layers were dark red-brown to light green-yellow in succession. The combined organic layers were extracted with water (2×300 ml) and then 2M sodium hydroxide (3×300 ml). The aqueous layers were red to yellow in succession. The combined aqueous layers (containing the phenol), were made slightly acidic by addition of 100 ml of acetic acid and then extracted with ethyl acetate (3×300 ml). These organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography (Rf=0.17 in 2/1 hexanes/ethyl acetate) on a Biotage Horizon, 65i column, eluting with 1 column volume of 5% ethyl acetate in hexanes, followed by a linear gradient from 5 to 80% of ethyl acetate in hexanes over 10 column volumes to provide 1.01 g (41%) of the title compound. The base-extracted organic layer was concentrated in vacuo and purified via flash chromatography on a Biotage Horizon in the same way to provide an additional 305 mg (12%) of the title compound. Mass spectrum (ESI) 177.0 (M−1). 1H NMR (500 MHz, CDCl3): δ 11.23 (s, 1H), 8.33 (s, 1H), 7.68 (s, 1H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH2:3][N:4]([CH3:14])[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.Cl[C:17](OC1C=CC=CC=1)=[O:18]>>[Cl:13][C:8]1[CH:7]=[C:6]([N:5]2[C:17](=[O:18])[NH:1][CH:2]([CH3:15])[CH2:3][N:4]2[CH3:14])[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(N)CN(C)Nc1cc(Cl)cc(Cl)c1
Product: CC1CN(C)N(c2cc(Cl)cc(Cl)c2)C(=O)N1

Procedure:
Reacting 1-(2-aminopropyl)-1-methyl-2-(3,5-dichlorophenyl)hydrazine with phenyl chloroformate under presence of base to provide the title compound. m.p. 129-130° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([C:25](=[O:36])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl.O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([OH:36])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(=O)C(=O)OCc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)NC1C(=O)N(C(O)C(=O)OCc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To a solution of benzyl [3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]glyoxylate (7.5 g.) and acetic acid (2.28 ml.) in tetrahydrofuran (30 ml.) was added portionwise sodium borohydride (480 mg.) over a period of half an hour at 0° C. After stirring for 10 minutes, the reaction mixture was diluted with methylene chloride (50 ml.), poured into a mixture of sodium bicarbonate (6.0 g.) in water (80 ml.) and a saturated aqueous solution of sodium chloride (20 ml.), and then extracted with methylene chloride (100 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then filtered through a pad of Celite. Removal of the solvent gave an amorphous solid (7.60 g.) of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].Cl>CS(C)=O.C(OCC)(=O)C>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1])#[N:21]
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(OC(F)(F)F)cc1I

Procedure:
To a suspension of 2-iodo-4-(trifluoromethoxy)phenol (Preparation 226, 600 mg, 1.97 mmol) and potassium carbonate (1125 mg, 8.14 mmol) in Dimethylsulfoxide (10 mL) was added 3-cyano-4-fluoro-N-[1,2,4]thiadiazol-5-yl-benzenesulfonamide (Preparation 65). The reaction was heated to 80° C. under N2 for 7 hours before the addition of ethyl acetate (20 mL) and 3M aqueous HCl solution (30 mL). The organic layer was collected, washed with brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was triturated in dichloromethane and filtered to afford 965 mg of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[NH:8][C:7](=[O:16])[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[NH:8][C:7](=[O:16])[CH:6]=1)[NH2:3]
Reactant: CC(C)Cn1c(Cl)cc(=O)[nH]c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
Hydrazine hydrate (5.9 ml) was added to a solution of 6-chloro-1-isobutylpyrimidine-2,4(1H,3H)-dione synthesized according to procedure described in Heterocycles, 1990, 31(9), 1641-1646, (5.9 g) in ethanol (100 ml). The mixture was heated at reflux for 16 hours, cooled to room temperature and then evaporated under reduced pressure. The residue was crystallized from ethanol to give the subtitle compound (5.8 g).
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cl
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
To a suspension of 50 ml of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.97 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. The resulting mixture became homogeneous after 5 minutes. There were added 2.00 g (7.09 mmol) of N-(4-bromobutyl)phthalimide and the mixture was refluxed for 58 hours. This was cooled to room temperature, then poured into 200 ml of saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated, was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 0.719 g of N-(4-chlorobutyl)-phthalimide and further development with chloroform resulted in 0.964 g (yield: 41%) of N-[4-(N-methoxy-N-methylamino)-butyl]phthalimide as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:26])[N:4]([CH2:24][CH3:25])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=1[CH2:21][CH2:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].C(SCCC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:26])[N:4]([CH2:24][CH3:25])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1cc(OC)ccc1OCCCNc1cnn(CC)c(=O)c1Cl
Agent: CCCSCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1cc(O)ccc1OCCCNc1cnn(CC)c(=O)c1Cl
Reaction time: 8 h

