Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[H-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6]2=[O:13]
Reactant: Cc1cc(C)c2c(c1O)C(=O)CC2
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-inden-1-one was dissolved in 200 ml of dimethylformamide, then 5.45 g of 60%-sodium hydride was added gradually thereto and the reaction mixture was stirred at room temperature for 30 minutes. Next, 6.91 ml of p-anisaldehyde was added to the reaction mixture and further stirred at room temperature for 1 hour. The reaction mixture was poured into 500 ml of ice-water, then acidified by adding hydrochloric acid, and the crystals formed were collected by filtration. The crystals were washed with water and with n-hexane and dried. Recrystallized from ethanol to obtain 16.09 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one. Yellow needle-like crystals. Melting point: 192°-193° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([N:10]1[CH2:16][C:15](=O)[C:14]2[CH:18]=[CH:19][S:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][S:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCc2sccc2C(=O)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccsc2CC1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
AlCl3 (3.95 g, 29.7 mmol) was added to 50 mL DCM at 0° C. Borane-t-butyl amine complex (5.2 g, 59.5 mmol) was added followed by the product of step (c) (2.37 g, 9.9 mmol) dissolved in DCM (50 mL). The reaction was stirred for 2 hours at room temperature after which time another 3.95 g (29.7 mmol) of AlCl3 was added. After stirring for 10 minutes, the reaction was quenched carefully with 0.1 M HCl (˜50 mL). After concentration of the organic solvent, the crude reaction mixture was partitioned between 1M HCl and EtOAc (70 mL each). The aqueous layer was back extracted 1× EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The sub-title product (1.45 g) was obtained after purification by silica gel chromatography (0 to 35% EtOAc in Hexanes). MS: ESI (positive): 226 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:20]=O>C(O)(=O)C.S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)OC
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of methyl 3-(4-chlorophenyl)-2-(ethoxycarbonylamino)propanoate (3.55 g, 12.4 mmol) in acetic acid (12 mL) and sulfuric acid (4 mL) was treated with paraformaldehyde (0.392 g, 13.0 mmol). After stirring at room temperature overnight, the mixture was added to ice (50-60 g), diluted with water (30 mL) and extracted with ethyl acetate (3×˜50 mL). The combined organic phase was washed with saturated aqueous sodium chloride (25 mL), dried over MgSO4 and concentrated. Purification by silica gel chromatography (90 g column, 25-50% ethyl acetate in hexanes) gave 2-ethyl 3-methyl 7-chloro-3,4-dihydroisoquinoline-2,3(1 H)-dicarboxylate (2.19 g, 59%) as a clear, viscous oil. 1H NMR (CDCl3, 400 MHz) δ 7.12 (m, 3 H), 5.20 (m, ˜0.6 H), 4.98 (m, ˜0.4 H), 4.76 (m, 1 H), 4.53 (m, 1 H), 4.25 (m, 2 H), 3.65 (s, 3 H), 3.20 (m, 2 H), 1.35 (t, J=7 Hz, ˜1.8 H), 1.28 (t, J=7 Hz, ˜1.2 H) (mixture of rotamers). ESI+ MS found for C14H16ClNO4 m/z 298.0 (M+H, weak).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][C:14](=[O:16])[CH3:15])=[CH:6][C:5]=1[O:17][CH3:18].[CH3:20]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]([C:14](=[O:16])[CH3:15])[CH3:20])=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COS(C)(=O)=O
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetylamino-2-methoxy-5-nitro-benzoic acid methyl ester (4.0 g, 14.9 mmol), methanesulfonic acid methyl ester (1.3 mL, 15.4 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 40 mL DMF was stirred overnight at ambient temperature. The mixture was poured onto ice water and diluted with dichloromethane. The organic phase was separated, dried and concentrated i.vac.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:21]([OH:23])[CH3:22].[OH-].[Na+]>O1CCOCC1.C(OC(=O)C)(=O)C>[C:21]([NH:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:23])[CH3:22]
Reactant: COc1cccc(CC(N)CCC(=O)OC(C)(C)C)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(CC(CCC(=O)OC(C)(C)C)NC(C)=O)c1
Reaction time: 1.33 h

Procedure:
