Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.O[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: OCc1ccncc1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccncc3)C2=O)cc1
Temperature: 120 °C
Yield: 29.1 %

Procedure:
A mixture of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.50 mmol, 147 mg), 4-hydroxymethylpyridine (0.75 mmol, 82 mg), diethyl azodicarboxylate (0.75 mmol, 131 mg) and triphenylphosphine (0.75 mmol, 197 mg) in dry THF (2 mL) was heated in a microwave reactor at 120° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 56 mg (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.59 (bs, 2H), 7.35-7.29 (m, br, 2H), 7.25 (s, br, 1H), 7.17-7.06 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.53 (m, 4H), 4.77 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1>C(#N)C>[NH2:29][C:27]1[N:28]=[C:23]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:9])[CH2:3]2)[CH:24]=[CH:25][C:26]=1[N+:30]([O-:32])=[O:31]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Yield: 104.7 %

Procedure:
To a suspension of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (45.56 g, 208.3 mmol) in anhydrous acetonitrile (200 mL) at 10° C. was added triethylamine (50 mL). The suspension was poured into a 2 L 3-neck flask equipped with a thermometer and a magnetic stirrer. To the original flask was added anhydrous acetonitrile followed by sonication and addition of triethylamine (80 mL). The suspensions were combined and cooled to 10° C. and 6-chloro-3-nitropyridin-2-amine (32.97 g, 190 mmol) was added. The bright yellow solution was stirred under nitrogen while the temperature was increased gradually to 80° C. over 1 h. The reaction mixture was cooled to room temperature. The resulting suspension was filtered and the solids were rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride (500 mL) was added to the residue and the mixture was extracted into ethyl acetate (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried for 18 h under high vacuum to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as a yellow foam (63.51 g). 1H NMR (400 MHz, CD3OD) δ 1.47-1.64 (m, 1H) 1.71-2.07 (m, 7H) 2.68 (tt, 1H) 3.01 (q, 2H) 3.33-3.46 (m, 2H) 3.52 (dt, 1H) 3.60-3.70 (m, 1H) 4.41 (br s, 1H) 4.71 (d, 1H) 6.23 (d, 1H) 8.05 (d, 1H); MS (ES+) (M+H) 320.4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35](=[O:36])[C:34]4[CH:38]=[CH:39][N:40]=[C:32]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:33]=4)[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccnc(N5CCOCC5)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-morpholin-4-ylisonicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/methanol=95:5) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:16]=1[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([NH2:23])=[N:19]1>>[Cl:14][C:15]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:16]=1[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([NH:23][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:19]1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4ccc(Cl)cc4Cl)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(2,4-dichloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil (yield=56%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 29B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46 (s, 1H), 8.63 (dd, J=5.0, 0.7 Hz, 1H), 8.40-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.77-7.79 (m, 1H), 7.74 (dd, J=1.4, 0.7 Hz, 1H), 7.66 (dd, J=5.0, 1.5 Hz, 1H), 7.43-7.46 (m, 2H), 7.29-7.33 (m, 2H), 7.16-7.21 (m, 1H), 2.63 (s, 2H), 1.47 (s, 6H); MS (APCI+) M/Z 433 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.[Br:30][C:31]1[C:40]([CH2:41]Br)=[CH:39][C:38]2[C:37]([CH3:44])([CH3:43])[CH2:36][CH2:35][C:34]([CH3:46])([CH3:45])[C:33]=2[CH:32]=1>O1CCCC1>[Br:30][C:31]1[C:40]([CH2:41][N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[CH:39][C:38]2[C:37]([CH3:44])([CH3:43])[CH2:36][CH2:35][C:34]([CH3:46])([CH3:45])[C:33]=2[CH:32]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21
Reactant: c1cn[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(Br)cc21
Yield: 48.1 %