Procedure:
A solution obtained by dissolving 0.35 g of 4-chloro-5-[3-(2-n-propyl-4-methoxyphenoxy)propylamino]-2-ethyl-3(2H)pyridazinone (Compound No. 82) in 10 ml of methylene chloride, was dropwise added to a mixture comprising 0.36 g of aluminum chloride, 0.44 g of di-n-propylsulfide and 15 ml of methylene chloride, under stirring and cooling with ice. After the completion of the dropwise addition, the mixture was stirred at 0° C. for 2 hours, and then left to stand overnight in a refrigerator. Ice pieces were gradually added to the mixture to decompose excess aluminum chloride, and the mixture was extracted with chloroform. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off, and the residue thereby obtained, was crystallized from ethyl ether-n-hexane to obtain 0.26 g of the above identified compound as colorless crystals having a melting point of from 112° to 112.5° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[CH:8]=[C:9]([C:15]2[N:16]=[CH:17][N:18]([C:20]([N:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH3:23])=[O:21])[CH:19]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C.O>O1CCCC1>[CH:24]1([N:22]([CH3:23])[C:20]([N:18]2[CH:19]=[C:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([NH:6][S:1]([CH3:4])(=[O:3])=[O:2])[CH:8]=3)[N:16]=[CH:17]2)=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 33.7 %

Procedure:
Mesyl chloride (0.247 mL, 3.17 mmol) was added to a stirred solution of 4-(3-amino-4-methoxyphenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (1.04 g, 3.17 mmol) and triethylamine (0.441 mL, 3.17 mmol) in tetrahydrofuran (6 mL) at room temperature. The brown mixture was allowed to stir at room temperature over the weekend. Water was added and the solvent was evaporated. Then the aqueous layer was acidified and the residue was extracted with ethyl acetate. The aqueous layer was extracted twice with a mixture of dichloromethane/isopropanol (7:3). The organic layer was separated, dried (MgSO4) filtered and evaporated to give an off-white solid. The solid was recrystallised from an ethanol/dichloromethane mixture to give the product as an off-white solid (434 mg, 34%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]1[CH2:13][O:12][S:9](=[O:11])(=[O:10])[CH2:8][CH2:7]1>O1CCCC1>[C:1]([NH:5][CH2:13][CH2:6][CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S1(=O)CCCCO1
Solvent: C1CCOC1
Product: CC(C)(C)NCCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-butylamine (1.0 mL, 9.5 mmol) in tetrahydrofuran (4 mL) was added 1,4-butane sultone (1.36 g, 10.0 mmol) at room temperature. The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×20 mL), and dried in vacuo; affording compound ER 690 mg, (34%); 1H NMR (D2O, 500 MHz) 8 ppm 2.92 (t, 2H, J=7.1 Hz), 2.82 (t, 2H, J=7.1 Hz), 1.68 (m, 4H), 1.22 (s, 9H). 13C NMR (D2O, 125 MHz) 8 ppm 57.07, 50.30, 40.95, 25.28, 24.96, 21.62. ES-MS 210 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20].I[CH2:22][CH:23]([CH3:25])[CH3:24].NC1N=C(OC)C(C(=O)CCC2CCNCC2)=CC=1.ICCCC>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Reactant: CC(C)CI
Agent: COc1nc(N)ccc1C(=O)CCC1CCNCC1
Solvent: CCCCI
Product: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(CC(C)C)CC1

Procedure:
The title compound was prepared according to the procedure of step 2 in the example 13 using 1-(6-amino-5-chloro-2-methoxy-3-pyridinyl)-3-(4-piperidinyl)-1-propanone and 1-iodo-2-methylpropane, instead of 1-(6-amino-2-methoxy-3-pyridinyl)-3-(4-piperidinyl)-1-propanone and 1-iodobutane.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:27])[C:18]2[S:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Cl>O>[CH3:27][N:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)[C:18]1[S:19][C:20]([C:23]([F:26])([F:24])[F:25])=[N:21][N:22]=1
Reactant: CN(c1nnc(C(F)(F)F)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: O
Product: CN(c1nnc(C(F)(F)F)s1)C1CCNCC1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A solution of 4-[M ethyl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amino]-piperidine-1-carboxylic acid benzyl ester (D1) (0.91 g, 2.27 mmol) in a solution 6 N of hydrochloric acid (15 ml) was stirred at 150° C. for 10 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane (25 ml). The aqueous layer was basified with a saturated solution of sodium carbonate and extracted with dichloromethane (3×25 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo to yield D2 (0.56 g, 93%) as a solid. C9H13F3N4S requires 266. Found 266 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:15])[C:3]1=[O:16].[ClH:17]>CN(C)C=O>[ClH:17].[NH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:16])[C:4](=[O:15])[NH:5]2
Reactant: Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(=O)[nH]c2cc(N)ccc21
Yield: 98 %

