Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=2)[O:5][C:4](=[O:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]3)=[CH:26][C:21]=2[O:20][CH2:19]1.C(N(CC)CC)C>CN1CCCC1=O.O>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH:34][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:10]=5)[O:5][C:4](=[O:17])[CH:3]=4)[CH2:30][CH2:29]3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: NC1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: O=c1cc(Cl)c2cc(OC(F)(F)F)ccc2o1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(OC(F)(F)F)ccc2o1
Temperature: 220 °C
Yield: 52.5 %

Procedure:
To a suspension of 4-chloro-6-trifluoromethoxycoumarin (0.04 g, 0.15 mmol) in 1 ml N-methylpyrrolidone in a Smith reaction vial was added 1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamine (0.039 g, 0.16 mmol) followed by 0.042 ml of triethylamine. The reaction vessel was sealed with a crimper and the reaction heated at 220° C. for 20 minutes in a Smith Synthesizer. The reaction was diluted with 20 ml water and extracted with 3×10 ml ethyl acetate. The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed using 2% CH3OH:DCM to afford 36.4 mg (52%) of a white solid. MS (ESI (+)) m/e 463 (M+H)+; 1H NMR (300 MHz, MeOD4) δ ppm 1.65-1.75 (m, 2H), 2.0-2.1 (m, 2H), 2.25 (m, 2H), 3.0 (m, 2H), 3.5 (s, 2H), 3.6 (m, 1H), 5.37 (s, 1H), 5.9 (s, 2H), 6.75 (m, 2H), 6.9 (m, 1H), 7.45 (m, 1H), 7.55 (m, 1H), 8.10 (br s, 1H).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH3:17].[C:18]1([B:24](F)F)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCCCC.C1COCC1>[CH3:2][C:1]1[CH:4]=[CH:17][C:8]2[C:7](=[CH:16][CH:11]=[CH:10][CH:9]=2)[C:3]=1[B:24]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH3:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FB(F)c1ccccc1
Reactant: Cc1ccc2ccccc2c1Br
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2ccccc2c1B(c1ccccc1)c1c(C)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
27 ml of a 1.5 M solution of t-butyllithium in pentane are added over the course of 1.5 hours at -78° C. to a solution of 4.42 g (0.02 mol) of 1-bromo-2-methylnaphthalene in 40 ml of THF. The reaction mixture is stirred for 1 hour. 1.1 ml of phenyldifluoroborane (1.26 g, 0.01 mol) are added. The mixture is then allowed to warm to room temperature and is stirred for 2 hours more. The mixture is poured into 300 ml of water and the resulting suspension is filtered. The product is purified by chromatography (SiO2, hexane), to give 1.43 g (i.e. 39% of theory) of the borane as a white solid with a melting point of 208-209° C. The 1H-NMR shifts δ measured in CDCl3 are: 7.72 ppm (d,4,J=8.3 Hz), 7.53 ppm (d,2,J=8.6 Hz), 7.40-7.35 ppm (m,3), 7.25-7.15 ppm (m,6), 7.03 ppm (t,2,J=7 Hz) and 2.16 ppm (s,6).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:28])[CH:6]([CH2:25][CH2:26]O)[N:7]([CH3:24])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH:2]=[CH2:3].C(OC(=O)[C@H](CCO)NC(OC(C)(C)C)=O)C=C.[CH3:47][N:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51](=[O:58])[NH:50][C:49]1=[O:59]>>[C:51]1(=[O:58])[NH:50][C:49](=[O:59])[C:57]2=[CH:56][CH:55]=[CH:54][CH:53]=[C:52]12.[CH2:1]([O:4][C:5](=[O:28])[CH:6]([CH2:25][CH2:26][N:50]1[C:51](=[O:58])[C:52]2[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:48]([CH3:47])[C:49]1=[O:59])[N:7]([CH3:24])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH:2]=[CH2:3]
Reactant: Cn1c(=O)[nH]c(=O)c2ccccc21
Reactant: C=CCOC(=O)C(CCO)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Product: C=CCOC(=O)C(CCn1c(=O)c2ccccc2n(C)c1=O)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Product: O=C1NC(=O)c2ccccc21
Yield: 72 %

Procedure:
In a similar manner to that described in Example 1(1), a reaction was carried out using (±)-2-(2-hydroxyethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine allyl ester, the product of Example 41(2), instead of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester, and using 1-methylquinazoline-2,4-dione, instead of phthalimide, to afford the desired compound (yield 72%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].O.O1CCCC1.OO>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=[O:11]
Reactant: CCC1(CC(=O)OC)CCCCC1=O
Agent: OO
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1(CC(=O)OC)CCC=CC1=O
Reaction time: 4 h
Yield: 55.3 %

