Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([Cl:25])[CH:5]=1.[OH-].[K+]>CO.O.C(O)C>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:26])=[O:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 90.5 %

Procedure:
The title compound is prepared by the procedure of Example 32 using 125.0 g of product from Example 36 in 1 L of methyl alcohol, 60 ml of water, 400 ml of ethyl alcohol and 54.94 g of potassium hydroxide. The residue is recrystallized from chloroform/hexane to give 109 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-chloro-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH3:14].[H-].[Na+]>CN(C)C=O>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)[CH3:14]
Reactant: CCBr
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(O)c(C(C)(C)C)c1
Temperature: -78 °C
Yield: 22 %

Procedure:
A mixture of 19.85 g of tert-butylhydroquinone, 10.7 ml of ethyl bromide and 200 ml of dimethylformamide (DMF) was cooled to -78° C., and 4.82 g of 62.5% sodium hydride was added to the mixture. The temperature of the mixture was raised to 0° C., and the mixture was further stirred under ice-cooling for 30 minutes. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1), and recrystallized from hexane to give 5.045 g of 4-ethoxy-2-tert-butylphenol (yield: 22%, melting point: 96°-98° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:4]1([CH2:3][CH2:2][O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCN2CCCC2)c1

Procedure:
A solution of 1-(2-chloroethyl)pyrrolidine D36 (9.2 g) and methyl 3-hydroxybenzoate (12.5 g, 82 mmol) and potassium iodide (13.68 g, 82 mmol) and potassium carbonate (11.37 g, 82 mmol) in acetone (200 ml) was refluxed for 2 days. The reaction was filtered and concentrated to give crude product which was purified by chromatography on silica gel eluting with pet eth/EtOAc 5/1 and EtOAc and MeOH to give 1.6 g of desired product D37 as a brown product. LCMS [MH+] 250.1 g 1.53 min (5 min run)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (10.23 mmol) of [4-(benzyloxy)-3-bromophenyl]methanol (Example I) are initially charged in 30 ml of DMF. At room temperature, 1.39 g (12.28 mmol) of 1H-imidazole (60% pure) and 2.01 g (13.3 mmol) of tert-butyl(chloro)dimethylsilane are added. The reaction mixture is stirred at room temperature overnight. Water is then added, and the mixture is extracted three times with diethyl ether. The combined organic phases are washed three times with water and once with saturated sodium chloride solution. The organic phase is dried with sodium sulphate and the solvent is removed under reduced pressure. This gives 4.02 g (86% of theory) of {[4-(benzyloxy)-3-bromobenzyl]oxy}(tert-butyl)dimethylsilane.
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:18].B(F)(F)F.CCOCC>O1CCCC1>[C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=[N:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: CCOc1cccc(N)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1cccc(N=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)c1
Yield: 2.7 %

Procedure:
A mixture of 22.0 g (0.10 mole) of 3,5-di-tertiary-butyl-p-benzoquinone, 15.1 g (0.11 mole) of m-ethoxyaniline, 125 ml of tetrahydrofuran and 1 ml of boron trifluoride etherate was heated at reflux for about 40 hours. The reaction mixture was evaporated to give an oil which was partitioned between hexane and 10% hydrochloric acid. The hexane phase was dried by filtering through Whatman IPS phase separation filter paper, then evaporated to give a solid. This solid was triturated with hexane, collected, rinsed with hexane, air dried and then recrystallized from ethanol to give a red solid. 1.0 g of this red solid was recrystallized from ethanol to give 0.9 g of red-orange crystalline 2,6-di-tertiary-butyl-4-(3'-ethoxyphenylimino)-2,5-cyclohexadiene-1-one, m.p. 105°-107° C. Calculated for C22H29NO2 : % C, 77.8; % H, 8.6; % N, 4.1; Found: % C, 77.4; % H, 8.5; % H, 3.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](C=O)=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: O=Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nccn1-2