Procedure:
A solution of 0.5 g (2.3 mmol) 1-methyl-6-nitroquinoxaline-2,3(1H,4H)-dione in 25 ml dimethylformamide was hydrogenated at atm. pressure by using 5% Pd-c (0.1 g) as a catalyst. The reaction mixture was added 1 ml 4N hydrochloric acid, filtered and evaporated in vacuo. The residue was stirred with ethyl acetate. The precipitate was filtered off to give 0.5 g (98%) of 6-amino-1-methyl-quinoxaline-2,3(1H,4H)-dione hydrochloride. NMR (DMSO-d6 +D2O): 7.3 (1H, d), 7.13 (1H, s), 7.1 (1H, d), 3.5 (3H, s), 2.6 (3H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]([N:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O.[NH3:28].CO>C1COCC1>[CH3:7][N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]([N:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[NH:28]
Reactant: CC(C)CN(C)C(=O)N(C1CCCCC1)C1CCCCC1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CN(C)C(=N)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (3.6 mL, 18 mmol) and triethylamine (5.6 mL, 40 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.98 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of N-methylisobutylamine (2.2 mL, 18 mmol) and triethylamine (5.5 mL, 40 mmol) in THF (35 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding N-methyl-N-isobutyl-N′,N′-dicyclohexylurea as a dark yellow oil. Yield: 4.8 g (90%). Oxalyl chloride (8 mL, 16 mmol, 2 M solution in dichloromethane) was added to a stirred solution of the urea (4.8 g, 16 mmol) in THF (65 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. Ammonia in methanol (7 mL, 49 mmol, 7 M solution in methanol) was added to a suspension of the formed solid in THF. The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and purified by treatment with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Evaporation to dryness yielded the desired guanidine as a brown oil. Yield: 2.95 g (75%). 1H NMR (CDCl3, 300 MHz): δ 0.80 (d, 6 H), 1.20 (d, 12 H), 1.8 (sept, 1 H), 2.7 (s, 3 H), 2.83 (d, 2 H), 3.52 (sept, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 19.1, 20.7, 25.6, 36.8, 46.4, 57.2, 164.7 ppm.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(F)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccccc1-c1nc2c(F)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 83.5 %

Procedure:
(S)-2-(1-(2-Chloro-8-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (14.0 g, 39.5 mmol), 2-(methylthio)phenylboronic acid (9.95 g, 59.2 mmol), and potassium carbonate (16.4 g, 118 mmol) were combined in 300 mL of anhydrous DMF under an atmosphere of N2. The solution was sparged with N2 for ˜5 min before adding PdCl2(dppf)CH2Cl2 (3.22 g, 3.95 mmol). The solution was heated at 100° C. for 3 h, and then cooled to 50° C. The solution was concentrated under vacuum to give a brownish residue, which was diluted with EtOAc (600 mL). The organic layers were then washed with H2O (3×80 mL), followed by brine (1×100 mL). The combined aq. layers were extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified by silica gel flash chromatography eluting with a gradient of 20% hexane to 40% EtOAc/hexane. The fractions containing the pure product were combined and concentrated under vacuum to give 2-((1S)-1-(8-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (14.6 g, 33.0 mmol, 84% yield) as a light yellow foam. The proton NMR reflects a 53/47 ratio of atropisomers at 25° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (br s, 0.53H), 8.65 (br s, 0.47H), 7.79 (m, 1H), 7.66 (s, 4H), 7.55 (m, 1H), 7.45-7.27 (series of m, 3.6H), 6.87 (m, 1.4H), 5.70 (q J=6.4 Hz, 0.47H), 5.63 (q, J=6.8 Hz, 0.53H), 2.47 (br s, 1.4H), 1.91 (m, 3H), 1.52 (br s, 1.6H). Mass Spectrum (ESI) m/e=443.2 (M+1).
Reaction SMILES: S(C)C.[Cl:4][C:5]1[CH:6]=[C:7]([C:11](=[O:23])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[CH:9][CH:10]=1.CO>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([OH:23])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH:8]=[CH:9][CH:10]=1
Reactant: CN(CCC(=O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CN(CCC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution R—CBS (20.2 mL, 20.2 mmol) and BH3.Me2S (30.3 mL, 303 mmol) in THF (250 mL) was added a solution of tert-butyl 3-(3-chlorophenyl)-3-oxopropyl(methyl)carbamate (60 g, 0.202 mol) in THF (300 mL) at −15° C. After addition, the mixture was stirred at room temperature for 1 hour. Methanol was added drop wise carefully at −15° C. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with AcOEt/petroleum ether (1:15→1:8) to provide the light yellow oil. 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.70 (m, 1H), 1.94 (m, 1H), 2.87 (s, 3H), 3.01 (m, 1H), 3.96 (m, 1H), 4.52 (m, 1H), 7.26 (m, 4H).