Procedure:
The ketone, 2-carbomethoxymethyl-2-ethylcyclohexanone (IX) (141 mmol, 28 g) was stirred in 1.25 L of ethyl acetate (dried over 3A molecular sieves) and treated with 169 mmol (32.5 g) of PhSeCL. The reaction was stirred under nitrogen for 4 hours then treated with 250 mL of water. The mixture was shaken vigorously in a separatory funnel and the organic phase was returned to the reaction flask. Tetrahydrofuran (550 mL) was then added followed by 35 mL of 30% H2O2 (aq.) added dropwise. The reaction mixture was stirred for one hour then washed with 500 mL of water and 500 mL of saturated Na2CO3 (aq.). The product was then dried over MgSO4 and concentrated in vacuo. Flash chromatography (4 inches diameter column, 20% ethyl acetate in petroleum ether eluent, 51/2 inches of silica gel) afforded 15.3 g (78.0 mmol, 55%) of the product as a pale yellow oil. Rf =0.9 in 15% ethyl acetate/petroleum ether on TLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=[C:2]2[CH:7]=1)[CH3:9]
Reactant: CCc1ccnc(N)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2ccc(CC)cc2n1
Yield: 18.6 %

Procedure:
A mixture of 2-amino-4-ethylpyridine (3.8 g), ethyl 3-bromo-2-oxopropionate (6.84 g) and ethanol (30 ml) was refluxed for 6 hours. After the reaction mixture was concentrated, water (30 ml) and ehtyl acetate (30 ml) were added to the residue. The mixture was made basic with an aqueous solution of potassium carbonate, and the separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to a column chromatography on silica gel (150 g) and eluted with 15% solution of ethyl acetate in chloroform. The fractions containing the object compound were combined and concentrated to give ethyl 7-ethylimidazo[1,2-a]pyridine-2-carboxylate (1.26 g).
Reaction SMILES: [Cs].C(OC=C)(=[O:4])C.[C:8]([O:21][CH:22]=[CH2:23])(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCC>O>[C:22]1(=[O:4])[O:21][C:8](=[O:20])[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:23]12
Reactant: C=COC(=O)CCCCCCCCCCC
Reactant: C=COC(C)=O
Agent: [Cs]
Solvent: O
Product: O=C1OC(=O)c2ccccc21
Reaction time: 18 h

Procedure:
For the preparation of the catalysts, 11.3 g of V2O5, 70.8 g of TiO2 (BET 8 m2/g), 17.7 g of TiO2 (BET 200 m2/g) and 0.2 g of cesium (as CsCO3) were suspended in 400 ml of demineralized water and stirred for 18 hours to obtain a homogeneous distribution. 1.5 g of organic binder, consisting of a copolymer of vinyl acetate and vinyl laurate in the form of a 50% strength by weight aqueous dispersion, were added to this suspension. The suspension obtained was then sprayed onto 1203 g of steatite rings, having in each case two notches in the upper side and two notches in the lower side, and was dried. The notches were offset by 90 degrees relative to one another. The rings had dimensions of 7×7×4 mm and the notch width was 1.4 mm and the notch depth 2 mm.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:44])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36](=[O:44])[CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(Cc1ccccc1)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (4-hydroxyphenyl)-2-phenylethanone are treated as described in Example 56, but crystallized in the form of hydrogen oxalate from diethyl ether and ethanol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[C:15][C:16]2[C:24]3[C:23]([Cl:25])=[N:22][C:21]([NH2:26])=[N:20][C:19]=3[N:18]([CH2:27][C:28]3[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=3)[CH:17]=2)(=O)=O)=CC=1.[F-].[Cs+].CO>CN(C=O)C.C(Cl)Cl>[C:15]([C:16]1[C:24]2[C:23]([Cl:25])=[N:22][C:21]([NH2:26])=[N:20][C:19]=2[N:18]([CH2:27][C:28]2[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=2)[CH:17]=1)#[C:14][CH:13]=[CH2:12]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCOS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N)nc32)c1C
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Temperature: 70 °C
Yield: 79.7 %