To a solution of tert-butyl 4-amino-5-(3-methoxyphenyl)valerate (0.22 g) in 1,4-dioxane (0.2 ml), acetic anhydride (0.08 ml) was added and the solution was stirred for 80 minutes. To the solution, ethanol was added and the solution was stirred for 15 minutes. The pH of the solution was adjusted to 12 with sodium hydroxide solution and the solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give tert-butyl 4-acetylamino-5-(3-methoxyphenyl)valerate (246 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=1.CC([O-])(C)C.[K+].O>C1COCC1>[Cl:7][C:8]1[N:9]=[C:10]([CH3:15])[N:11]=[C:12]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:13]=1
Reactant: Nc1nccs1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)cc(Nc2nccs2)n1
Temperature: 0 °C
Yield: 51.5 %

Procedure:
To a cool (0° C.), stirring suspension of 2-aminothiazole (3.05 g, 0.0305 mol), 4,6-dichloro-2-methylpyrimidine (5.84 g, 0.0358 mol) in THF (50 mL) was added dropwise over 10 minutes via addition funnel a solution of t-BuOK (40 mL, 30% wt in THF, 0.1069 mol). The reaction was allowed to slowly warm to room temperature overnight. To the reaction was added water (40 mL) and the resulting clear solution was extracted with chloroform and then chloroform/methanol (4:1). The combined extracts were concentrated to near dryness to give a precipitate. The solid was collected by filtration to give the title material (3.559 g) as a solid. The filtrate was concentrated to dryness and the resulting solid was dissolved in boiling methanol and allowed to precipitate overnight aided with the addition of some water. The solid was collected by filtration, washed with water and air dried to give the title material (1.451 g) as a solid. The aqueous layer from the extraction was acidified with 10% HCl and a precipitate was formed. The solid was collected by filtration, washed with water to give the title material (1.559 g) as a solid. The solids were combined to give the title material (6.569 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.53 (3H, s), 6.90 (1H, s), 7.21 (1H, d, J=3.5 Hz), 7.46 (1H, d, J=3.5 Hz), 11.87 (1H, s). LC/MS (M+H)+: 227, 229. HPLC ret. time (Condition E): 1.427 min.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:40]1[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (800 mg), thiomorpholine (290 mg) and tetrahydrofuran (30 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (450 mg) was added at room temperature, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3:2-1:4, volume ratio) to give the title compound (590 mg, yield 64%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 160-161° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([N:35]1[CH2:43][CH2:42][CH:38]([C:39]([OH:41])=O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCN(C(C)C)C(C)C.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([CH:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[CH:57][C:56]=1[C:67]1[N:68]=[C:69]([NH2:72])[S:70][CH:71]=1>C(#N)C>[CH:61]1([C:58]2[CH:59]=[CH:60][C:55]([O:54][CH3:53])=[C:56]([C:67]3[N:68]=[C:69]([NH:72][C:39]([CH:38]4[CH2:37][CH2:36][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:43][CH2:42]4)=[O:41])[S:70][CH:71]=3)[CH:57]=2)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
1.68 g of BOP, 0.75 g of Boc-isonipecotic acid and then 1.41 mL of DIPEA are added, at a temperature of 0° C., to a solution of 1 g of 4-(2-methoxy-5-cyclohexylphenyl)-1,3-thiazol-2-amine, obtained in preparation I.3, in 6 mL of acetonitrile. The medium is stirred at room temperature for 24 hours and then filtered. The solid thus obtained is rinsed with acetonitrile and then dried. 1.13 g of a white solid are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=S)[CH:23]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:29]([NH:28][C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add m-tolyl isothiocyanate (69 uL, 0.512 mmol) and stir for 3.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and recrystallize from toluene/EtOAc. Suspend the solid in 1 N NaOH. Collect the solid wash with water and Et2O to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) ppm 2.38 (s, 3 H) 6.90 (d, J=7.58 Hz, 1 H) 7.26 (t, J=7.77 Hz, 1 H) 7.37 (d, J=1.77 Hz, 1 H) 7.43 (s, 1 H) 7.56-7.65 (m, 3 H) 7.82 (d, J=8.59 Hz, 1 H) 8.01 (dd, J=8.53, 1.33 Hz, 1 H) 8.27 (s, 1H); MS m/z=436.1 (M+1).