Procedure:
A mixture of 1.0 g. of 8-chloro-6-phenyl-4H-imidazo-[1,2-a][1,4]benzodiazepine-1-carboxaldehyde (ll) and 0.1 g. of tris(triphenylphosphine)rhodium chloride in 50 ml. of benzene is refluxed for about 6 hours. The mixture is then allowed to cool and filtered to remove the catalyst. The filtrate thus obtained in concentrated in vacuo to give 8-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine, which is further purified by chromatography on silica gel and/or crystallization, m.p. 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20]>CS(C)=O.C(O)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH3:20])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
2,6-Dichloropurine (378 mg, 2.0 mmol) was dissolved in dimethylsulfoxide (10 mL), and dry potassium carbonate (345 mg, 2.5 mmol), and iodoethane (312 mg, 2.0 mmol) added. The mixture was stirred at room temperature for 16 hours, then the mixture was diluted with ice, acetic acid was added to adjust the pH to 5, and the solution was extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered, and the filtrate evaporated in vacuo. The residue was purified by flash chromatography, eluting initially with cyclohexane-EtOAc (75:25) to give 2,6-dichloro-9-ethylpurine (280 mg, 65%), a compound of formula (2). mp 100–103° C.; UV λmax (MeOH) 214 nm (ε 22900), 274 (ε 9500), (pH 1) 213 nm (ε 22800), 273 (ε 9500), (pH 12) 214 nm (ε 17900), 260 (ε 7800), 266 (ε 8100); 1H NMR (Me2SO-d6) δ 1.45 (t, 3H, J=7.2 Hz, CH2CH3), 4.28 (q, 2H, J=7.2 Hz, CH2CH3), 8.77 (s, 1H, H-8). Anal. (C7H6Cl2N4) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31].CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C.C(Cl)Cl>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: C[C@@H](N)c1ccccn1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(N[C@H](C)c3ccccn3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 50 g, 151 mmol,) and [(1R)-1-(2-pyridinyl)ethyl]amine (35.3 g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250 ml). DIPEA (79 ml, 452 mmol) was added, the solution was heated at 120° C. overnight, cooled and diluted with ethyl acetate (1 l). The solution was washed with water (2×1 l), brine (500 ml), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2×600 ml). The combined extracts were washed with a mixture of saturated brine (300 ml) and water (1 l) giving a dense emulsion which took around 2 h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200 ml), washed with water (2×200 ml), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150 ml) and loaded onto a silica column (750 g), which was eluted with a 2M ammonia in methanol/DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-{[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g). Used in the subsequent step (Example 36) without further purification.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([I+:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[F:26][C:27]([F:34])([F:33])[S:28]([O:31]C)(=[O:30])=[O:29]>COC(C)(C)C>[F:26][C:27]([F:34])([F:33])[S:28]([O-:31])(=[O:30])=[O:29].[C:22]([C:19]1[CH:20]=[CH:21][C:16]([I+:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Solvent: COC(C)(C)C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
tert-Butyl methyl ether (5 ml) was added to bis(p-tert-butylphenyl)iodonium acetate (467 mg; 1 mmol) and methyl trifluoromethanesulfonate (170 mg; 1.05 mmol), and the resultant mixture was allowed to react for 4 hours at room temperature while being stirred. The solid formed by reaction was purified and separated through filtration, and dried under vacuum, to thereby yield 412 mg of bis(p-tert-butylphenyl)iodonium trifluoromethanesulfonate (yield: 76%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 33A and methyl-4-bromobenzoate were processed as described in Example 52A to provide the title compound. MS (ESI+) m/z 519 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH2:8][CH2:9]I.[CH3:11][O:12][C:13](=[O:42])[N:14]=[C:15]([S:40][CH3:41])[C:16]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([OH:38])[C:31]=1[F:39])=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[CH:20][CH:19]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:42])[N:14]=[C:15]([S:40][CH3:41])[C:16]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH2:9][CH2:8][F:7])[C:31]=1[F:39])=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[CH:20][CH:19]=1
Reactant: FCCI
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
After adding 3.32 g of potassium carbonate and 3.13 g of 1-fluoro-2-iodoethane to a solution of 5.5 g of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 100 ml of DMF, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (5.88 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:27]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(NC(=O)c2cc(Br)cnc2N)ccn1
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccnc(C)c3)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A20”;
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[OH-].[Na+].CO.ClCCl.C(O)(=O)C.COC>C1COCC1.CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([OH:22])=[O:2])=[N:7][CH:8]=2)=[O:21])=[CH:19][CH:18]=1
Reactant: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: COC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 16.3 %

