Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Br.C(O)(=O)C>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Yield: 43.7 %

Procedure:
A solution of 1-phenyl-2-(4-methoxyphenyl)benzimidazole(0.60 g, 2.0 mmol) in hydrobromic acid (6 ml) and acetic acid (6 ml) was refluxed for 40 hours. The reaction mixture was extracted with diethyl ether (5×150 ml) at a pH of 3-5. The organic solvents were discarded. The aqueous phase was alkalinized to pH 8-9 and extracted with ethyl acetate (5×150 ml). The organic fractions were combined and dried over potassium carbonate, then filtered and the solvents were removed in vacuo to yield a white solid. The solid was triturated in diethyl ether and filtered to yield 0.25 grams of the desired product.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([NH:20][C@@H:21]([CH3:37])[CH2:22][N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=3)=[N:24]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (300 mg, 1.05 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile (273 mg, 1.05 mmol). The product was purified with flash-chromatography. Yield 366 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.6 (s, 3H), 3.49 (t, 2H), 4.31-4.47 (m, 3H), 5.66 (s, 2H), 6.95 (s, 1H), 7.85 (d, 1H), 7.92-7.97 (m, 2H), 8.06 (s, 2H), 8.17 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O.CS(O)(=O)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CS(C)=O>[F:1][C:2]1[C:21]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Temperature: 20 °C
Yield: 46.9 %

Procedure:
A suspension of 0.93 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine- 3-carboxylic acid in 0.6 g of 1-methylpiperazine and 20 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 5 minutes. After cooling to about 20° C., the reaction mixture is poured into 30 cm3 of water, 1.5 cm3 of 2N methanesulphonic acid are added and the product is drained and washed with 3 times 5 cm3 of water. After recrystallizing from 30 cm3 of dimethylformamide containing 30% of ethanol, 0.55 g of 7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a brown solid melting at 270° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COCCN
Product: COCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 93.5 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2-methoxyethyl amine (1.62 g, 22 mmol) to give the title compound (5.5 g, 95%) as an off-white crystalline solid. MS (ISP) 294.1 [(M+H)+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:38]1[S:39][CH:40]=[CH:41][N:42]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCO>[S:39]1[CH:40]=[CH:41][N:42]=[C:38]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=2)=[CH:11][CH:10]=1
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(CCOc2ccc(-c3nccs3)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 80 °C
Yield: 6.6 %

Procedure:
A mixture of 4-[(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g, 0.19 mmol; step A above), 2-bromothiazole (0.020 mL, 0.21 mmol), Pd(PPh3)4 (0.011 g, 0.010 mmol), Na2CO3 (0.106 g, 1.00 mmol), toluene (1 mL), EtOH (0.50 mL) and H2O (0.5 mL) was sparged with N2 for 10 min and then heated at 80° C. in a sealed vial for 72 h. The mixture was cooled, poured into water, and extracted with EtOAc (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.0059 g of the title compound as a yellow film: MS (ESI) m/z 472 (M+1).
Reaction SMILES: [N:1]1([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[N:1]1([C:13]2[CH:19]=[CH:18][C:16]([NH:17][C:21]3[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)aniline (55 mg) and 2-chloro-3-nitropyridine (35 mg) in NMP (3 mL) was stirred at 140° C. overnight. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) to afford N-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-3-nitropyridin-2-amine (34 mg) as a dark brown solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C@:10]3([CH2:25][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[O:26]=[C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[C@@:10]21[CH2:25][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH:17]=[C:12]1[CH2:11]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (6S)-4′-chloro-6′-oxo-5,6′,7,7′-tetrahydrospiro[cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylate (200 mg, 0.537 mmol) in dry ethyl acetate (5.37 mL) was added triethylamine (299 μL, 2.15 mmol) and palladium on carbon (571 mg, 10%, 0.537 mmol). The reaction was placed on a Parr apparatus at 50 psi hydrogen gas. After 16 h, the reaction mixture was filtered under a nitrogen atmosphere through Celite®, washing with ethyl acetate. The filtrate was concentrated to give the title compound, along with one equivalent of triethylamine hydrochloride. MS: m/z=339.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cc3ccccc3)cc2)cc1
Yield: 94.1 %

