Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1C([C:11]2[N:12]=[C:13](C3C=CC=CC=3)[S:14][CH:15]=2)C(C(OC)=O)=C(C)NC=1C)=O.[CH:28]([O:31][C:32]([C:34]1[CH:39](C2N=C(C3C=CC=CC=3)SC=2)[C:38]([C:51]([O:53][CH:54]([CH3:56])C)=[O:52])=[C:37]([CH3:57])[NH:36][C:35]=1[CH3:58])=[O:33])([CH3:30])[CH3:29]>>[CH:28]([O:31][C:32]([C:34]1[CH:39]([C:13]2[S:14][CH:15]=[CH:11][N:12]=2)[C:38]([C:51]([O:53][CH2:54][CH3:56])=[O:52])=[C:37]([CH3:57])[NH:36][C:35]=1[CH3:58])=[O:33])([CH3:29])[CH3:30]
Reactant: CC1=C(C(=O)OC(C)C)C(c2csc(-c3ccccc3)n2)C(C(=O)OC(C)C)=C(C)N1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1csc(-c2ccccc2)n1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1nccs1

Procedure:
The following compounds were obtained in an analogous manner: (b) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl ester and (c) 2,6-dimethyl-4-thiazol-2-yl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl 5-propyl ester.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][CH:15]([OH:17])[CH3:16].[H-].[Na+]>O1CCCC1>[CH3:14][CH:15]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])[CH3:16]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C(F)(F)F
Temperature: -10 °C
Reaction time: 6 h

Procedure:
To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (10 g), i-PrOH (8.15 mL) in tetrahydrofuran (THF) (90 mL) stirred under nitrogen at −10° C. was added solid NaH (3.46 g) portionwise during 30 min. The reaction mixture was stirred at −10° C. for 6 h. The reaction mixture was quenched with water, partitioned between ether (100 mL) and water (50 mL). The organic phase was dried over magnesium sulphate and evaporated in vacuo to give the crude product 4-[(1-methylethyl)oxy]-3-(trifluoromethyl)benzonitrile (D10) (15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:40](=[O:41])[CH2:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Reaction time: 22 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.027 ml phenyl-acetyl chloride (0.2 mmol). After 22 h stirring at reflux, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 90 mg of a light brown solid (94%). MS (ISP) 469.3 (M+H)+.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:24])[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])C>CO.C1COCC1.O>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:7]([OH:24])=[O:6])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
LiOH.H2O (29 mg, 0.7 mmol) was added to a solution of N-biphenyl-4-yl-malonamic acid ethyl ester (100 mg, 0.35 mmol) in methanol (2.1 mL), THF (2.5 mL) and H2O (2.5 mL). The resulting mixture was stirred for 2 hours at room temperature then concentrated. The residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with concentrated HCl and filtered. The resulting precipitate was dried to afford 80 mg (89%) of N-biphenyl-4-yl-malonamic acid. 1H NMR: (DMSO-d6): δ11.6 (s, 1H), 7.64 (m, 6H), 7.44 (t, 2H), 7.32 (t, 1H), 3.2 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]2[CH:13]3[C:14]([CH3:16])([CH3:15])[C:10]([CH3:17])([CH2:11][CH2:12]3)[C:9]2=[O:18])=[CH:5][CH:4]=1.[S:22]([O-:27])([O:25][CH3:26])(=[O:24])=[O:23]>C(OCC)(=O)C>[CH3:26][O:25][S:22]([O-:27])(=[O:24])=[O:23].[O:18]=[C:9]1[C:8](=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([N+:2]([CH3:26])([CH3:1])[CH3:21])=[CH:20][CH:19]=2)[CH:13]2[C:14]([CH3:16])([CH3:15])[C:10]1([CH3:17])[CH2:11][CH2:12]2
Reactant: CN(C)c1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1
Agent: COS(=O)(=O)[O-]
Solvent: CCOC(C)=O
Product: CC12CCC(C(=Cc3ccc([N+](C)(C)C)cc3)C1=O)C2(C)C
Yield: 140.7 %

