Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=[O:17])/[C:5]/2=[N:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[C:8]1([N:7]2[C:11]3[C:12](=[CH:13][C:14]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:15][CH:16]=3)/[C:5](=[N:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)/[C:6]2=[O:17])[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2cc(Br)ccc2N1c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2cc(-c3ccccc3)ccc2N1c1ccccc1
Temperature: 67 °C
Yield: 18.1 %

Procedure:
A mixture of (3z)-5-bromo-1-phenyl-3-{[3-(trifluoromethyl)phenyl]imino}-1,3-dihydro-2H-indol-2-one (22 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (12.0 mg, 0.01 mmol), benzene boronic acid (10 mg, 0.08 mmol) in THF (5 mL), and aqueous Na2CO3 (2M, 10C μL) was heated at 67° C. for 24 h. The crude product was concentrated in vacuo and the residue was extracted with CH2Cl2 (3×1 ml), concentrated, and purified by preparative TLC using 10% methanol in CHCl3, giving the desired product (4 mg, 18%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[C:7]([CH3:10])[C:6]([NH2:11])=[C:5]([CH2:12][CH3:13])[CH:4]=1)[CH3:2]>[Pt].C(C(C)=O)C>[CH:1]([NH:11][C:6]1[C:5]([CH2:12][CH3:13])=[CH:4][C:3]([CH2:1][CH3:2])=[C:8]([NH:9][CH:5]([CH2:6][CH3:7])[CH3:12])[C:7]=1[CH3:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CCc1cc(CC)c(N)c(C)c1N
Agent: [Pt]
Solvent: CCC(C)=O
Product: CCc1cc(CC)c(NC(C)CC)c(C)c1NC(C)CC
Temperature: 120 °C
Yield: 96.5 %

Procedure:
Diethyl(methyl)-1,3-benzenediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers (10.0 g; Ethacure® 100, Albemarle Corporation), Pt(S)/C (0.5 g), Amberlyst-15 (0.5 g), and methyl ethyl ketone (50 g) were charged into a 100 mL metal autoclave at 22° C. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The reaction mixture was then heated at 120° C. under 125 psig (9.63×105 Pa) of H2 for 5.5 hrs (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (100° C. for 5 minutes at 10° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of diethyl(methyl)-1,3-benzenediamine, and a 96.5% yield of N,N′-di-sec-butyl-[diethyl(methyl)-1,3-benzenediamine].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccn2)CC1
Yield: 19.6 %

Procedure:
Amine preparation: A mixture of 1-BOC-4-piperidone (496 mg), 2-aminopyridine (234 mg), sodium triacetoxyborohydride (580 mg) and acetic acid (0.14 mL) was stirred together in dry 1,2-dichloroethane (10 mL) at room temperature. After 24 h the reaction was quenched with saturated NaHCO3 solution and extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo to give 4-(pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (135 mg) after flash chromatography. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].ClC1C=CC=C(C(OO)=[O:49])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:32]=[CH:33][N+:34]([O-:49])=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Solvent: ClCCl
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-methyl-carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (Example G-17) (0.051 g, 0.073 mmole) in dichloromethane (0.44 ml) was added by small portions 3-chloroperbenzoic acid (purity 70%) (0.027 g, 0.11 mmole). After 2.5 hours stirring at 25° C., the yellow solution was quenched with aqueous sodium sulfite, diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate, then with brine. The organic solution was dried over sodium sulfate. The product (Compound G18 of Table G) was isolated after removal of the solvent, as a white powder (melting range: 105-194° C.) showing, by LC-MS analysis (method 6 described hereunder) a retention time of 0.99 min and a M+H+ peak of 716.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](#[N:13])[CH2:11][CH3:12].[OH-].C[N+](C)(C)C>O>[CH3:12][C:11](=[C:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:10]#[N:13]
Reactant: CCC#N
Reactant: CCCCCCC(C)=O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: CCCCCCC(C)=C(C)C#N

Procedure:
Into a 100 ml. flask, equipped with magnetic stirrer, thermometer, condensor and static nitrogen head, was placed 23.6 g. of 2-octanone (0.18 m), 22 g. of propionitrile (0.4 m), 7 g. of Ca(OH)2 (0.09 m), 7 g, of CaO (0.12 m), and 0.6 g. of 25% tetramethyl ammonium hydroxide in water. The solution was held at reflux for 64 hours, whereupon a gas chromatographic analysis of a sample of the reaction mixture showed 10.7% conversion of the ketone to the product nitrile.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[CH2:32][CH2:31][N:30]([C@@H:33]3[CH2:37][CH2:36][N:35]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)[C:34]3=[O:46])[CH2:29][C@H:28]2[F:47])=[CH:23][CH:22]=1)=[O:19])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.[ClH:48].C(OCC)C>C(Cl)Cl>[ClH:48].[NH2:8][C@@H:9]([CH2:17][C:18]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]2[CH2:32][CH2:31][N:30]([C@@H:33]3[CH2:37][CH2:36][N:35]([CH2:38][C:39]4[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=4)[C:34]3=[O:46])[CH2:29][C@H:28]2[F:47])=[CH:25][CH:26]=1)=[O:19])[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)C[C@H](N)C(=O)O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 57 %

