Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Cl)[CH:15]([CH3:17])[CH3:16]>C1COCC1>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:4][N:3]=1
Reactant: CON(C)C(=O)c1ccc(O)nc1
Reactant: CC(C)C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(O)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Dissolve 6-hydroxy-N-methoxy-N-methyl-nicotinamide (1.89 g, 10.4 mmol) in anhydrous THF (40 mL), then cool the solution to 0° C. Add isobutyl magnesium chloride (16 mL, 32 mmol, 2M solution in diethyl ether) under nitrogen, allow the mixture to warm gradually to room temperature and then stir for 16 h. Quench the reaction with 1M aqueous HCl and concentrate the mixture in vacuo. Extract the aqueous mixture with EtOAc (4×50 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain a yellow solid. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (23:2) to obtain the desired intermediate as a white solid (1.28 g, 69%). MS (ES+) m/z: 180.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[C-:20]#[N:21].[Na+].O>CS(C)=O>[C:1]1([C:7]2([CH2:12][C:20]#[N:21])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccccc2)CCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (24-01) (6 g, 23.59 mmol) in dimethyl sulfoxide (18 mL) were added potassium iodide (392 mg, 2.59 mmol) and sodium cyanide (1.734 g, 35.384 mmol). The mixture was stirred for 140° C. for 16 h. After completion of the reaction, water was added and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, dried and evaporated to get a crude product which was purified using a normal silica column using 15% ethyl acetate in hexane to afford (1-phenyl-cyclopentyl)-acetonitrile (25-01) (2.25 g, 51.4%) as a yellow liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[N:19]1([CH2:25][CH2:26][C@@H:27]([NH2:36])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][C@@H:27]([NH:36][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: N[C@H](CCN1CCOCC1)CSc1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine and a sixth base to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:20])=[C:4]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.0 g, 30 mmol) in CHCl3 (80 mL) at 0° C. was treated with m-CPBA (12 g, 53 mmol) in portions. The reaction was stirred at about room temperature overnight. The reaction was cooled to 0° C. and to this was added Na2SO3 (25 g, 200 mmol) in water (100 mL) (slurry), followed by dropwise addition of Na2CO3 (14 g, 130 mmol) in water (100 mL). The mixture was stirred for about 30 minutes. The aqueous phase was extracted with CHCl3. The organic phase was dried with MgSO4 and concentrated under reduced pressure at low temperature (<25° C.) to afford the crude (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (5.5 g, 100%) which was not purified further. 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[NH2:11]C(N)=O>C1(C)C=C(C)C=C(C)C=1.P(O)(O)O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC(N)=O
Agent: OP(O)O
Solvent: Cc1cc(C)cc(C)c1
Product: NC(=O)c1ccc(F)cc1
Temperature: 154 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
70.0 g (0.5 mol) of 4-fluorobenzoic acid, 30.0 g (0.50 mol) of urea and 0.5 g of phosphorous acid are heated in 100 ml of mesitylene with stirring at from 150 to 158° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and is washed with 50 ml of mesitylene. The filter cake is introduced into 250 ml of water, and the mixture is adjusted to a pH of 12 with aqueous sodium hydroxide solution and subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 50.7 g of 4-fluorobenzamide are obtained having a melting point of from 147° to 150° C. This corresponds to a yield of 72.9% of theory. By acidification of the aqueous mother liquor to a pH of 2, 5.9 g of 4-fluorobenzoic acid (8.4% of theory) are obtained, which can be employed again in a subsequent batch.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[CH2:13]O)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]2[CH2:13][Cl:17])[CH2:3][CH2:2]1
Reactant: OCC1c2ccccc2CN1C1CC1
Reactant: O=S(Cl)Cl
Product: ClCC1c2ccccc2CN1C1CC1

