Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][CH:5]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:4][CH:5]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[CH2:1][CH3:2]
Reactant: Cc1cccc(CCNCCCC(O)c2ccc(NS(C)(=O)=O)cc2)n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCc1cccc(C)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
0.24 ml (3.04 mmol) of ethyl iodide was added to a suspension of 1.0 g (2.77 mmol) of N-[4-[1-hydroxy-4-[2-(6-methyl-2-pyridyl)ethylamino]butyl]phenyl]methanesulfonamide prepared in Example 3-(4) and 0.70 g (8.31 mmol) of sodium hydrogencarbonate in 15 ml of dimethylformamide. The mixture was stirred at 50° C. for 2 h and then filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3). 0.96 g (yield: 89%) of the intended compound was obtained in the form of a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[K])(C)(C)C.O>CN1C(=O)CCC1>[CH2:11]([O:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 125 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
2-Chloro isonicotinic acid (9.45 g) and benzyl alcohol (12.977 g) were dissolved in NMP (180 mL), and treated with tBuOK (20.2 g) between 10-25° C. The reaction mixture was then stirred at 125° C. (Bath-temperature) for 6 h, cooled down to r.t., poured into water (1500 ml) and extracted twice with water. The combined aqueous phases were treated with concentrated aqueous HCl until pH 3 (16 ml). After 10 min the solid was filtered, washed with water and dried under high vacuum, to give the title compound as an off-white solid (9.8 g). MS (m/e)=228.1 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@@:9]([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)([O:23][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and tridecanoic acid to yield (3aR,4S,7aR)-4-m-tolylethynyl-4-tridecanoyloxy-octahydro-indole-1-carboxylic acid methyl ester. MS [M+Na]=532; RT=7.113 min; LC-MS Method V
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][C:14](=[S:18])[N:15]([CH3:17])[CH3:16])=[C:6]([F:19])[C:5]=1F.Cl.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][C:14](=[S:18])[N:15]([CH3:17])[CH3:16])=[C:6]([F:19])[C:5]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC(=S)N(C)C)c(F)c1F
Reactant: Cc1ccccc1N
Agent: Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(OC(=S)N(C)C)c(F)c1Nc1ccccc1C
Reaction time: 1 h

Procedure:
The compound 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitro-benzoic acid methyl ester is dissolved in excess o-toluidine. The stirring mixture is brought to 200° C. for one hour. The mixture is then poured into 5% aqueous hydrochloric acid. The aqueous mixture is extracted with diethyl ether. The organic phase is washed with water and brine, is dried over magnesium sulfate, and is concentrated in vacuo. The crude product is purified by ordinary methods such as chromatography or crystallization from an appropriate solvent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[N:33]1(OC(N(C)C)=[N+](C)C)[C:37]2C=CC=CC=2N=N1.CN>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][CH:22]([C:25]([NH:33][CH3:37])=[O:26])[CH2:23][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CNC(=O)C1CCN(c2ncc3ncnc(Nc4cccc(C)c4)c3n2)CC1