Reaction SMILES: O([C:8]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][N+:10]([O-:12])=[O:11])C1C=CC=CC=1.[NH2:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[N:26]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[S:28][CH:29]=1>O1CCCC1.C(O)(C)C>[CH3:33][N:31]([CH2:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][S:23][CH2:22][CH2:21][NH:20][C:8]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N+:10]([O-:12])=[O:11])[N:26]=1)[CH3:32]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.07 g (27.5 mmol) of 1,1-diphenoxy-2-nitroethene in 70 ml of tetrahydrofuran was stirred at 25° C. To this solution was added a mixture of 6.83 g (27.5 mmol) of 93% pure 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine in 100 ml of isopropyl alcohol. The reaction mixture was stirred for approximately one hour at 25° C. and the progress of the reaction was followed by thin-layer chromatography to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine. The product was not isolated but rather used directly in the following reaction.
Reaction SMILES: [OH-].[K+].[C:3]1([C:13]2[CH:18]=[CH:17][C:16](S([O-])(=O)=O)=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6](S([O-])(=O)=O)=[CH:5][CH:4]=1.[K+].[K+]>O>[CH:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=S(=O)([O-])c1ccc(-c2ccc(S(=O)(=O)[O-])cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Yield: 95.7 %

Procedure:
A 50% aqueous solution of potassium hydroxide and dipotassium 4,4'-biphenyldisulfonate were sent to a mixing tank 1 at a rate of 896 kg/hr and 390 kg/hr, respectively, and mixed with stirring. A hydrogenated triphenyl mixture was added to the resulting mixture in a dispersing tank 2 at a rate of 2900 kg/hr to disperse them. The dispersed mixture was dehydrated in a dehydrating tank 3, and then sent to a reservoir. From the reservoir 4, the dehydrated mixture of dipotassium 4,4'-biphenyldisulfonate, potassium hydroxide and hydrogenated triphenyl mixture was sent to a reaction tank 5 at a rate of 4190 kg/hr, and continuously reacted at 310° C. with a residence time of 6 hours in a nitrogen stream. After the reaction, the mixture was cooled by a heat exchanger 6, and sent to a water mixing tank 7 where it was mixed with 2000 liters/hr of water. Then, in a separating tank 8, the reaction medium layer was separated, and the aqueous layer was mixed with 45 kg/hr of activated tank in a mixing tank 9. The activated carbon was removed in a filtration device 10, and the residue was precipitated with dilute sulfuric acid in an acid precipitating tank 11. By separation in a centrifugal separator 12, 178 kg (yield 95.7%) of 4,4'-biphenyl was obtained hourly.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.Br[C:16]1[C:17]([N:19]([CH3:34])[C:20](=[O:33])[C:21]=1[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=2)[N:24]([CH3:32])[CH:23]=1)=[O:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH3:32][N:24]1[C:25]2[C:30](=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:22]([C:21]2[C:20]([N:19]([CH3:34])[C:17](=[O:18])[C:16]=2[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:33])=[CH:23]1
Reactant: Cc1ccc2c(c1)c(C1=C(Br)C(=O)N(C)C1=O)cn2C
Reactant: Cc1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]cc(C3=C(c4cn(C)c5ccc(C)cc45)C(=O)N(C)C3=O)c2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
To a solution of 5-methylindole (77 mg, 0.66 mmol) dissolved in toluene (1 mL) was added 0.95M ethylmagnesium bromide (0.7 mL, 0.66 mmol) at 40° C., and the whole was stirred at 40° C. for 45 minutes. Successively, a solution of 2-bromo-3-(1,5-dimethyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.3 mmol) dissolved in toluene (5 mL) was added thereto, followed by stirring under heating and refluxing for 3 hours. After 20% aqueous citric acid solution (1 mL) was added thereto under ice cooling and the whole was stirred, toluene was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:2) to obtain 2-(1,5-dimethyl-1H-indol-3-yl)-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 86.9%) as red solids.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH:16]2C)[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:32]O>[Pd]>[CH:23]1([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C@@H:12]3[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH2:20][CH2:19]2)[CH2:22][CH2:32]1