Procedure:
2-Cyclopropyl-1-hydroxymethylisoindoline (3.8 g) was stirred with thionyl chloride (35 ml) for 3 hr. Thionyl chloride was evaporated to give crude 2-cyclopropyl-1-chloromethylisoindoline (as an oil) which was dissolved in chloroform (50 ml) and treated with diethylamine (15 ml). The reaction mixture was left for 12 hr, evaporated to dryness and the residue was partitioned between aqueous sodium hydroxide and ether. The ether layer was washed (water), evaporated to dryness in vacuo, and the residue was redissolved in ether and extracted with aqueous hydrochloric acid. The acidic extract was evaporated to dryness and the residue was recrystallised from iso-propanol/ethyl acetate to give 2-cyclopropyl-1-diethylaminomethylisoindoline dihydrochloride, (0.35 g, m.p. 150°).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].CS(O[CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)(=O)=O>>[NH2:24][CH2:23][CH2:22][N:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:8]=2)[C:6]#[N:7])=[N:16]1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: N#Cc1cc(-c2ccn[nH]2)ccc1[N+](=O)[O-]
Product: N#Cc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitro-5-(1H-pyrazol-5-yl)benzonitrile (1.00 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.45 g) using the method of Example 37(c). Yield 0.32 g (as HCl-salt). 1H-NMR (400 MHz; d6-DMSO): δ 3.34 (t, 2H), 4.50 (t, 2H), 7.15 (d, 1H), 7.99 (d, 1H), 8.21 (br s, 2H), 8.39 (dd, 1H), 8.45 (d, 1H), 8.61 (d, 1H).
Reaction SMILES: C[Mg]Br.[CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:5].O.[C:16](OCC)(=O)C>O1CCCC1>[OH:5][CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH3:16]
Reactant: CCOC(C)=O
Reactant: NC(=O)c1cccc(C=O)n1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cccc(C(N)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (546 ml) was added dropwise to a solution of 6-formyl-2-pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0°-13° C. with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:5]([C:7]1C=CC=CC=1)=[O:6].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=1)(=[O:6])[CH3:7]
Reactant: Nc1cc(C(=O)c2ccccc2)cc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Amino-5-nitrobenzophenone (4 g; synthesized by the process reported by Berend et al., J. Prakt. Chem., vol. 69, p. 471 (1904)) was dissolved in pyridine (40 mL), and the temperature was maintained at 50° C. Methanesulfonyl chloride (1.9 mL) was added, followed by stirring for 2 hours. Additional methanesulfonyl chloride (1.7 mL) was added, followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled down to room temperature and then poured into water (200 mL). The deposited precipitate was collected by filtration and dried under reduced pressure to yield N-(3-acetyl-5-nitrophenyl)methanesulfonamide (5.4 g) as a crude product. The whole quantity of the crude product was dissolved in ethanol (40 mL), and zinc dust (20 g) was added. After further adding concentrated hydrochloric acid (2 mL), the mixture was heated to reflux for 4 hours. The reaction mixture was filtered. To the filtrate, ethyl acetate (100 mL) was added. The resulting mixture was washed with water (100 mL) three times and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (95:5 chloroform/methanol) to yield N-(3-acetyl-5-aminophenyl)methanesulfonamide (3.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)c(C)c1
Yield: 84 %

Procedure:
A solution of 4-hydroxy-3-methylbenzoic acid (5.13 g, 33.7 mmol) and aqueous 12 N HCl solution (1.0 mL) in MeOH (100 mL) was heated to reflux for 16 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was taken in EtOAc. The resulting solution was washed with aqueous saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated with Hexane:EtOAc (9:1) to give the title compound (4.70 g, 84% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][C@H:22]5[C@H:28]([F:29])[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl-].[CH3:38][Zn+].[NH4+].[Cl-].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C@H:28]1[C@H:22]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:6]4[CH:7]=[C:2]([CH3:38])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]1
Reactant: C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(Br)cn45)nc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nnc(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OC(C)(C)C)CC[C@H]5F)c4n3)n2c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (trans)-tert-butyl 4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (0.125 g, 0.225 mmol) and Pd(PPh3)4 (0.0519 g, 0.0449 mmol) in 1.9 mL THF was added 2M methyl zinc chloride in THF (0.225 mL, 0.449 mmol) by syringe, and the reaction mixture was heated in an 80° C. reaction block. After 6 hours, the reaction mixture was cooled to ambient temperature and saturated NH4Cl and water were added, causing a precipitate to form. The solids were isolated by vacuum filtration through qualitative filter paper, rinsed with water, air dried, and dried in vacuo. The crude was purified on silica gel (1-8% MeOH in DCM gradient) to give the racemic (trans)-product. The resulting mixture was separated by chiral HPLC using a Chiracell OJ-H column, 9.5% EtOH in hexanes, flow rate 16 mL/min to give Peak 1 trans-product (0.018 g, 16%, 99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92% ee) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 47.8 %

Procedure:
In a manner similar to that described in Example 3, 4-chloro-3-nitro-benzoyl chloride (0.073 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.045 g of 4-[4-(4-chloro-3-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+377.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH3:17]>>[CH:9]([C:17]1[CH:16]=[CH:3][CH:2]=[CH:1][C:6]=1[N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:15])[CH3:10]
Reactant: CCO
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Product: CC(C)c1ccccc1-n1c(-c2ccccc2)nc2ccccc21
Temperature: 25 °C