Procedure:
Prepared from compound 46 of Example 1 by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and methylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH3:24])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Product: Cc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1
Yield: 89 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazole (0.25 g) and methyl iodide (0.06 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.23 g, 89%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11](O)[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[CH:16]1([CH:19]([OH:22])[C:20]#[CH:21])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH:16]1([CH:19]([O:22][C:11]2[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=2[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])[C:20]#[CH:21])[CH2:18][CH2:17]1
Reactant: C#CC(O)C1CC1
Reactant: COC(=O)c1cc(O)c(OC)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#CC(Oc1cc(C(=O)OC)cc(OC)c1OC)C1CC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
63.6 g of methyl 3,4-dimethoxy-5-hydroxy-benzoate [E. Spath and H. Roder, Monatsh. fur Chemie, 43, 93 (1923)], 38.5 g of (RS)-1-cyclopropyl-prop-2-yn-1-ol and 118 g of triphenylphosphine were dissolved in 600 ml of toluene under argon and cooled to 5° C. A solution of 70 ml of diethyl azodicarboxylate in 150 ml of toluene was slowly added dropwise thereto at 5° C. over 90 min. The mixture was stirred at 5° C. for a further 1 hr. and at 20° C. for 3 hrs. Then, 300 ml of toluene were distilled off on a rotary evaporator and the suspension obtained was stirred in an ice bath for 30 min. The separated triphenylphosphine oxide was filtered off and the filtrate was evaporated. The resulting oil was chromatographed on silica gel with hexane/ethyl acetate 4:1, then 3:1. Crystallization was effected from diethyl ether and hexane. There was obtained methyl (RS)-3-(1-cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-benzoate as white crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].C1C(=O)N([Cl:21])C(=O)C1>CO>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:21])=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1scc(C)c1C(N)=O
Solvent: CO
Product: CC(=O)Nc1sc(Cl)c(C)c1C(N)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-acetylamino-4-methylthiophene-3-carboxylic acid amide (2 g, 10.1 mmol) is dissolved in MeOH (40 mL). NCS (1.47 g, 11.1 mmol) is added and the resulting suspension is stirred at 60° C. for 1 h. The mixture is then concentrated under vacuo, the obtained residue is dissolved in DCM and washed with aqueous NaHCO3. The organic phase is then dried over MgSO4, filtered and concentrated under vacuo to yield the desired compound which is used as such.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH3:10])[CH:4]=1)[CH3:2].[Mg+2].[Cl-].[Cl-].Cl.C[CH2:16][O:17]C(C)=O>CC#N.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6]([OH:9])=[C:7]([CH:8]=1)[CH:16]=[O:17])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1ccc(O)c(C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C)c(O)c(C=O)c1
Yield: 53 %

Procedure:
To a solution of the phenol of Example 150 Step 1 (5.0 g, 36.7 mmol) in 200 mL CH3CN, was added MgCl2 (5.25 g, 55.1 mmol), TEA (13.9 g, 19.2 mL, 137.6 mmol), and (CHO)N (8.3 g, 280 mmol). The reaction was heated at reflux for 3 h. After cooling, the reaction was diluted with EtOAc (500 mL) and acidified with aqueous 2N HCl until the reaction was pH 4. The reaction was diluted with 300 mL H2O. The organic layer was washed with H2O, with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (on SiO2, hexane/EtOAc=94/6) to give 3.2 g (53%) of the desired product as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.NN>CCO.C(OCC)(=O)C.[Ru]>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[OH:10]
Reactant: COc1cc(O)c([N+](=O)[O-])c(Cl)c1
Agent: [Ru]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(O)c(N)c(Cl)c1
Temperature: 85 °C
Yield: 76 %

Procedure:
To 3-chloro-5-methoxy-2-nitrophenol, synthetic method A [1], (200 mg) in 95% EtOH (10 mL) was added 5% Ru/C (20 mg) and hydrazine (0.36 mL). The mixture was placed in an oil bath and heated to 85° C. for 2 h. After reaction cooled, the mixture was diluted with ethyl acetate and filtered through a pad of celite and concentrated. Flash chromatography on silica gel eluting with 30% ethyl acetate-hexane afforded 138 mg (76%) of the title compound as a solid. MS: 174 (MH+), HPLC tR: 0.84 min.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33](=[O:46])[CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45]>CN(C=O)C>[C:36]1(=[O:45])[N:35]([CH2:34][C:33](=[O:46])[CH2:32][NH:1][C@@H:2]([C:6]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[C:13]3[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=3)[N:7]=2)[CH:3]([CH3:5])[CH3:4])[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]12
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (5.0 g, 14.6 mMol) and K2CO3 (2.1 g, 15.2 mMol) in DMF (50 mL) was added N-(3-Bromo-2-oxopropyl)-phthalimide (4.5 g, 14.8 mMol) (Nair et al.; J. Org. Chem.; 40; 1975; 1745). The reaction was stirred at RT for 3 h, concentrated under vacuum, taken up in EtOAc, washed with water, brine, dried (Na2SO4) and evaporated to give the title compound (7.94 g, 14.6 mMol) as an off-white solid: MS (ES) m/e 543.2 (M+H)+.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3,3-difluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 438 [M+H]
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]([N:13]=[C:14]=[O:15])[CH:11]=[CH2:12]>>[CH2:10]([NH:13][C:14](=[O:15])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:9])[CH:11]=[CH2:12]
Reactant: N#Cc1ccccc1N
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1ccccc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.2 %

