Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:24][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(OC1CCCCO1)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
To a solution of methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (2.2 g), dihydropyran (2.3 ml) and ethyl ether was added a catalytic amount of para-toluene sulfonic acid. The reaction was stirred at room temperature for four days. The ethyl ether was removed in vacuo and the remaining oil was purified by HPLC on silica gel using 7:93 ratio of ethyl acetate/hexanes as an eluent (1.8 g., 67% yield). In like manner as above, using appropriate starting materials, the following compound was made:
Reaction SMILES: [Cl-].[C:2]1([CH:8]([O:10][NH3+:11])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]3[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[N:29]3)[CH2:22][CH2:21]2)[S:18][CH:19]=1)(=O)[CH3:13]>C(O)C>[CH3:33][C:32]1[N:28]([CH2:27][C:26]([N:23]2[CH2:24][CH2:25][CH:20]([C:17]3[S:18][CH:19]=[C:15]([C:12](=[N:11][O:10][CH:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:9])[CH3:13])[N:16]=3)[CH2:21][CH2:22]2)=[O:38])[N:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=1
Reactant: CC(O[NH3+])c1ccccc1
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Cl-]
Solvent: CCO
Product: CC(=NOC(C)c1ccccc1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reaction time: 24 h

Procedure:
At room temperature, (1-phenylethoxy)ammonium chloride (91 mg) and Amberlyst A21 (300 mg) are added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (200 mg) in ethanol. The reaction mixture is stirred for 24 hours, and the solvent is then removed under reduced pressure. The residue is separated by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient). This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[N-(1-phenylethoxy)ethanimidoyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (230 mg, 89%) which consists of an about 9:1 mixture of trans and cis isomers (log P(pH2.7)=4.38 (89%), 4.54 (11%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[C:13](Cl)(Cl)=[S:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([N:6]=[C:13]=[S:14])=[C:7]([CH2:9][CH3:10])[CH:8]=1
Reactant: CCc1cc(C)cc(CC)c1N
Reactant: S=C(Cl)Cl
Product: CCc1cc(C)cc(CC)c1N=C=S

Procedure:
Using the same process, 4-methyl-2,6-diethylaniline and thiophosgene give 4-methyl-2,6-diethyl-phenyl isothiocyanate, boiling point 113°-116° C./1.2 mm Hg.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:20]=2[O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: COC(=O)CBr
Reactant: Oc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
(4-(3-(2-naphthylmethylamino)propyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (166 mg) was dissolved in DMF (3 ml), and potassium carbonate (63 mg) and methyl bromoacetate (0.045 ml) were added. to the resultant solution at 0° C., followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=2:3) to obtain the object compound (140 mg, yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([CH3:18])[CH3:17]>O1CCOCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH:16]([CH3:17])[CH3:18])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)C)c(C(=O)OC)c1
Yield: 69.3 %

Procedure:
Dimethyl-4-amino-isophthalate (10 g) in 10 ml of dioxane and 20 ml of anhydrous pyridine are treated with 20 g of 2-isopropoxy-benzoyl chloride at room temperature, overnight. After dilution with water, the precipitate is collected, dissolved in ethyl acetate, and washed with 5% NaHCO3 and then with water. After evaporation to dryness under vacuum, the material is crystallized from isopropyl ether, yielding dimethyl-4-(2'-isopropoxybenzoylamino)-isophthalate (12.3 g; m.p. 107°-110° C.), which is dissolved in 80 ml of dioxane and treated with 80 ml of 1 N NaOH at room temperature for one night. After acidification with dilute HCl, the precipitate is collected under vacuum and washed with water until neutral. The yield is 10.9 g of 4-(2'-isopropoxybenzoylamino)-isophthalic acid, which are treated with 60 ml of acetic anhydride at 90°-100° C. for 15'. After cooling, dilute with 60 ml of isopropyl ether and filter. The yield is 9 g of 6-carboxy-2-(2'-isopropoxyphenyl)-4H-3,1-benzoxazin-4-one (m.p. 246°-250° C.), which are reacted at room temperature first with 90 ml of 32% ammonium hydroxide and then with 45 ml of 2 N NaOH for 120'. After acidification with 4 N HCl, the precipitate is filtered off and crystallized from ethanol-chloroform to give 6-carboxy-2-(2'-isopropoxyphenyl)-3,4-dihydro-4-oxo-quinazoline (6.6 g; m.p. 316°-318° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O=[C:12]1[CH2:16][S:15][CH2:14][CH:13]1[C:17](OC)=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:18]=[C:17]1[N:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]2=[N:1][C:12]2[CH2:16][S:15][CH2:14][C:13]1=2
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Temperature: 170 °C
Yield: 63.2 %