Procedure:
To a suspension of 0.955 g (8.52 mmol) of potassium tert-butoxide and 1.877 g (7.10 mmol) 18-crown-6 ether in 35 ml tetrahydrofuran was added 0.580 g (8.52 mmol) pyrazole. After 10 minutes 2.557 g (7.10 mmol) 2-bromo-5,5,8,8-tetramethyl-3-bromomethyl-5,6,7,8-tetrahydronaphthalene was added in 15 ml THF. After 17 hours the reaction was concentrated under reduced pressure and acidified with 1M hydrochloric acid. The aqueous solution was extracted with ethyl ether, washed with saturated sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (gradient elution with hexane-25% ethyl acetate/hexane) to afford 1.185 g (48%) of 2-bromo-5,5,8,8,-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalene (M+1=348).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:36])[NH:17][C:18]([N:21]3[C:29]4[C:28]5[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:27]=5[CH2:26][CH2:25][C:24]=4[CH:23]=[N:22]3)([CH3:20])[CH3:19])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:36])[NH:17][C:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:28]5=4)[CH:23]=[N:22]3)([CH3:20])[CH3:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)-c1c(cnn1C(C)(C)NC(=O)OCC1c3ccccc3-c3ccccc31)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2ccc3cnn(C(C)(C)NC(=O)OCC4c5ccccc5-c5ccccc54)c3c2c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To a solution of the product from Step A (0.08 g, 0.17 mmol) in 1,4-dioxane (10 mL) was added DDQ (0.08 g, 0.34 mmol). The solution was stirred at 23° C. for 3 hr and poured into saturated aqueous NaHCO3 and this mixture was extracted with ether (2×20 mL). The combined extracts were washed with aqueous NaHCO3, dried (MgSO4), and evaporated to a crude product which was purified by chromatography (silica, 40% ethyl acetate in hexanes) to obtain an oil (0.045 g, 55%): MS m/z: 478 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(N(CC)CC)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(F)cc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-(4-fluorophenoxy)-3-[4-(2-hydroxyethoxy)phenyl]propionate (2.68 g), which is the product of Reference example 37(d), triethylamine (1.61 ml) and methanesulfonyl chloride (0.65 ml) and the reaction mixture was treated to afford the desired compound (3.17 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: Brc1nccs1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CN(c2nccs2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 24.2 %

Procedure:
The product of Step A in Preparation 17, methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in 1,4-dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 2-bromo-1,3-thiazole (1.57 g, 9 6 mmol) were added. The reaction was conducted at 180° C. for 20 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (0.15 g, 25%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.C[CH2:16][N:17](C(C)C)C(C)C.CN>C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>[CH3:16][NH:17][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([NH:2][CH3:1])[CH:4]=1
Reactant: CNc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CNC(=O)c1ccc([N+](=O)[O-])c(NC)c1

Procedure:
N-Methyl-3-methylamino-4-nitro-benzamide (407 mg) was prepared by following General Procedure N starting from 3-methylamino-4-nitro-benzoic acid (500 mg), DPPA (550 uL), DIEA (445 uL), and methylamine (2 M in THF, 2.55 mL).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:33])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 54.2 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-acetyl-4-piperidinecarboxylic acid (5.1 g) and 1,8-diazabicyclo-[5.4.0]-undec-7-ene (4.6 g), and after successive recrystallization in a mixture of acetone and water (2:1 by volume) and then in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-acetyl-4-piperidinecarboxylate (7.5 g), m.p. 101° C., is obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[CH2:5][C:4](=O)[CH2:3]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[C:19]([SH:21])[CH:20]=1>CS(C)=O>[Cl:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:22][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[C:5]=1[S:21]2
Reactant: COC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccc(Cl)cc1S
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Cl)cc1S2