Procedure:
A mixture of anthranilonitrile (10.0 g, 85 mmol) and allyl isocyanate (7.5 mL, 85 mmol) was slightly heated to dissolve. The resulting solution was allowed to stir at room temperature for two days. The solid was collected by filtration and washed with ether (10 mL) to give 14.4 g (100%) of 2-(3-allylureido)benzonitrile. An analytical sample was recrystallized from ethanol. IR (KBr): 3331, 3263, 2226 (CN), 1639 cm-1. 1H NMR (300 MHz, DMSO-d6): δ3.74 (p, 2H, CH2), 5.09 (q, 1H, =CH), 5.17 (q, 1H, =CH), 5.86 (m, 1H, CH), 7.09 (t, 2H, Ar--H), 7.56 (t, 1H, Ar--H), 7.67 (d, 1H, Ar--H), 8.43 (d, 1H, Ar--H), 7.65 (d, 1H, NH), 8.54 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ41.47, 101.00, 114.97, 116.99, 120.61, 120.73, 122.22, 132.96, 133.83, 135.69, 142.66, 154.32. Anal. Calcd for C11H11N30 (201.23): C, 65.66; H, 5.51; N, 20.89. Found: C, 65.38; H, 5.51; N, 21.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:18])[C:5]2=1>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:18])[C:5]2=1
Reactant: Cc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12
Agent: [Pt]
Solvent: CO
Product: Cc1cncc2[nH]c3c(N)cc(Cl)cc3c12
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
A solution of 6-chloro-4-methyl-8-nitro-9H-β-carboline (80 mg, 0.31 mmol) in MeOH (10 ml) was stirred at RT. Platinum (10% wt. on carbon, 24 mg) catalyst was added thereto and the reaction vessel was capped and vacuum purged 3 times with argon, followed similarly by hydrogen. The reaction mixture was stirred 1.5 hr under 1 atm hydrogen, then vacuum purged with argon, diluted with DCM (10 ml) and filtered through a 0.2 μM syringe filter. The filtrate was concentrated to yield 6-chloro-4-methyl-9H-β-carbolin-8-ylamine (67 mg) as a light brown oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1); 8.29 (s, 1); 7.74 (d, 1); 7.10 (d, 1); 2.98 (s, 3). NH4OAc standard conditions. DAD Rf=1.89 min. M+H=231.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:4]([CH:5]([C:13]([OH:15])=O)[CH2:6]2)[N:3]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][Li]>CCOCC>[CH3:1][CH:2]1[CH:7]2[CH:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:4]([CH:5]([C:13](=[O:15])[CH3:23])[CH2:6]2)[N:3]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [Li]C
Reactant: CC(C)C1CC2C(C(=O)O)CC1C(C)N2Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)C1CC2C(C(C)C)CC1N(Cc1ccccc1)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6-carboxylic acid (30.1 g, 100 mmol) and ether (300 mL) was cooled to 0° C. and methyllithium (330 mL, 1.2N solution in ether) was added dropwise over 2 hours. The mixture was stirred for 1 hour at 0° C. and quenched by the addition of saturated NH4Cl (100 mL). The mixture was poured into water (1 L), and the aqueous layer was separated and extracted with ether (1×200 mL). The ether extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 25% ether/hexane to afford 14.3 g (48%) of 1-[3-methyl-8-isopropyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octan-6-yl]-ethanone. The product was treated with ethereal.HCl to afford 15.2 g of the hydrochloride salt as a white solid, m.p. 208.5°-210° C. (dec.) when recrystallized from ethanol/ether.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31][CH:30]=1>>[CH3:27][N:26]([CH3:28])[CH2:25][CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15](=[O:16])[CH2:14][CH:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:4](=[N:3][O:2][CH3:1])[CH2:5][CH2:6]3)[C:35]([C:32]2[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=2)=[O:36])=[CH:22][CH:21]=1
Reactant: O=Cc1ccncc1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OCCN(C)C)cc3)ccc21
Product: CON=C1CCc2cc(C(CC(=O)c3ccc(OCCN(C)C)cc3)C(=O)c3ccncc3)ccc21

Procedure:
The title compound was prepared from the product of Step 1 and pyridine-4-carboxaldehyde using the method described in Example 1 Step 4; MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][S-:12]>C(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([S:12][CH3:11])[CH:9]=1
Reactant: C[S-]
Reactant: N#Cc1ccc(F)cc1F
Solvent: ClCCl
Product: CSc1cc(F)ccc1C#N
Reaction time: 48 h