Procedure:
6-Aminonicotinic acid (10 g., 0.072 mol) [Berichte, 26, 2187,(1893)], methyl 4-oxotetrahydro-thiophene-3-carboxylate (28 g., 0.175 mol) [Monats, Chem., 104, 1520(1973)]and p-toluenesulfonic acid monohydrate (1.0 g) are thoroughly mixed and heated at 170° C. under nitrogen for 75 minutes. The distillate is collected in a Dean-Stark trap. The residue is cooled, tritrated with boiling chloroform and filtered to give the product as a yellow powder (11.3 g.). Recrystallization from dimethylformamide gives an analytical sample mp 314°-315° C. (dec).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][O:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: OCCCl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.9 %

Procedure:
2-Chloroethanol (1168 g, 975 mol) and benzene sulfonyl chloride (2780 g, 2015 mol) were stirred together at −5° C. and pyridine (2158 g, 2200 mol) was added over a 3 hours period, maintaining the temperature below 0° C. The reaction was stirred for a further 3 hours at −5° C. to 0° C. and was then allowed to warm to room temperature over 18 hours. After pouring into a mixture of ice (10 liters) and water (10 liters) the reaction was stirred for 15 minutes, extracted with ether (10 liters) and the organic phase was washed with 5N HCl (2×2 liters) and water (2×4 liters). It was then dried over MgSO4 and concentrated under reduced pressure to give benzene sulfonic acid 2-chloro-ethyl ester (1921 g) as an orange oil. 1H NMR (250 MHz, CDCl3): δ=7.78-8.02 (2H, m), 7.58-7.78 (3H, m), 420-4.45 (2H, t), 3.60-3.81 (2H, t) ppm.
Reaction SMILES: C([O:4][C:5]([C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13](OCC3C=CC=C(OCC4C=CC5C(=CC=CC=5)N=4)C=3)=[CH:12][C:10]=2[N:11]=1)=[O:6])CC.C(=O)(O)[O-].[Na+]>C(O)C.O>[O:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[C:5]([OH:6])=[O:4]
Reactant: CCCOC(=O)c1nc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.64 g of n-propyl-5-(3-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazole-2-carboxylate and 0.45 g of sodium bicarbonate in 20 ml of ethanol in 20 ml of water is refluxed for 1.5 hours, then stirred at room temperature overnight. The mixture is neutralized and the resulting solid is filtered off, washed with water and dried in vacuo to give 5-(3-quinolin-2-ylmethyloxy)-benzyloxy)benzoxazole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([CH3:16])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Br:17][C:18]1[C:19]([O:25][CH3:26])=[N:20][C:21](Cl)=[N:22][CH:23]=1>>[CH2:14]([O:13][C:11]([N:10]=[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:21]2[N:20]=[C:19]([O:25][CH3:26])[C:18]([Br:17])=[CH:23][N:22]=2)[CH:3]=1)([CH3:16])=[O:9])=[O:12])[CH3:15]
Reactant: COc1nc(Cl)ncc1Br
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(N)c1
Product: CCOC(=O)N=S(C)(=O)c1cccc(Nc2ncc(Br)c(OC)n2)c1
Yield: 43.3 %

Procedure:
Intermediate 14 was prepared in analogy to GP 2 by reaction of Intermediate 5 (1.73 g, 7.16 mmol) with commercial 5-bromo-2-chloro-4-methoxypyrimidine (2.00 g, 8.95 mmol, 1.25 eq) to give 1.33 g (43% yield) of the title compound (after crystallization from acetonitrile and column chromatography of the mother liquor residue).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)=O.[NH3:14]>C(Cl)(Cl)Cl>[Cl:11][C:9]1[N:8]=[C:7]([S:12][CH3:13])[N:6]=[C:5]([C:3]([NH2:14])=[O:2])[CH:10]=1
Reactant: N
Reactant: COC(=O)c1cc(Cl)nc(SC)n1
Solvent: ClC(Cl)Cl
Product: CSc1nc(Cl)cc(C(N)=O)n1
Reaction time: 0.33 h
Yield: 103.4 %