Procedure:
A slurry of 5.72 g of 4-chlorophenyl methyl sulfone, 6.08 g of 4-benzylphenol and 4.56 g of K2CO3 in 150 ml of DMSO was heated at 160° C. for 8.5 hrs. The product (9.55 g, 94.1% yield) was recovered from the reaction mixture essentially as described in Example 18. Recrystallization from 2-propanol and then from aqueous acetic acid afforded purified 1-(4-(methylsulfonyl)phenoxy)-4-(phenylmethyl)benzene, mp 109°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[C:19]([C:23]1[O:24][C:25]([CH3:31])=[C:26]([CH2:28][CH2:29]O)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:29][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])[O:24][C:25]=2[CH3:31])=[CH:8][C:7]=1[CH3:14]
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCO[C@@H](Cc1c(C)cc(OCCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the Mitsunobu-procedure described in example 1, step f], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester (example 51 e]) was reacted with 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (example 1, step e])) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield (S)-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester as colorless oil.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][O:12]1.C(N(CC)CC)C>C1C=CC=CC=1>[C:2]([N:17]1[CH2:18][CH:14]2[CH2:13][O:12][CH2:11][CH:15]2[CH2:16]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C1NCC2COCC12
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CC2COCC2C1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
Nicotinoyl chloride hydrochloride, represented by formula (XII), (0.1 mole, 17.81 grams) was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (X), (0.1 mole, 11.3 grams), and triethylamine (0.2 mole, 20.24 grams) in 160 ml of benzene at 15°C. The reaction mixture was stirred for 1.5 hours at 15°C. and then left overnight at room temperature. The HCl salt of triethylamine was filtered and the salt was washed with benzene. The washings were combined with the filtrate and benzene was stripped under vacuum. The product, 5-nicotinoyl-hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (XIII), light yellow viscous liquid, was purified by column chromatography (Alumina-eluted with methyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][C:7]=1[CH3:8].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:7]([CH3:8])=[N:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(=O)Nc1ccc(Br)c(C)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a degassed solution of N-(5-bromo-6-methyl-pyridin-2-yl)-acetamide (4.16 g, 18.18 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.37 g, 21.81 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.10 g, 45.44 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.17 g, 0.36 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.51 g, 1.45 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→9:1) and then recrystallized from diethylether to provide 0.38 g (6%) of the title compound in 90% purity according to 1H NMR. 1H NMR (250 MHz, DMSO): δ 1.31 (d, J=9.2 Hz, 2H), 1.40 (s, 9H), 1.86 (d, J=11.4 Hz, 2H), 1.99 (s, 3H), 2.24 (s, 3H), 2.86 (br s, 2H), 3.41 (br s, 1H), 3.92 (d, J=14.0 Hz, 2H), 4.51 (d, J=8.1 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 9.98 (s, 1H). MS (ESI): 349.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](OC)([O:10]C)[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:18][CH3:19].C([Li])CCC.B(OC)(OC)[O:26]C.[OH-].[Na+].OO.Cl>C1COCC1.CC(=O)OCC.O>[C:14]([C:4]1[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([OH:26])[C:3]=1[O:18][CH3:19])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(C)(C)C
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reaction time: 0.5 h

Procedure:
1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene (O4.070; 36.3 g) was dissolved in THF (1 l), n-butyllithium (52.6 ml; 2.5 M in hexane) was added dropwise at −75° C. under argon, and the mixture was stirred for a further 30 min. Then trimethyl borate (37.3 ml) was added dropwise and the mixture was allowed to come to RT within 2 h. Subsequently, sodium hydroxide (4.4 g, dissolved in 10 ml of water) and hydrogen peroxide solution (62.3 ml; 35% in water) were added successively. After stirring at RT for 2 h, the mixture was left to stand overnight. Then water and EA were added and the mixture was acidified with hydrochloric acid. After removing the EA phase, this was dried over magnesium sulfate and concentrated. The residue was purified using silica gel (330 g cartridge, n-heptane/EA gradient of 0-50% within 60 min). 14 g of the title compound were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[S:13][C:12]([C:14]([O-:16])=[O:15])=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1
Reactant: O=C([O-])c1ccc(C#Cc2ccccn2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccccn2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a solution of 5-(pyridine-2-ylethynyl)thiophene-2-carboxylate (1.43 g, 5.54 mmol) in ethanol (40 mL) was added sodium hydroxide (0.585 g, 14.6 mmol). The reaction mixture was allowed to stir at rt for 20 h. The solution was concentrated and diluted with 1N aqueous HCl. A precipitate formed and was filtered to give 5-(pyridine-2-ylethynyl)thiophene-2-carboxylic acid (1.02 g, 4.46 mmol) as a yellow solid. LCMS: (FA) ES+ 230.2, ES-229.4.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CCOCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
2-Bromo-thiazole (0.27 mL, 2.99 mmol) was dissolved in Et2O (8 mL) and cooled down to −78° C. BuLi (1.3 mL, 2.5 M) was added dropwise. The resulting yellow solution was stirred at −78° C. for 45 min. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (720 mg, 3.61 mmol) in Et2O (5 mL) was then added dropwise. The reaction temperature rose to rt naturally overnight. H2O (10 mL) was added to quench the reaction and extracted with ethyl acetate. The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to give 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (800 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+]>[Cl-].C([N+](CCCCCCCCCCCCCCCCCC)(C)C)CCCCCCCCCCCCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 68.6 %