Procedure:
2,4-difluorobenzonitrile (2.0 g, 14.38 mmol) and thiomethoxide (1.02 g, 14.38 mmol) were placed in an oven dried 100 mL round bottom flask fitted with a reflux condenser. Toluene (40 mL) was added and the reaction solution was put under an atmosphere of Argon. The reaction was heated to 90 deg C. over 48 hours. The crude reaction was cooled and concentrated in vacuo. The residue was taken up in methylene chloride and extracted with water. The organic phase was dried (MgSO4), filtered and concentrated to afford a white solid. The solid was dissolved in a minimal amount of methylene chloride and purified on an ISCO column (110 g silica) with a gradient of 100% hexanes to 80% hexanes/20% ethylacetate over 15 min, then 20% EtOAc/80% Hexanes for 5 min. The collected fractions were evaporated in vacuo to afford the desired material in a 7.5:1 ratio 4-fluoro-2-(methylthio)benzonitrile: 2-fluoro-4-(methylthio)benzonitrile. The white solid was carried on to the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(OC)OC)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[CH2:2][O:1]2)=[CH:26][CH:27]=1
Reactant: CC(CO)(CO)C(=O)O
Reactant: COC(OC)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C(=O)O)COC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round bottom flask, (0.9 g) 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid and (9.8 mg) p-toluene sulfonic acid and 2 ml toluene was taken. The reaction mixture was stirred at room temperature and subsequently 2 g (1 equiv) bis-(4-chlorophenyl)-dimethoxymethane [IIa4] diluted with 5 ml toluene was added through droping funnel. The reaction mixture was heated at reflux temperature and the water was removed azeotropically under Dean Stark. Continuous removal and addition of toluene was done up to 2 hrs. Then the reaction mixture was cooled at room temperature to obtain off white solid. It was filtered and washed with toluene and then water.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I[CH:31]([CH3:33])[CH3:32]>>[CH:31]([N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)=[N:18][C:17]=4[C:16]=3[CH:19]=2)[C:24]1=[O:29])([CH3:33])[CH3:32]
Reactant: CC(C)I
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(C(C)C)c3=O)cc1-2
Yield: 12 %

Procedure:
Following the procedure for 477, compound 330 and 2-iodopropane were reacted to give 489 (0.018 g, 12%). 1H NMR (400 MHz, DMSO) δ 9.06 (d, J=2.3, 1H), 8.20-8.01 (m, 1H), 7.77 (dd, J=6.9, 1.9, 1H), 7.62 (ddd, J=10.8, 7.7, 2.2, 2H), 7.08 (d, J=8.4, 1H), 6.41 (t, J=6.9, 1H), 6.11-5.79 (m, 1H), 5.20 (dt, J=13.8, 6.9, 1H), 4.55-4.22 (m, 2H), 3.46 (t, J=5.0, 2H), 1.56 (t, J=7.5, 6H), 1.36 (d, J=6.8, 6H). MS (ESI(+)): m/z 448.2 (M+H)
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[N:15]3[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)NC(=O)CC2
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)N1C(=O)CCc2ccc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of 7-(2,5-dimethyl-1H-pyrrol-1-yl)-3,4-dihydroquinolin-2(1H)-one (1.4 g, 5.8 mmol) and potassium carbonate (2.4 g, 17.5 mmol) in ACN (40 mL) was stirred for 30 min then ethyl 2-bromopropanoate (2.1 g, 11.6 mmol) was added and the mixture was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. EtOAc (50 mL) and water (30 mL) was added to the residue and the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to give ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (1.6 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 7.26 (d, J=7.2 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 5.91 (s, 2H), 4.98 (q, J=6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.96 (m, 2H), 2.72 (m, 2H), 2.05 (s, 6H), 1.61 (d, J=7.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>>[Br:18][C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[NH:15][CH:14]=1
Reactant: COc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: BrBr
Product: COc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1

Procedure:
The target compound was prepared as in Preparation Example 6 using 6-(4-methoxyphenyl)-1H-indole (500 mg, 2.24 mmol) and bromine (115 μL, 2.24 mmol).