Procedure:
750 g of 4-dimethylamino benzylidene camphor (prepared in Example 1) and 334 g of methyl sulfate are progressively heated to reflux in ethyl acetate. An exothermic precipitation suddenly occurs and when it has abated the reaction mixture is then heated for three hours at reflux. A pale yellow solid precipitates which is then filtered, washed with ethyl acetate and recrystallized in a benzene-acetonitrile mixture, yielding 866 g of white product melting at 20° C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:23]>>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:23])=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2cc(C(C)(C)C)ccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1Cl
Temperature: 120 °C

Procedure:
A mixture of Ethyl 7-tert-butyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (4.54 g, 16.6 mmol) in POCl3 (60 ml) was heated at 120° C. for 3 hours. After the solvent was evaporated in vacuo, the residue was diluted with CH2Cl2. The organic layer was poured into ammonia-water with ice-cooling. The aqueous layer was extracted with CH2Cl2 and the organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (8:1 to 6:1) to give the title compound (4.82 g) as colorless oil. 1H NMR (270 MHz, DMSO-d6) δ ppm 1.35-1.44 (3H, m), 1.42 (9H, s), 4.38-4.49 (2H, m), 7.97-8.06 (2H, m), 8.30-8.36 (1H, m),9.15 (1H, s).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9][N:10]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=2)=[O:12])[CH:24]2[CH2:25][CH2:26][N:27]([C:43]([NH:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:44])[CH2:28][CH2:29]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 2.5 h
Yield: 40 %

Procedure:
N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24 mg, 0.05 mmol) is dissolved in dichloromethane. Phenylisocyanate (9 mg, 0.075 mmol, 1.5 eq.) is added and the mixture is agitated for 2.5 hours. The aminomethyl resin (0.02 mmol) is added and the reaction is again agitated overnight. The resin is filtered, rinsed with dichloromethane and the filtrate is concentrated. The oil obtained is passed through a silica gel cartridge eluting with an equimolar mixture of heptane and ethyl acetate in order to obtain 12 mg (yield=40%) of a yellow oil after concentration.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:18][CH2:17][CH2:16]3)[NH:14][C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4].CS(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])(=O)=O.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:16][CH2:17][CH2:18]3)[N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])[C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4]
Reactant: O=C1NC2(CCC2)C(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C2(CCC2)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Yield: 33 %

Procedure:
NaH (to 60%) (44 mg, 1.1 mmole) is added under argon to a solution of 7-[4-nitro-3-(trifluoromethyl)phenyl]-5,7-diazaspiro[3.4]octane-6,8-dione (329 mg, 1 mmole) in anhydrous DMF (9 ml). A release of gas accompanies the change in colour of the reaction medium which becomes orange. Stirring is maintained for 1 hour at 23° C. before adding 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate (prepared according to an experimental protocol described in WO 2005077968) (332 mg, 0.8 mmole). After reaction for 15 hours, the reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on an RP18 silica column (eluent: ACN/H2O: 8/2 to 100). The expected compound is obtained in the form of a colourless oil with a yield of 33% (214 mg).
Reaction SMILES: N([O-])=[O:2].[Na+].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:7]=1N>O.S(=O)(=O)(O)O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu]=O>[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:7]=1[OH:2]
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Reactant: O=N[O-]
Agent: O=[Cu]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Oc1cc(O)c(F)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
A solution of sodium nitrite (1.63 g, 23 mmol) in water (19 ml) and ice (48 g) was added dropwsie to a solution of 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (3.93 g, 20 mmol) in 35% sulphuric acid (48 ml) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and a solution of copper(II)nitrate trihydrate (467 g, 1.93 mol) in water (780 ml) followed by copper(II)oxide (2.65 g, 18 mmol) were added. The solution was extracted with ethyl acetate, the organic layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (8/2) to give 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (2.13 g, 53%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:1][C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccnc1C
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C=Cc2ncccc2C(=O)O)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
A mixture consisting of 15.1 g of methyl 2-methylnicotinate, 36.0 g of 4-methylbenzaldehyde and 15.0 g of anhydrous zinc chloride was stirred for 30 minutes at 180° C. The resulting reaction mixture was cooled to room temperature. Thereto were added 151 ml of a 10% aqueous sodium hydroxide solution and 100 ml of toluene. The resulting mixture was stirred. The insolubles were removed by filtration. An aqueous layer was separated, washed with toluene and then adjusted to pH 5.0 with acetic acid. The resulting crystals were collected by filtration and dried to obtain 13.2 g of 2-(p-methylstyryl)nicotinic acid. It was recrystallized from ethanol to obtain 10.6 g of colorless crystals having a melting point of 208°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20](O)=[O:21])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH2:10][N:9]=1.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29]O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)Cl>[CH3:29][C:28]1([CH3:32])[CH2:31][O:21][C:20]([CH2:19][CH2:18][C:16]2[S:17][C:13]3[N:12]4[C:23]([CH3:26])=[N:24][N:25]=[C:11]4[CH2:10][N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:14]=3[CH:15]=2)=[N:27]1
Reactant: Cc1nnc2n1-c1sc(CCC(=O)O)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(C)(N)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1sc(CCC3=NC(C)(C)CO3)cc1C(c1ccccc1Cl)=NC2