Procedure:
A 500 mL flask was charged with the 6-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester (4.37 g, 20 mmol), and chloroform (30 mL). Ammonia (57 mL, 7 M in methanol, 0.4 mol, 20 eq.) was added with stirring. HPLC analysis after 20 minutes indicated no starting methyl ester remained. The mixture was sparged with nitrogen for 30 min, then concentrated in vacuo, and dried under high vacuum to afford the 6-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid amide (4.21 g, quant.) in sufficient purity for use in the next step. 1H NMR (500 MHz, CDCl3) □ 7.76 (s, 1H), 7.60 (br s, 1H), 5.97 (br s, 1H), 2.61 (s, 3H); ESI-MS m/z 204.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1>C(OCC)(=O)C.Cl>[CH3:2][O:3][C:4]1[CH:21]=[C:19]([C:18]2[C:4]3[O:3][CH:2]([CH3:1])[CH2:8][NH:7][CH2:6][C:5]=3[S:16][CH:17]=2)[CH:20]=[CH:6][CH:5]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C(C)C)c2O1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 140.5 %

Procedure:
tert-Butyl 2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (235 mg) was stirred in 4N hydrogen chloride-ethyl acetate solution (5 mL) for 20 min. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 2-methyl-8-(1-methylethyl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (146 mg, 78%) as colorless crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:10][N:9]([CH3:11])[C:8](=[S:12])[S:7]1.S(OC)(O[CH3:17])(=O)=O.[K]>C(O)C>[CH:6](=[N:10][N:9]([CH3:11])[C:8]([S:7][CH3:17])=[S:12])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CN1NC(c2ccco2)SC1=S
Reactant: COS(=O)(=O)OC
Agent: [K]
Solvent: CCO
Product: CSC(=S)N(C)N=Cc1ccco1
Reaction time: 2.5 h

Procedure:
1 g of 2-(2-furyl)-4-methyl-1,3,4-thidiazolidine-5-thione was dissolved in 50 ml of warm ethanol, and after cooling to room temperature 1.26 g of dimethyl sulphate was added. After stirring for 2.5 hours at 50°, 0.69 g potassium was added, the mixture was heated for 1.5 hours at 50°, then allowed to stand overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallised from ethanol and pure S-methyl 3-furfurylidene- 2-methyl-dithiocarbazate (mp = 103°) was obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O.[OH-].[Na+]>O>[Cl:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(O)c2c(ccc3cn[nH]c32)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)c2c(ccc3cn[nH]c32)n1
Temperature: 80 °C
Yield: 92692.9 %

Procedure:
To a suspension of 9-hydroxy-7-methyl-1H-pyrazolo[3,4-f]quinoline (8.00 g, 0.04 mmol) in phosphorus oxychloride (61.6 g, 0.40 mol) was added slowly N,N-dimethylformamide (40 ml). After the addition was complete, the reaction mixture was warmed to 80° C. for 1 hour and then allowed to cool to room temperature. The reaction was poured onto ice and dissolved in water (2 L total volume) and neutralized to pH 7 with 20% sodium hydroxide (NaOH). The precipitate which formed upon neutralization was collected by filtration, washed with water and dried under vacuum to give 9-chloro-7-methyl-1H-pyrazolo[3,4-f]quinoline as a white solid (8.07 g, 92%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:19]2[C:14](=[CH:15][N:16]([CH3:22])[C:17](=[O:21])[C:18]=2[CH3:20])[NH:13]C1=O.[Si]([O:31][CH2:32][CH2:33][C:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1)(C(C)(C)C)(C)C>CN(C=O)C.C1COCC1>[OH:31][CH2:32][CH2:33][C:34]1([S:37]([NH:13][C:14]2[C:19]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=3[F:3])=[C:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=2)(=[O:39])=[O:38])[CH2:36][CH2:35]1
Reactant: Cc1c(=O)n(C)cc2[nH]c(=O)n(-c3ccc(I)cc3F)c12
Reactant: CC(C)(C)[Si](C)(C)OCCC1(S(=O)(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil) (21.8 mg, 0.544 mmol) is added to a solution of 1-(2-fluoro-4-iodophenyl)-5,7-dimethyl-1H-imidazo[4,5-c]pyridine-2,6(3H,5H)-dione (100 mg, 0.251 mmol) in dry DMF (5 mL) at 0° C. The cooling bath is removed and the solution stirred at room temperature for 1 hour. The solution is re-cooled to −5° C. in a dry-ice/acetone bath, and 1-[2-(tert-butyldimethylsilanyloxy)ethyl]-cyclopropanesulfonyl chloride (300 mg, 1 mmol) in dry THF (2 mL) is added. The mixture is warmed to room temperature and stirred for an additional 16 hours. The mixture is concentrated to give an oily residue and purified via flash chromatography (SiO2, EtOAc:MeOH=9:1) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[N:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][CH:57]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:56]2[CH:57]=[CH:58][CH:59]=[C:60]([O:62][CH3:63])[N:61]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Yield: 52 %