Procedure:
576 g (3 mol) of 3,4-dichloronitrobenzene, 58 g (0.1 mol) of distearyldimethylammonium chloride and 139 g (2.4 mol) of potassium fluoride were reacted analogously to Example 1. After filtering with suction, the residue was dissolved in water, the organic phase was separated off and the combined organic phases were fractionated. 289 g (69%, relative to potassium fluoride employed) of 3-chloro-4-fluoronitrobenzene were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([CH2:36]Br)[O:34][CH:35]=1)=[O:30])[CH3:27]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:36][C:33]4[O:34][CH:35]=[C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[N:32]=4)[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1coc(CBr)n1
Product: CCOC(=O)c1coc(Cn2cc(C3c4ccc(CC)cc4C=Cc4oc(C)nc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product of example 3 step (vii) (2.2 g) and 2-bromomethyl-4-oxazolecarboxylic acid ethyl ester (0.52 g) using the method of example 1 step (viii). Purification was by chromatography eluting with ethyl acetate.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[Cl:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH:18]([C:20]([CH2:22][CH3:23])=[O:21])=[CH2:19].N12CCCN=C1CCCCC2>O1CCCC1.CCOC(C)=O>[CH2:1]([C:5]1([CH2:19][CH2:18][C:20](=[O:21])[CH2:22][CH3:23])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[Cl:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Cc2c(ccc(OC)c2Cl)C1=O
Reactant: C=CC(=O)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2Cl)C1=O
Temperature: 60 °C
Yield: 93.9 %

Procedure:
A solution of 2-butyl-4-chloro-5-methoxy-1-indanone (200 mg, 0.79 mmol) in anhydrous tetrahydrofuran (0.8 mL) was placed under a nitrogen atmosphere and treated with ethyl vinyl ketone (0.118 mL, 1.19 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.024 mL, 0.158 mmol). The resulting solution was stirred and heated in an oil bath at 60° C. for 47 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide crude 2-butyl-4-chloro-5-methoxy-2-(3-oxopentyl)-1-indanone (250 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17]#[N:18])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.ClCCl>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[C:7]3[N:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:6]=3[C:5]([C:17]#[N:18])=[CH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cnc(Cl)c2nc(-c3ccccc3)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(C#N)c3sc(-c4ccccc4)nc23)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 4-chloro-2-phenyl-thiazolo[4,5-c]pyridine-7-carbonitrile 47 (54.2 mg, 0.2 mmol) and potassium carbonate (66 mg, 0.48 mmol) in NMP (1 mL) was treated with 4-methoxybenzylamine (32.5 μL, 2.4 mmol) and the mixture stirred at 130° C. for 8 hours. Silica gel column chromatography (eluent: dichloromethane and ethyl acetate (10 to 1)) afforded 48 as a pale yellow solid (70 mg). 1H NMR (400 MHz, d6-DMSO) δ: 3.71 (s, 3H), 4.72 (d. J=5.9 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.60 (m, 3H), 8.15 (m, 2H), 8.47 (s, 1H), 8.84 (t, J=6.1 Hz, 1H). MS (EI) m/z (M+H+) 373.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl) amino]pyrimidine and 4-fluoronitrobenzene
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:23][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc(S)ncc2-c2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(-c2nc(SC)ncc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-mercapto-4-(4-methoxyphenyl)-5-(4-chlorophenyl)pyrimidine* (7 g) and potassium carbonate (8 g) in 200 ml acetone was treated with methyl iodide (4.8 ml) and stirred 5 hours at room temperature. The reaction mixture was filtered and concentrated on the rotary evaporator. Chromatography on silica gel and crystallization from ethanol gave the title compound (3.4 g), m.p. 127°-130°. Infrared and H-NMR spectra were consistent with the assigned structure. MS 342 (M+).