Procedure:
A mixture of 4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)but-3-ynyl 4-methylbenzenesulfonate (516 mg) and CsF (2.0 g) in DMF (7.0 mL) was heated to 70° C. for 1 h. Work-up and flash chromatography (1→3% MeOH in DCM) gave the title compound (280 mg), as a pale yellow oil. HPLC Rt=5.90 min.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][S:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)=[N:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:8][CH2:9][S:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:1])#[N:26]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: Cc1ccc(C(SCCN(C)CCCCN)c2ccccc2)cc1
Product: Cc1ccc(C(SCCN(C)CCCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccc2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.87 g (2.5 mmol) of N-methyl-N-[2-[[(4-methylphenyl)phenyl-methyl]thio]ethyl]-1,4-butanediamine and 0.95 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=624 ([M+H]+,6), 181 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 134°-140° C. with decomposition.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1
Yield: 21.1 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (543 mg, 1.65 mmol), the [4-(methyloxy)phenyl]boronic acid (500 mg, 3.29 mmol), copper (II) acetate (448 mg, 2.47 mmol), powdered molecular sieves (400 mg) and pyridine (0.27 mL, 3.29 mmol) in DCM (75 mL) were stirred at room temperature in the presence of air. After 4 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (880 mg) was purified by flash chromatography (Biotage SP4) with a gradient of Et2O (0 to 30%) in hexane to afford 115 mg of title compound (D32).
Reaction SMILES: [CH:1]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][S:7]2)=[C:3]([CH2:10][C:11]([OH:13])=O)[CH:2]=1.[CH3:14][NH:15][C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[N:25]1([C@@H:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:16]2[N:15]([CH3:14])[C:11](=[O:13])[CH2:10][C:3]2[C:4]3[CH:5]=[CH:6][S:7][C:8]=3[CH:9]=[CH:1][CH:2]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reactant: O=C(O)Cc1cccc2sccc12
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cccc2sccc12)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 0.5 g of 4-thianaphthene-acetic acid, 0.422 g of carbonyldimmidazole and 20 ml of tetrahydrofuran was stirred for one hour and then a solution of 0.432 g of the product of Step B in 5 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred for 31/2 hours and the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in 100 ml of ether and the solution was washed with aqueous saturated sodium bicarbonate solution, then with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 0.61 g of trans (±)- N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-inden-1-yl]-N-methyl-4-benzo[b]thiophene-acetamide in the form of an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1I.[F:16][C:17]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:18]=1[NH:19]C.[C:29]([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:19][C:18]1[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([C:25]([F:28])([F:27])[F:26])[C:17]=1[F:16]
Reactant: CNc1cccc(C(F)(F)F)c1F
Reactant: CCc1ccc(I)c(CC(=O)N(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1

Procedure:
A mixture of N,N-dimethyl-5-ethyl-2-iodophenylacetamide (2.0 g, 6.3 mmol), 2-fluoro-methyl-3-trifluoromethylaniline (2.4 g, 12.6 mmol), copper (0.2 g, 3.2 mmol), cuprous iodide (0.6 g, 3.2 mmol), and K2CO3 (0.9 g, 6.3 mmol) in xylenes (6.0 mL) are heated at reflux for 24 h. After cooling, the crude reaction mixture is diluted with EtOAc and filtered through Celite®. The filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with hexanes, then up to 25% EtOAc/hexane mixtures to give the target compound 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:28][CH:27]=1)=[N:1]2
Reactant: NC(=O)c1c(N)cccc1Cl
Reactant: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(c2ccc(-c3nc4cccc(Cl)c4c(=O)[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 2-amino-6-chlorobenzamide (0.314 g, 1.85 mmol) and 4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.430 g, 1.85 mmol) in DMA (25 mL) were treated with p-TsOH (0.035 g, 0.185 mmol) and NaHSO3 (0.212 g, 2.04 mmol), and the mixture was heated at 140° C. for 18 hours. Then, the mixture was cooled, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 6:3:1 CHCl3/MeOH/concentrated NH4OH. The resulting solids were rechromatographed with 9:1 CH2Cl2/MeOH to afford the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.66-7.71 (m, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.64-2.73 (m, 1H), 2.55-2.59 (m, 4H), 1.01 (d, J=6.4 Hz, 6H). ESI MS m/z 383 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:4].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1sccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccsc1C(=O)O
Reaction time: 1 h