Procedure:
To a solution of (S)-1-tert-butyl 4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl) 2-((tert-butoxycarbonyl)amino)succinate (0.032 g, 0.049 mmol) in DCM (2 mL) at −20° C. was added HCl in diethyl ether (2.0 ml, 2.0 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a YMC Triart C18 (150×19 mm) 5 μm column using a gradient of 10% solvent B to 40% solvent B over 7 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 17 mg (57%) of (S)-2-amino-4-(4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenoxy)-4-oxobutanoic acid hydrochloride, the titled compound of example 5 as an off-white solid. LC-MS (Method A) RT=1.808 min, (M+H)+=498.2 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J=8.5 Hz, 2H), 7.21-7.03 (m, 8H), 6.75 (d, J=8.5 Hz, 1H), 4.95-4.72 (m, 1H), 4.42-4.24 (m, 3H), 4.10 (t, J=5.3 Hz, 1H), 4.07-4.01 (m, 1H), 3.93-3.84 (m, 1H), 3.83-3.68 (m, 1H), 3.33-3.10 (m, 5H), 3.04 (br. s., 1H), 2.93 (br. s., 1H), 2.89-2.71 (m, 2H), 2.26 (s, 3H), 1.96 (br. s., 1H), 1.82 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ −180.707.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[N:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=2)=[O:10])[CH3:7].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH2:6]([O:8][C:9]([C:11]1[N:12]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH2:4][CH:1]1[CH2:3][CH2:2]1)=[CH:15][CH:14]=2)=[O:10])[CH3:7]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC3CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Cyclopropylmethyl bromide (0.072 ml, 0.75 mmol) was added to a suspension (5.0 ml) of 5-hydroxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (173 mg, 0.48 mmol) and potassium carbonate (276 mg, 1.0 mmol) in acetonitrile, and stirred at 80° C. for five hours. After cooling to room temperature, the reaction mixture was combined with ethyl acetate and water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-cyclopropylmethoxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colorless gum-like material (112.5 mg, 56%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].[Cl-].[CH2:14]([Zn+])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: OC1CCOc2ccc(I)cc21
Reactant: CC(C)(C)C[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)C(O)CCO2
Temperature: 0 °C
Reaction time: 19 h

Procedure:
To a flame dried round bottom flask containing 6-iodo-chroman-4-ol (3.0 g, 10.8 mmol) and Pd(dppf)Cl2 (0.44 g, 0.54 mmol) was added 6 ml of anhydrous THF and the mixture chilled to 0° C. The mixture was treated with neopentyl zinc chloride (prepared as previously described) (50 ml, 30 mmol, 0.6 M in THF) and stirred under nitrogen at r.t. for 19 h. followed by 5 h at 50° C. (oil bath). The reaction was cooled to r.t. and quenched with NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to 1.9 g (79%) of a white solid after flash chromatography (10% EtOAc/heptanes, Biotage 40M) Rf=0.11. HRMS (ESI+) calcd for C14H20O2 m/z 220.1463 (M+H)+; found 220.1460.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH3:16][C:17]1[C:22]([CH:23]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[CH:5]=3)[NH:1][CH:2]=2)[CH2:24][N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Reactant: c1cc2cc(N3CCOCC3)ccc2[nH]1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2ccc(N3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.4 %

Procedure:
4-(1H-Indol-5-yl)morpholine (1.102 g, 5.45 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.2154 g, 3.89 mmol) were dissolved in THF and concentrated in vacuo to dryness. The mixture was then melted at 140° C. After 5 h, the reaction was cooled to room temperature and purified by flash chromatography using an ISCO 120 g column eluting with 0-60% EtOAc/hexanes to give the desired product (0.8047 g, 1.454 mmol, 37.4% yield) as a tan foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][CH:14]3[NH:17][C:18]3[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=3)[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][CH:14]3[N:17]([C:18]3[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=3)[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:39](=[O:41])[CH3:40])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1cccc(N(C(C)=O)C2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (8 mg, 0.02 mmol) and dimethylaminopyridine (2 mg, 0.016 mmol) in dichloromethane (1 mL) at 0° C. was added acetyl chloride (12 mL, 0.173 mmol) and triethylamine (0.25 mL, 0.176 mmol). The reaction was warmed to room temperature and allowed to stir for approximately 2 hours. The resultant mixture was concentrated and the resulting crude residue was purified on a preparative TLC (1000 mm thickness) with a 1:1 ratio of ethyl acetate and hexane solution to afford 7 mg (94%) of methyl 2-(3-(N-(6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)acetamido)phenoxy)acetate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O.[Cl-].[Na+].O>[Br:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Cc1cccc(F)c1N
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(F)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of crude 2-fluoro-6-methylaniline from step 3 (about 32 mmol) in anhydrous N,N-dimethylformamide (100 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (5.7 g, 32 mmol), and then stirred at room temperature for 10 minutes. The reaction mixture was poured into a water solution of diluted brine and extracted with EtOAc. The organic extracts were washed with diluted brine three times, dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford 4-bromo-2-fluoro-6-methylaniline as a yellow foam.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH:9]1([CH2:12][N:13]([CH3:23])[S:14]([N:17]2[CH:21]=[CH:20][N+](C)=C2)(=[O:16])=[O:15])[CH2:11][CH2:10]1.[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=C(N)C=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[CH:9]1([CH2:12][N:13]([CH3:23])[S:14]([NH:17][C:21]2[CH:20]=[C:41]3[C:36](=[CH:37][CH:38]=2)[N:35]=[C:34]([NH:33][C@H:24]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]2)[CH:43]=[CH:42]3)(=[O:15])=[O:16])[CH2:10][CH2:11]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(CC1CC1)S(=O)(=O)n1cc[n+](C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(CC1CC1)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with step C of the general method described in example 76 from 3-(cyclopropylmethyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium trifluoromethanesulfonate and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=423.7 (M+H+).
Reaction SMILES: [C:1]1(=[C:11]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1>C(OC(=O)C)(=O)C>[C:1]1(=[C:11]2[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[O:20][C:12]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)CCCC(C(=O)O)=C1CC=Cc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(=C2CC=Cc3ccccc32)C(=O)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
100 ml of acetic anhydride were added to 10 g (35 mmole) of 2-(1-naphthylidene)adipic acid (prepared as described above) and the mixture was stirred at 60° C. for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was triturated with a 1: 1 by volume mixture of benzene and hexane. The solvent was decantated to afford 8.8 g of 2-(1-naphthylidene)adipic anhydride as an oily material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-].N.CCO>>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(c3cccc(Cl)c3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(Br)cc32)N=C1N
Yield: 45.4 %