Procedure:
3 g (7.7 mmol) of 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]ethane-1-carboxylic acid, 0.69 g (7.7 mmol) of 2-amino-2-methylpropan-1-ol, 2,35 g (23 mmol) of triethylamine and 4.8 g of carbon tetrachloride are stirred in 15 ml of pyridine/acetonitrile (1:1) at ambient temperature. Within 2 hours a solution of 6.2 g (23.6 mmol) of triphenylphosphine in 15 ml of the above pyridine/acetonitrile mixture is added dropwise to the mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([CH:22]([CH3:24])[CH3:23])[CH2:15]1.O[N:26]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N.O1CCOCC1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:26])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([CH:22]([CH3:24])[CH3:23])[CH2:15]1
Reactant: CC(C)C1CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CCS1(=O)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)C1CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Temperature: 100 °C
Yield: 134.9 %

Procedure:
5-Bromo-3-[2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-7-carboxylic acid (1.12 g, 2.69 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 mL). HOBt (1-hydroxybenzotriazole) (0.364 g, 2.69 mmol) and EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1.445 g, 7.54 mmol) were added. The mixture was stirred and a solution of 0.5 N ammonia in dioxane (16.15 mL, 8.07 mmol) was added. The reaction mixture was heated under microwave at 100° C. for 20 minutes. The reaction was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with water, dried (MgSO4) and the solvent was removed in vacuo to afford 1.5 g of brown oil. The oil was purified by Flash Chromatography (hexanes/ethyl acetate) to afford a pure fraction of a yellow pure solid (190 mg). The remaining product was recovered from the column as a mixture and was purified by dissolution in ethyl acetate, and sonicating to precipitate 420 mg of white crystals. Both the 190 mg from chromatography and 420 mg from the crystallization are combined to afford 610 mg of the title compound, which was >90% of a single isomer based on LC/MS and 1H NMR. The stereochemistry of the major isomer was assigned as trans based on a series of NOE experiments. The filtrate from the crystallization step above was concentrated to afford 37 mg of mostly the minor (cis) isomer, (racemic)-5-bromo-3-[cis-2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-7-carboxamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][C@@H:2]([NH:1][C:13](=[O:15])[CH3:14])[CH3:12])=[CH:10][CH:9]=1
Reactant: C[C@H](N)CCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](C)CCc1ccc(O)cc1