Reactant: CO
Reactant: CC1CN(C2CC2)CCN1[C@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd]
Product: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
8.5 g (20 mmol) cis-dibenzyl-[4-(4-cyclopropyl methyl-piperazin-1-yl)-cyclohexyl]-amine are dissolved in 170 ml of methanol and hydrogenated on 1.7 g Pd/C (10%) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and conc. HCl. Yield: 4.4 g
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.CS([Cl:27])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][Cl:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(OCC(F)(F)F)c(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)COc1ccc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of the title compound from Step 2 (300 mg, 1.05 mmol) in DCM (10 mL) was cooled to 0° C. and treated with triethylamine (91 mg, 1.15 mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The reaction mixture was warmed to room temperature and stirred overnight. It was then diluted with DCM (10 mL) and washed with 1 M hydrochloric acid (10 mL) and sat. NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford the title compound (260 mg, 82%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J=2.0 Hz, 1H), 7.32 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.53 (s, 2H), 4.42 (q, J=8.0 Hz, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([O:26]C)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(NC(=O)c2cc(NC(=O)OC(C)(C)C)cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)Nc1cn(C)c(C(=O)O)n1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Methyl 4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxylate (2.0 g, 5.30 mmol) in 50 ml of DMA was added 2 g of LiOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 with vacuum to afford 1.44 g (75%) of the title product. 1H NMR (DMSO) 10.41 (br, 1H), 9.07 (s, 1H), 7.48 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 3.92 (s, 1H), 3.81 (s, 1H), 1.47 (s, 9H); 13C NMR 160.46, 158.42, 152.85, 145.21, 135.81, 129.11, 127.77, 122.39, 121.57, 113.58, 79.81, 36.06, 35.25, 28.17; MS m/z−362.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][CH2:13][OH:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:14][CH2:13][CH3:12])=[O:5]
Reactant: CCO
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
2,6-Difluorobenzoyl chloride was diluted with CH2Cl2 (5 ml) and cooled to 0° C. A mixture of EtOH (1.2 ml, 20 mmol) and pyridine (1.6 ml, 20 mmol) was added, dropwise, over 5 minutes to the reaction mixture. The ice bath was removed after 5 minutes and the reaction mixture strirred at 25° C. for 45 min. The solvent and volatiles were evaporated under reduced pressure and the residue was partitioned between 1N HCl and EtOAc (10 ml each). The aqueous phase was separated and extracted with 2×7 ml EtOAc. The combined organic extracts was washed with NaHCO3 (10 ml), brine (7 ml), dried over MgSO4 and concentrated to give 1.562 g ethyl 2,6-difluorobenzoate as an almost colorless oil. (84% yield from steps B and C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([N:8]([CH2:18][C:19](=O)[CH3:20])[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:7])[CH3:6].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([N:8]1[CH2:18][C:19]([CH3:20])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]1=[O:17])([CH3:7])[CH3:6]
Reactant: CC(=O)CN(C(=O)Cc1ccccc1)C(C)(C)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cccc(Cl)c2)C1
Yield: 65.1 %

Procedure:
34.4 g (0.1 mol) of N-(3-chloro-α,α-dimethylbenzyl)-N-(2-oxopropyl)phenylacetamide prepared in accordance with the method of Reference Example 6, was dissolved in 200 ml of ethanol, and 0.5 (0.009 mol) of sodium hydroxide powder was added thereto. The mixture was refluxed under heating for 10 minutes. Then, the solvent was distilled off under reduced pressure, and then water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 21.2 g (yield: 65.2%) of the desired compound.