Procedure:
A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (2.53 g, 13.7 mmole) and 5-chloro-2-aminobenzenethiol, 6 (X=Cl, 2.20 g, 13.7 mmole), in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4e, (R=Cl), mp 226-227° C. occurs as light orange crystals; yield: 1.70 g (36.7%).
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([F:20])([F:19])[C:4]([F:18])([F:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O.[BrH:26].S(=O)(=O)(O)O>O>[Br:26][CH:5]([C:4]([F:18])([F:17])[C:3]([F:20])([F:19])[C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCC(Br)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
To a mixture of 19.52 g of 11-(nonafluorobutyl)-1-undecanol and 200 mL of 48 weight percent hydrobromic acid was slowly added 20 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 24 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to an amber liquid, which was eluted through 3 inches of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 19.82 g of 1-bromo-1-(nonafluorobutyl)undecane as a clear, colorless liquid, b.p. 120-170° C. at 0.06 torr (8 Pa).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34]Cl>CN(C=O)C.C1COCC1>[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazole (3) (1 g 4.18 mmol) is dissolved in DMF/THF (50 ml/20 ml) and cooled to −78° C. Potassium bis-(trimethylsilyl)-amide (15% in toluene; 6.7 ml 5 mmol) is introduced at −78° C., stirred for 30 min. then 2-(trimethylsilyl)ethoxymethylchloride is added and the reaction mixture warmed up to r.t., poured on water after 2 hrs. and extracted 3× with ethyl acetate. The combined organic phases are dried over Na2SO4, evaporated to dryness and chromatographed (SiO2 acetone/hexane 4/6 to 6/4) to give 1-(2-(trimethylsilyl)ethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole, being eluted first as white crystals (218 mg 14%) followed by 4-(4-pyridyl)-5-(4-fluorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl) imidazole as white crystals (590 mg 38%). The correct assignment of the structures was achieved by ROESY, HSQC and HMBC spectrometry.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Cl:18]N1C(=O)CCC1=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([Cl:18])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 ml round bottom flask was added methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (1.100 g, 3.71 mmol) as a solution in THF and a magnetic stir bar. To the same was added 1-chloro-2,5-pyrrolidinedione (0.546 g, 4.09 mmol) and the system stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (60 ml) and washed with saturated NaHCO3 (20 ml) and brine (8 ml). The organic layer was dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography provided methyl 6-bromo-3-chloro-1-isopropyl-1H-indole-4-carboxylate (as a thick gold oil), which was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=1.52 Hz, 1H), 7.93 (s, 1H), 7.50 (d, J=1.77 Hz, 1H), 4.90 (quin, J=6.63 Hz, 1H), 3.89 (s, 3H), 1.43 (d, J=6.57 Hz, 6H). MS (ES) [M+H]+ 332.2.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC(C)C)cc1
Yield: 67 %

Procedure:
3.0 g of 4-isopropoxy-benzoic acid (16.7 mmol, 1.0 eq) were dissolved in MeOH (20 mL) and a catalytic quantity of sulfuric acid was added; the mixture was heated at reflux for 2 days. The solvent was then evaporated and the residue was dissolved in DCM and washed with 10% NaOH. The organic phases were dried and evaporated to give 2.2 g of title product (yield 67%).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Pd].N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C#CCn3ccnc3)ccc2N1
Agent: [Pd]
Solvent: c1ccncc1
Product: O=C1CCc2cc(C=CCn3ccnc3)ccc2N1
Reaction time: 0.25 h

Procedure:
A suspension of 75 mg of 5% palladium on barium sulfate catalyst in 8 ml of pyridine was stirred under hydrogen for 15 minutes. A solution of 502 mg of 6-[3-(imidazol-1-yl)prop-1-yn-1-yl]-3,4-dihydrocarbostyril in 3 ml of pyridine was added and the mixture stirred under hydrogen until the theoretical volume of hydrogen had been absorbed. The reaction mixture was filtered and the solvent removed from the filtrate under reduced pressure to give a residue which was recrystallized from a mixture of methanol and ethyl acetate to give 6-[3-(imidazol-1-yl)prop-1-en-1-yl]-3,4-dihydrocarbostyril, m.p. 158°-160° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](Cl)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23]([N:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Reactant: c1ccc2c(c1)CCCN2
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 100 mg (0.22 mmole) of N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl chloride (from Example 2, Step B), 0.2 mL (1.15 mmole) of N,N-diisopropylethylamine, and 44 mg (0.33 mmole) of 1,2,3,4-tetrahydroquinoline in 2.5 mL of toluene was stirred at 110° C. for two days. After cooling to room temperature, volatiles were removed by rotary evaporation, and the residue was flash chromatographed over silica gel (gradient elution using 10% to 12.5% EtOAc in hexane) to give 81 mg (66%) of the desired product as an oil, homogeneous by TLC (4:1 hexane-EtOAc), FAB-MS m/e 548 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(OC(=O)C)(=O)C>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Br:1])[CH:9]=1)[O:11][C:21](=[O:22])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[CH:5]2
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: COc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3oc2=O)cc1
Temperature: 80 °C

Procedure:
3,5-Dibromo-2-hydroxybenzaldehyde (30.0 g, 107 mmol) [CAS-Nr. 90-59-5] and 4-methoxyphenylacetic acid (35.7 g, 166 mmol) are heated in 51 ml acetic anhydride and 60 ml triethylamine overnight at reflux. The reaction mixture is cooled down to 80° C. and poured onto 1000 ml 2 M sodium hydroxide under stirring. After 5 min the precipitated product is filtered by vacuum, washed with water and digested two times with 100 ml ethanol. 6,8-Dibromo-3-(4-methoxy-phenyl)-chromen-2-one is obtained as a yellow solid.