Procedure:
Intermediate 1 (1.5 g, 2.1 mmol) and 142-isopropylphenyl)-2-phenyl-1H-benzo[d]imidazole (2 g, 6.4 mmol) were mixed with 30 ml of ethanol in a three-neck flask under nitrogen. The mixture was heated up to reflux for 24 hours. After cooled to room temperature, the precipitate was collected by filtration. The product was purified by column chromatography using 1:2 dichloromethane and hexanes as eluent. 0.7 g of desired product was obtained after purification.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.O.[OH-].[NH4+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(#N)C>[ClH:1].[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[NH:2][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Acetonitrile (800 ml) is added to 2-aminoindan hydrochloride (50 g, 0.295 mole) followed by the addition of water (100 ml) and concentrated ammonium hydroxide (100 ml). To the resulting stirring solution tert-butyl bromoacetate (60 g, 0.308 mole) in acetonitrile (150 ml is added dropwise at room temperature and the resulting mixture stirred overnight at room temperature. The acetonitrile is evaporated on a rotary evaporator, water added to the residue and the product extracted several times into methylene chloride. The combined methylene chloride extract is washed twice with water, dried over magnesium sulfate, filtered and evaporated to afford the crude product as a tan oil. The crude product is purified further by silica-gel chromatography (chloroform). The desired fractions are concentrated and the hydrochloride prepared with ether-hydrochloric acid to afford tert-butyl N-(2,3-dihydro-1H-inden-2-yl)glycinate hydrochloride as a colorless solid (60 g, 72%); m.p. 175°; mass spectra (CI): 248(m+1, 100%).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][C:49]1[C:54]([NH2:55])=[CH:53][CH:52]=[C:51]([CH3:56])[N:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:55][C:54]4[C:49]([CH3:48])=[N:50][C:51]([CH3:56])=[CH:52][CH:53]=4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: Cc1ccc(N)c(C)n1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccc(C)nc2C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2,6-dimethyl-pyridin-3-ylamine (Alfa) to give the title compound. HR-MS (ES, m/z) calculated for C42H50Cl2N7O3 [(M+H)+] 770.3347, observed 770.3351.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=[O:5])[CH3:2].OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][C:13]=2[N+:25]([O-:27])=[O:26])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CCC2
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn2c3c(ccc([N+](=O)[O-])c3c1=O)CCC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
1-Oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (1.0 g) was placed in round bottom flask and to that, mixture of H2SO4/HNO3 (1:1) was added and stirred for 3 hours at 0° C. The reaction mixture was poured on ice and precipitate was filtered off affording 900 mg of title product (LC/MS: 95%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:3]([CH3:29])=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cc1
Yield: 40 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (4-methoxyphenyl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 40%. Melting point: 129-131° C. (hexane-ethyl acetate).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O>C1(C)C=CC=CC=1>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCCCCNCc1ccc2ccccc2c1
Yield: 18.1 %

Procedure:
A mixture of N-(6-Aminohexyl)-2-nitrobenzenesulfonamide hydrochloride (0.67 g, 2.0 mmol) and 2-naphthaldehyde (0.32 g, 2.1 mmol) in 75 mL of toluene was refluxed using a Dean Stark trap for 20 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethanol (40 mL) and sodium borohyride (0.020 g,6.0 mmol) was added. After the reaction was complete (6 h), the solvent was evaporated and residue taken up in 30 mL of saturated sodium chloride solution and extracted with ethyl acetate(3×40mL), washed with saturated sodium chloride solution, dried over sodium sulfate and concetrated to afford an oil. The oil was flash chromatographed over silica gel to afford the titled compound (0.16 g, 37%) which was converted into hydrochloride salt (mp 169° C.).
Reaction SMILES: [C:1]([C:3]1[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[CH:7][CH:6]=2)#[N:2].[Br:22]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:14][C:8]1[C:9]([O:12][CH3:13])=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]([C:1]#[N:2])=[CH:11]2
Reactant: COc1c(C)ccc2c1cc(C#N)n2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(CBr)ccc2c1cc(C#N)n2C(=O)OC(C)(C)C
Yield: 119 %

Procedure:
To a stirred solution of 561 mg of tert-butyl 2-cyano-4-methoxy-5-methyl-1H-indole-1-carboxylate (1.96 mmol) in carbon tetrachloride (9 mL) was added 349 mg of N-bromosuccinimide (1.96 mmol) and 64 mg of AIBN (0.39 mmol). The mixture was refluxed for 1 h, then cooled and concentrated and filtered through short silica gel plug using hexane-ethyl acetate 10:1 to give 852 mg of crude tert-butyl 5-(bromomethyl)-2-cyano-4-methoxy-1H-indole-1-carboxylate that was used in the next step without further purification.