Procedure:
A solution containing the product from Example 23I (0.20 g, 0.28 mmol) in DMF (3 mL) was treated with LiCl (0.119 g, 2.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and the product from Example 113A (0.338 g, 0.85 mmol), heated at 85° C. for 64 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to give the title compound (0.097 g, 51% yield).
Reaction SMILES: [F:1][CH:2]([NH:32][CH:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH2:39]=O>>[F:1][CH:2]([N:32]([CH3:39])[CH:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: C=O
Reactant: Cc1ccc(NC(=O)c2ccc(C(F)NC3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(C(F)N(C)C3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The product from Example 11 was methylated via reductive amination with HCHO/NaBHCN afforded the title compound. Mass: (M+1), 526.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:24]=2)=[C:13]([C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([C:32]([F:35])([F:34])[F:33])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[CH2:3]([N:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:24]=2)=[C:13]([CH:25]([OH:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([C:32]([F:33])([F:35])[F:34])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Reaction time: 2 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (6.44 mg, 0.17 mmol) was added portionwise to a solution of ethyl 2-[1-benzyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-oxoacetate (49e) (78 mg, 0.17 mmol) in anhydrous methanol (2 mL). After 2 hours stirring, water was added (3 mL). The methanol was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The organic layer was successively washed with water (3 mL) and brine (3 mL), before being dried over sodium sulfate and concentrated in vacuo to provide the desired alcohol (49f) (70 mg, 0.17 mmol, 89%) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Temperature: 138 °C
Yield: 98.8 %

Procedure:
A mixture of 350 mg (1.45 mmol) of 1-(5-chloro-2-nitro-phenyl)-piperidine (as prepared in Example 4, step (a)) and 482 μL (4.35 mmol) of 1-methylpiperazine was heated in a sealed vial at 138° C. for 30 h. The mixture was cooled and poured into 60 mL of water and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated in vacuo to afford 436 mg (99%) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 305.2 (M+H), found 305.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].[Li+].[OH-]>C(O)(=O)C>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(CCO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(CCO)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a vial containing 2-(3-aminophenyl)ethanol (137.0 mg, 1.0 mmol) in glacial acetic acid (3 mL) was added acetic anhydride (1 mL). The reaction vial was sealed and heated at 110° C. for 6 h. The mixture was concentrated under reduced pressure. The crude product was dissolved in MeOH (3 mL) and LiOH (120.0 mg, 5.0 mmol) was added. The solution was allowed to stir overnight at rt. The solution was concentrated under reduced pressure and diluted with ethyl acetate. The organic phase was washed with water (2×5 mL), brine and dried (Na2SO4). The solvent was removed under reduced pressure and the crude mixture was purified by column chromatography to afford the desired product in 39%. 1H NMR: 1.65 (t, 1H, J=6.0 Hz), 2.13 (s, 3H), 2.81 (t, 2H, J=6.4 Hz), 3.81 (q, 2H, J=6.0 Hz), 6.94 (t, 1H, J=6.8 Hz), 7.22 (t, 1H, J=7.6 Hz), 7.30-7.40 (m, 3H).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:25][C:18]1[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]2[NH:8][C:7]3[C:2]([C:36]4[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=4)=[CH:3][C:4]([C:27]([F:30])([F:29])[F:28])=[CH:5][C:6]=3[N:10]=2)[C@H:12]([CH3:26])[CH2:13]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Bromo-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (152 mg, 0.3 mmol, Example 151) and 4-trifluoromethylphenylboronic acid (114 mg, 0.6 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 570 (M+1).