Procedure:
48.5 g (0.31 mmoles) of 3-hydroxy-2-thiophene carboxylic acid methyl ester (IV: R3 =H) are dissolved in 400 ml of acetone, 84.7 g (0.61 moles) of potassium carbonate, 77.3 g (0.61 moles) of dimethylsulfate are added, and the mixture is refluxed with stirring for 1 hour. The salt mass is aspirated, washed several times with acetone and the combined filtrate is concentrated in vacuo. 750 ml of aqueous 2N sodium hydroxide are added and boiled. The reaction solution is cooled, washed with ether and acidified with concentrated HCl. The precipitating colorless crystals are aspirated and recrystallized from ethanol. Yield: 43.1 g (89%), m.p. 184°-185° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]#[N:25])[C:21]3[N:26]=[CH:27][NH:28][C:20]=3[CH:19]=2)=[CH:14][C:13]=1[C:29]([F:32])([F:31])[F:30])[CH3:6].[CH:33](N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]#[N:25])[C:21]3[N:26]=[CH:27][N:28]([CH3:33])[C:20]=3[CH:19]=2)=[CH:14][C:13]=1[C:29]([F:32])([F:30])[F:31])[CH2:5][CH3:6])(=[O:3])[CH3:2]
Reactant: CCNCCCOc1ccc(-c2cc3[nH]cnc3c(C#N)n2)cc1C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CCN(CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.009 ml) was added dropwise to a solution of 6-(4-(3-(ethylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (17.5 mg) and diisopropylethylamine (0.034 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. The product was then purified by acidic prep HPLC to 6-{4-[3-(N-acetyl-N-ethylamino)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (MeOD) δ: 8.43 (s, 1H), 8.34-8.30 (m, 2H), 7.30 (t, 1H), 4.25-4.18 (m, 2H), 4.02 (s, 3H), 3.52-3.63 (m, 2H), 3.45 (q, 2H), 2.20-2.11 (m, 5H), 1.22+1.15 (2xt, 3H). MS m/z 446 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]([F:52])([F:51])[C:40]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:41]=1[NH2:42]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([NH:42][C:41]2[CH:43]=[C:44]([C:47]([F:48])([F:49])[F:50])[CH:45]=[CH:46][C:40]=2[C:39]([F:38])([F:51])[F:52])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Example 43, step (a)) and 2,5-bis-trifluoromethyl-aniline under the conditions described in Example 37, step (b).
Reaction SMILES: C(OC(N([CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Br:24])C(OC(C)(C)C)=O)=O)(C)(C)C.[Br:25]C1C=CC(Cl)=CC=1C.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH2:16][Br:25]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Cl)ccc1Br)C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 80 °C

Procedure:
N,N-bis(tert-butoxycarbonyl)-2-bromo-5-chlorobenzylamine: To 1-bromo-4-chloro-2-methylbenzene (3.3 g, 16.06 mmol) in CCl4 (30 mL) were added NBS (3.43 g, 19.27 mmol) and benzoyl peroxide (10 mg, 0.041 mmol). The reaction was heated 80° C. overnight, then filtered and purified by flash chromatography to give 1-bromo-2-bromomethyl-4-chloro-benzene (4.5 g). 1HNMR (400 MHz, CDCl3) δ: 4.53 (s, 2H) 7.15 (dd, J=8.59, 2.27 Hz, 1H), 7.40-7.47 (m, 1H), 7.49 (d, J=8.59 Hz, 1H). This intermediate was combined with di-tert-butyl iminodicarbonate (3.49 g, 16.06 mmol) and cesium carbonate (5.23 g, 16.06 mmol) in DMF (16 mL) and stirred overnight. The reaction was partitioned with EtOAc/water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and evaporated. The resulting residue was purified by flash chromatography to give 126A (3.4 g). 1HNMR (400 MHz, CDCl3) δ: 1.43-1.51 (m, 18H), 4.82 (s, 2H), 7.08-7.18 (m, 1H), 7.39-7.53 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)#[N:21].NC(N)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[O:30])[CH:5]=1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: COC(=O)c1cccc(CNCc2ccccc2)c1
Agent: NC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(Cc2ccccc2)C(=O)Nc2ccc(C#N)cc2)c1
Yield: 34.4 %

Procedure:
Dissolved 3-(benzylamino-methyl)-benzoic acid methyl ester (197 mg, 0.77 mmol) in 5 mL of DMF. To this was added 4-cyanophenyl isocyanate (112 mg, 0.78 mmol). The mixture stirred for 48. LC-MS analysis indicated the desired urea. The mixture was diluted with 100 mL EtOAc, washed with 3×50 mL of H2O and 1×20 mL of brine. The organic phase was dried with MgSO4, filtered and concentrated. The resulting residue was applied to a SiO2 prep plate and eluted with 50% EtOAc/hexanes to give two fractions-one clear band and a tail. LC-MS analysis indicated both band and tail were composed of the product. Both fractions were combined to give 105.7 mg of 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester.