Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21]([OH:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:24][O:22][C:21]([C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH:19]=[N:18][C:17]=1[NH2:20])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4-tert-butyl ester (510 mg, 1.6 mmol; see Example 16 (e) above) in benzene (4 mL) and methanol (4 mL) was added a solution of trimethylsilyldiazomethane (2 M in hexane, 2 mL). The reaction was stirred at room temperature for overnight. The solvent was then removed in vacuo and the residue was purified by flash chromatography using ethyl acetate/hexanes (40:60) as eluant to afford 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4-tert-butyl ester 6′-methyl ester as a yellow solid (520 mg, 96%). 1H NMR (300 MHz, CDCl3) δ1.49 (s, 9H), 3.40 (s, 4H), 3.59 (s, 4H), 3.95 (s, 3H), 8.01 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 28.41, 46.30, 52.52, 80.05, 119.69, 135.58, 148.24, 150.00, 154.70, 167.10.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2>>[CH3:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(C)ccc1N
Reactant: Brc1cnc2ccccc2c1
Product: CCOC(=O)c1cc(C)ccc1Nc1cnc2ccccc2c1

Procedure:
Obtained (0.845 g, 97% of yield) following the procedure described in Example 14 (step B) starting from ethyl 2-amino-5-methylbenzoate (0.395 g, 2.20 mmol) and 3-bromoquinoline (0.46 g, 2.20 mmol).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:9](C2C=CC=CC=2)[CH:10]([C:16](=[O:19])[CH2:17][Cl:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CCO>[NH2:28][C:29](=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:4]=1)[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16](=[O:19])[CH2:17][Cl:18])[CH3:36]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)C(C(=O)CCl)C(c1ccccc1)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CCOC(=O)C(=C(C)N)C(c1cccc(C(F)(F)F)c1)C(C(=O)CCl)C(=O)OCC
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A solution of ethyl 2-(m-trifluoromethylphenyl-phenylmethyl)-4-chloro-3-oxobutanoate (8 g) and ethyl 3-aminocrotonate (3.4 g) in EtOH (80 ml) is heated to reflux temperature for 10 minutes, then it is cooled at room temperature and after usual work-up the residue is purified by column-chromatography on silica-gel (300 g, eluent Et2O/isopropylether 50/50) to give 6 g of 2-amino-7-chloro-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-oxo-2-heptene as an oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Yield: 96.3 %

Procedure:
To a solution of ethyl [4-({butyl[4-(4-chlorophenyl)pyrimidin-2-yl]amino}methyl)-2-methylphenoxy]acetate (178 mg, 0.38 mmol) in THF (3 mL) and MeOH (3 mL) was added NaOH (2M; 2 mL) and the resultant mixture agitated for 1.5 h. The mixture was evaporated and acidified with 2M HCl, extracted with CH2Cl2 (10 mL), EtOAc (10 mL). The aqueous was filtered, the filtered solids and solvent extracts combined and the solvent removed in vacuo to afford the title compound as a white solid (161 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.C(#N)C.Cl[C:34]1[N:39]=[C:38]([NH:40][C@H:41]2[CH2:46][CH2:45][CH2:44][C@@H:43]([O:47][CH3:48])[C@@H:42]2[OH:49])[C:37]([F:50])=[CH:36][N:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:34]3[N:39]=[C:38]([NH:40][C@H:41]4[CH2:46][CH2:45][CH2:44][C@@H:43]([O:47][CH3:48])[C@@H:42]4[OH:49])[C:37]([F:50])=[CH:36][N:35]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CO[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)[C@H]1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)[C@H]1O
Temperature: 120 °C

Procedure:
In a microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.10 g, 0.23 mmol). To this was added acetonitrile (0.61 mL) and the solution was deoxygenated with nitrogen. To the reaction was added (1R,2S,6R)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-6-methoxy-cyclohexanol, 51j, (0.04 g, 0.14 mmol) and palladium catalyst (24 mg), and then aqueous sodium carbonate (0.21 mL of 2 M solution, 0.41 mmol). The reaction was sealed and heated to 120° C. in the microwave reactor for 15 min. The reaction was diluted with ethyl acetate (40 mL), filtered thru florisil, and concentrated in vacuo to give crude as a green solid. This was purified by silica gel chromatography (20-75% EtOAc/hexanes gradient). Used resulting product directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH3:21])=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[N:40]=[C:41]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[NH:40][C:41]1[N:20]([CH3:21])[C:3]2[CH:4]=[C:5]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:11]3)[C:6]([C:7]#[N:8])=[CH:9][C:2]=2[N:1]=1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(C#N)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to Example 76 using 5-amino-4-(methylamino)-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile (179 mg, 0.60 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (4 mL).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CBr)nc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To (5-trifluoromethyl-pyridin-2-yl)-methanol (1.65 g) in dichloromethane (20 ml) at 0° C. (ice-bath) under nitrogen was added triphenylphosphine (3.66 g, 13.98 mmol) in portions, followed by addition of carbon tetrabromide (3.23 g) in portions. The ice-bath was removed and the flask was sealed with a glass stopper. The reaction mixture was gently stirred for 1 hour. The crude reaction mixture was loaded onto a silica gel column (120g), and eluted with methyl acetate/hexane to give 2-bromomethyl-5-trifluoromethyl-pyridine as a light orange oil (1.65 g, 73%).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([OH:14])=[O:13])=[CH:3]1>[Pd].C(O)(=O)C>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH:4]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccccc2O1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
4-Oxo-4H-chromene-2-carboxylic acid (Aldrich, 3.0 g, 15.8 mmol) was added to a mixture of acetic acid (30 mL) and 10% palladium on carbon (0.3 g) in a Parr shaker. The glass reactor was sealed and flushed with nitrogen, and it was pressurized with hydrogen (60 psi). The mixture was shaken at 70° C. for 2.5 hours. The mixture was filtered and the solids were rinsed with methanol. The filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with 0-to-10% methanol in ethyl acetate to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.04 (m, 1H), 2.14 (m, 1H), 2.63 (dt, 1H), 2.78 (dt, 1H), 4.76 (dd, 1H), 6.80 (m, 2H), 7.05 (m, 2H). MS (ESI) m/z 177.09 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([C:10]2[C:11]([F:20])=[CH:12][C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]=3[CH:19]=2)[C:3]1=[O:21].[H-].[Na+].Cl[CH2:25][C:26]([NH2:28])=[O:27].O>CN(C)C=O>[C:26]([CH2:25][N:15]1[C:14]2[CH:19]=[C:10]([N:4]3[C:5](=[O:9])[CH:6]=[C:7]([CH3:8])[N:2]([CH3:1])[C:3]3=[O:21])[C:11]([F:20])=[CH:12][C:13]=2[S:17][C:16]1=[O:18])(=[O:27])[NH2:28]
Reactant: Cc1cc(=O)n(-c2cc3[nH]c(=O)sc3cc2F)c(=O)n1C
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc3c(cc2F)sc(=O)n3CC(N)=O)c(=O)n1C
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3.07 g of 1,6-dimethyl-3-(6-fluoro-2-oxo-5-benzothiazolinyl)-2,4(1H,3H)-pyrimidinedione (see Example 79) and 0.48 g of a 55% sodium hydride dispersion are stirred at 25° C. for 1 hour in 50 ml of absolute dimethylformamide. Subsequently, 1.02 g of chloroacetamide are added and the mixture is stirred at 50° C. for 6 hours. The reaction mixture is cooled and treated with 400 ml of water. The precipitated product is filtered off under suction, washed with water and the filter cake is suspended in 200 ml of ethyl acetate at 60° C. The suspension is concentrated to about 50 ml, cooled to 25° C., the solid is filtered off under suction and dried at 50° C. In this manner there is obtained 3-(3-carbamoylmethyl-6-fluoro-2-oxo-5-benzothiazolinyl)-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p.>260° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.CO.N>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (313 mg, 683 μmol) produced in Example C1(vii) in pyridine (10 mL) were added 2-chloro-2-oxoethyl acetate (254 mg, 1.86 mmol) and N,N-dimethylpyridine-4-amine (85 mg, 696 μmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, the mixture was stirred for 1 hr, conc. aqueous ammonia (4 mL) was added, and the mixture was further stirred for 1 hr. The reaction solution was concentrated under reduced pressure, and residue was dissolved in tetrahydrofuran (10 mL) and ethyl acetate (50 mL). The solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (125 mg, 35%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:31][CH2:32][S:33][CH3:34])[NH:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:9][C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH:36](=O)[CH2:37][CH2:38][CH3:39]>>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:31][CH2:32][S:33][CH3:34])[NH:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:9][C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNCCN2CCCCC2)cc1-c1ccccc1C
Reactant: CCCC=O
Product: CCCCN(CCN1CCCCC1)Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2C)c1

Procedure:
The desired compound was prepared using the method described in Example 403H starting with the compound prepared in Example 1196A and butyraldehyde. m/e (ESI) 552 (MH−)
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>O>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 72 h
Yield: 89.2 %

Procedure:
Toluene (0.7 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.35 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-chlorophenyl boronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (43 mg, yield 90%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[O:16])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (0.88 g, 4.0 mmol) and 5-aminoindole (0.53 g, 4.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 334 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:17]=[C:16]([CH2:18][CH3:19])[NH:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[CH2:20]([NH:22][C:23]([N:15]1[C:16]([CH2:18][CH3:19])=[CH:17][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)=[N:14]1)=[O:24])[CH3:21]
Reactant: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1CC
Yield: 23 %