Procedure:
A solution of 6-bromo-2-(3-chlorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 0.22 mmol) and NH4I (64 mg, 0.44 mmol) in a solution of NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(3-chlorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 46%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([Cl:12])[C:7]([F:13])=[CH:6][C:4]=1N.N([O-])=O.[Na+].[BrH:18]>O>[Cl:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([Cl:12])[C:7]([F:13])=[CH:6][C:4]=1[Br:18]
Reactant: COc1c(Cl)c(N)cc(F)c1Cl
Reactant: Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)c(F)cc(Br)c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To 165 ml of a mixture of concentrated hydrochloric acid and water (1:1) was added 52.5 g of 2,4-dichloro-5-fluoro-3-methoxyaniline (0.25 mol). The resultant was stirred to be a slurry, and cooled to 0-5° C. Over 30 minutes, a solution of sodium nitrite (18.2 g) in water (50 ml) was added dropwise to the slurry. The resulting solution was added slowly to a solution of cuprous bromide (0.299 mol) and hydrobromic acid (160 ml). The reactant was stirred for 2 hours, and kept overnight. The resulting mixture was wet-distilled and the distilled materials were extracted with toluene. The oil layer was washed with 10% aqueous solution of NaOH, concentric sulfuric acid and water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel chromatography eluting with n-hexane-dichloromethane to give 58.1 g of 2,4-dichloro-5-fluoro-3-methoxybromobenzene (0.212 mol) in 84.9% yield.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.CN(C)C(=O)C>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Fc1ccccn1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(c4ccccn4)CC3)cc2C2=CCCCC2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (75 mg, 0.15 mmol) (as prepared in Example 14, step (b)), K2CO3 (84 mg, 0.60 mmol), 2-fluoropyridine (27 μL, 0.30 mmol) and 0.3 mL of N,N-dimethylacetamide and stirred for 8 h at 120° C. The reaction was diluted with 3 mL of H2O and the title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 9 min to give 50 mg (75%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.18 (d, 1H), 8.06 (m, 1H), 8.02 (s, 1H), 7.94 (dd 1H), 7.48 (d, 2H), 7.22 (dd, 1H), 7.12 (d, 1H), 6.98 (t, 1H), 5.82 (m, 1H), 4.32 (m, 2H), 3.46 (m, 2H), 3.00 (m, 1H), 2.30 (m, 4H), 2.18 (m, 2H), 1.96-1.74 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H28N6O, 453.2 (M+H), found 453.2.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([C:17]([O:19]CC)=[O:18])=[CH:15][N:16]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.O>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:23]1[CH:22]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[Cl:1])[CH:24]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=1)=[O:10]
Reactant: CCOC(=O)c1cnc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ncc(C(=O)O)s1)c1cc(OCc2ccccc2Cl)cc(OCc2ccccc2Cl)c1

Procedure:
A solution of ethyl 2-[3,5-di-(2-chlorobenzyloxy)benzoyl]aminothiazole-5-carboxylate (158 mg, 0.28 mmol) in THF (2 ml) was treated with sodium hydroxide solution (0.57 ml of 2M, 1.4 mmol), and the reaction stirred at 40-50 deg C., until complete hydrolysis was achieved (with tlc monitoring, approximate reaction time 2 hrs). The resulting solution was cooled, diluted with water (5 ml) and acidified to pH1 using c.HCl. The precipitate thus formed was filtered off, washed (water) and dried to give the title compound as a colourless solid, 130 mg, 1 NMR δ (d6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.2 (1H, d).