Procedure:
4-((S)-3-Aminobutyl)phenol (1.3 g, 7.87 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 1.24 g (76%), M+H+: 208.13.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:60]2[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)cc1
Yield: 24.9 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (220 mg), 1,3-bis(diphenylphosphino)propane (24 mg) and palladium(II) acetate (6.1 mg) in 30 ml benzene, were added 2 M aqueous sodium carbonate (0.22 ml) and 4-methoxybenzeneboronic acid (90 mg). The reaction solution was kept at reflux for 24 hours. Then the solvent was removed under reduced pressure. The resulting residue was purified by a procedure similar to the purification method in Example 2 to yield 55 mg of 2,2-dimethyl-4-(4-methoxyphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. NMR: δ1.56 (s, 6H), 3.07 (s, 3H), 3.83 (s, 3H), 6.92 (d, J=8.7 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.89(dd, J=8.7, 8.7 Hz, 4H). IR (cm−1): 2925, 1697, 1592, 1149, 1031, 912, 745.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](SC3C=CC=C(C(OCC)=O)C=3F)=[C:7](C3CC3)[N:8]2[C:12]2C=N[N:15]([CH2:17][CH2:18][CH2:19]C(O)=O)[CH:16]=2)=[CH:4][CH:3]=1.BrC1C=NC=CC=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:16]=[N:15][CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCCC(=O)O)c3)c3c(F)c(Cl)ccc23)c1F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: Brc1cccnc1
Product: Fc1c(Cl)ccc2ccn(-c3cccnc3)c12
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
To a stirred solution of indole 1 (Example 4, Step 1; 2.0 g, 11.8 mmol) in toluene (50 mL) were added 3-bromopyridine (2.9 g, 17.7 mmol), N,N′-dimethylethylenediamine (418 mg, 4.73 mmol), K3PO4 (6.3 g, 29.5 mmol), CuI (225 mg, 1.18 mmol) at RT under inert atmosphere. The mixture was purged with argon for 15 min and heated to 140° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, added n-hexane (20 mL), stirred for 5 minutes and then filtered. The filtrate was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water and brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 10% EtOAc/Hexanes) to afford compound 2 (2.0 g, 69%) as light brown solid. 1H NMR (500 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.06-8.02 (m, 1H), 7.74-7.72 (m, 1H), 7.64-7.58 (m, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.28-7.24 (m, 1H), 6.82 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19](Br)([F:21])[F:20].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.[Zn]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[C:19]([F:21])[F:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(Br)Br
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Zn]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(=C(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid benzyl ester (0.50 g, 2.14 mmol, 1.0 eq.) in THF (20 mL) was added dibromodifluoromethane (0.90 mL, 4.5 eq.) at −30° C. followed by HMPA (1.75 mL, 4.5 eq.). The cooling bath was removed and the reaction mixture was swirled periodically. After 30 min, zinc dust (0.63 g, 4.5 eq.) and HMPA (80 μL 0.4 eq.) was added and the mixture was heated at reflux for 18 h. Upon cooling to room temperature, the residue was washed with diethyl ether several times. The combined ether washings were washed successively with saturated aqueous copper (II) sulphate, brine, dried over Na2SO4 and concentrated. The residue was purification by chromatography (20% EtOAc-hexanes) to afford 4-difluoromethylene-piperidine-1-carboxylic acid benzyl ester (0.32 g, 56%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.CCOC(C)=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of hydroquinone (3.2 g, 29.0 mmol) and K2CO3 (8.0 g, 54.0 mmol) in 40 mL of DMF was heated at 100° C. with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g, 19.3 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane giving an orange oil (1.89 g, 40%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].C(Cl)Cl.CO>[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2=[O:27])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCn1ccn(-c2ccc(OCc3ccccc3)cc2)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN1CCN(c2ccc(O)cc2)C1=O

Procedure:
Prepared from 1-(4-benzyloxyphenyl)-3-[2-(ethoxycarbonyl)ethyl]-3H-imidazol-2-one by hydrogenation in the presence of palladium on charcoal in ethanol at 40° C. and a hydrogen pressure of 50 psi. Rf value: 0.20 (silica gel; methylene chloride/methanol=100:2)
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[CH2:22]([O:24][CH2:25][C:26]1[N:27]([CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[C:28]2[C:33]([CH3:34])=[C:32]([CH3:35])[N:31]=[C:30]([NH2:36])[C:29]=2[N:37]=1)[CH3:23]>>[CH3:1][N:2]([CH3:3])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:43]3[CH2:44][CH2:45][CH:40]([CH2:39][CH2:38][N:27]4[C:28]5[C:33]([CH3:34])=[C:32]([CH3:35])[N:31]=[C:30]([NH2:36])[C:29]=5[N:37]=[C:26]4[CH2:25][O:24][CH2:22][CH3:23])[CH2:41][CH2:42]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(S(=O)(=O)c2ccc(N=Nc3ccc(N(C)C)cc3)cc2)CC1

Procedure:
Using the method of Examples 49-56, 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 619.3185.