Procedure:
Reaction of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole with ethyl isocyanate was carried out in the same manner as in Example 164, to give a white solid of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (0.25 g, yield: 23.0%). mp: 85-86° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H), 3.13 (q, J=7.5 Hz, 2H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 6.08 (s, 1H), 6.90-7.15 (m, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.37 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[S:16](=[O:18])=[O:17]>>[CH3:9][C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[CH:7][CH2:6][CH2:5][C:3]1[CH2:4][S:16]([CH2:1][CH:2]=1)(=[O:18])=[O:17]
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Reactant: O=S=O
Product: CC(C)=CCCC(C)=CCCC1=CCS(=O)(=O)C1
Reaction time: 18 h
Yield: 58 %

Procedure:
The (E)-β-farnesene containing product of Example 1 (17 g) and liquid sulphur dioxide are sealed in a glass ampoule and stored at ambient temperature for 18 hours. The ampoule is opened after cooling and the excess SO2 is allowed to evaporate. The residue is then chromatographed on Florisil using sequentially hexane, an ether/hexane mixture of increasing concentration in ether, and finally ether, the effluent being monitored by n.m.r. Removal of the solvent under vacuum from the appropriate fractions gives 3-(4,8-dimethyl-3,7-nonadienyl) sulpholene (II) as a straw coloured liquid (9 g, 58%); nD20 1.5080; M+ (m/z as % of base peak): 268 (0.02); δ(CCl4) 1.70 (m, 9H), 2.08 (m, 8H), 3.70 (m, 4H), 5.16 (m, 2H), 5.78 (br, t, 1H). Note: On heating at 180° C. under a vacuum of 1τ the sulpholene regenerates an (E)- and (Z)-β-farnesene mixture in high yield.
Reaction SMILES: C([O-])(=O)C.[NH4+].C[O:7][C:8](=O)[C:9]([CH3:23])([CH3:22])[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=O.C([BH3-])#[N:26].[Na+]>CO>[F:21][C:16]1[CH:15]=[C:14]([CH:12]2[NH:26][C:8](=[O:7])[C:9]([CH3:23])([CH3:22])[CH2:10][CH2:11]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: [BH3-]C#N
Reactant: COC(=O)C(C)(C)CCC(=O)c1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCC(c2ccc(F)c(F)c2)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ammonium acetate (36.62 g, 475.1 mmol) was dissolved in 200 mL of methanol. To this solution was added methyl-5-(3,4-difluorophenyl)-2,2-dimethyl-5-oxopentanoate (12.76 g, 47.2 mmol) and sodium cyanoborohydride (2.96 g, 47.1 mmol). This reaction mixture was stirred at ambient temperature for 24 hours. Another portion of sodium cyanoborohydride (1.50 g, 23.9 mmol) was added, and the mixture was stirred at ambient temperature for another 66 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between dichloromethane and saturated sodium carbonate. A 1.0M solution of aqueous sodium hydroxide was added to the aqueous phase to achieve a pH of 10. The phases were then separated, and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were then washed once with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. This residue was purified by “flash” chromatography (98:2 dichloromethane:methanol). The product fractions were evaporated to dryness to give the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, white solid (40 mg, 31%), MS (ISP) m/z=373.1 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (92.0 mg, 447 μmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:34])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](Cl)(=[O:31])=[O:30])=[C:13]1[CH3:33])[CH3:8]>N1C=CC=CC=1.O>[CH2:7]([O:9][C:10](=[O:34])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:31])=[O:30])=[C:13]1[CH3:33])[CH3:8]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Reactant: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a stirred solution of piperidine (0.36 mL, 3.6 mmol) in pyridine (50 mL) was added 2-(3-(2-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (1.53 g, 3.6 mmol), and the resulting solution stirred at room temperature for 18 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated copper sulfate solution (×3), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid ethyl ester (1.23 g, 2.60 mmol, 72%) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Yield: 79.1 %

Procedure:
5-Bromo-2,3-dihydro-isoindol-1-one (1.0 g, 4.72 mmol), 1-bromomethyl-4-methyl-benzene (1.14 g, 6.14 mmol) and cesium carbonate (3.08 g, 9.44 mmol) were suspended in anhydrous NMP (10 mL). The mixture was immersed in a 60° C. oil bath for 16.5 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Column chromatography (20% to 40% ethyl acetate/hexanes) provided the title compound as a yellow solid (1.18 g, 79%). 1H NMR CDCl3: 7.76 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 4.76 (s, 2H), 4.24 (s, 2H), 2.35 (s, 3H).