Procedure:
To a solution of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid methyl ester (prepared above, 82 mg, 0.269 mmol) in THF/methanol (6 mL/0.3 mL) was added 1 N NaOH (0.3 mL, 0.3 mmol). Additional 1 N NaOH aliquots were added after 5 min (0.15 mL), 25 min (0.25 mL), and 2 h (1.0 mL). By thin layer chromatography (15/84/1 methanol/dichloromethane/acetic acid) it appeared that the starting material never disappeared, but LC/MS showed the presence of mostly methyl ether, with some desired acid and no starting material. The reaction mass was extracted with ethyl acetate. The combined organic layers were washed 1× with water, then 2× with 5% NaHCO3. The aqueous layers were combined, acidified to pH 1 with 3% HCl and extracted with dichloromethane. The organic layers were combined, washed with brine, dried and concentrated in vacuo to afford 12.8 mg (16% yield) of the titled carboxylic acid as a white solid. ESI-MS m/z 292 (MH+), 290 (M−H)−.
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Br[C:17]1[CH:22]=[C:21]([O:23][CH2:24][F:25])[CH:20]=[C:19]([Br:26])[CH:18]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[OH-].[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>[Br:26][C:19]1[CH:18]=[C:17]([CH:1]=[CH2:2])[CH:22]=[C:21]([O:23][CH2:24][F:25])[CH:20]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: FCOc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1cc(Br)cc(OCF)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Tri(butyl)vinyltin (10.0 g, 31.4 mmol) was added dropwise to a solution of 1,3-dibromo-5-monofluoromethoxybenzene (8.5 g, 29.9 mmol; see step (iii) above), tetrakis(triphenylphosphine)palladium(0) (690 mg, 0.599 mmol), and 2,6-di-tert-butyl-4-methylphenol (spatula tip) in toluene (100 mL) under nitrogen. The mixture was stirred at 70° C. for 8 h. The mixture was cooled to 0° C. and 1N NaOH (70 mL) was added. After 1 h, the mixture was extracted with CH2Cl2 (3× 300 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (4.3 g, 57%) as a colourless oil.
Reaction SMILES: C#C.[C:3](O[K])(C)(C)[CH3:4].[CH2:9]1[C:13]2([CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1.[NH4+].[Cl-]>C1COCC1>[C:3]([C:15]1([OH:19])[CH2:16][CH2:17][CH2:18][C:13]2([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:14]1)#[CH:4]
Reactant: CC(C)(C)O[K]
Reactant: O=C1CCCC2(CCCC2)C1
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCCC2(CCCC2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Acetylen was bubbled for 30 mn through a mixture of tBuOK (14.11 g, 125.8 mmol, 1.1 equiv) in THF (100 ml) cooled to 0° C. The resulting white suspension was diluted with more THF (50 ml) and treated with spiro[4.5]decan-7-one (1) (17.20 g, 113.2 mmol) added dropwise for 20 mn. The reaction mixture was stirred at room temperature for 3 h, treated with saturated NH4Cl (500 ml) and extracted with MTBE (4×150 ml). The combined organic phases were washed with H2O (6×70 ml) until neutral pH and dried over MgSO4. 16.90 g (84%) of crude product (2) was isolated as an orange oil that was used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[C:23]([C:29]#[N:30])=[CH:24][CH:25]=[CH:26][C:27]=2[F:28])[CH:21]=1>>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([C:29]#[N:30])[C:22]=1[C:20]1[CH:21]=[C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)[CH:17]=[CH:18][C:19]=1[F:31]
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Reactant: N#Cc1cccc(F)c1-c1cc(Br)ccc1F
Product: N#Cc1cccc(F)c1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 31.2 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 5′-bromo-6,2′-difluorobiphenyl-2-carbonitrile (221 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 6,2′-difluoro-5′-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)-biphenyl-2-carbonitrile (65 mg, 31%) as a white solid: δH (360 MHz, CDCl3) 6.99 (1H, dd, J 7 and 6), 7.41-7.51 (2H, m), 7.54-7.60 (1H, m), 7.62-7.69 (3H, m), 7.87 (1H, s), 8.33 (1H, d, J 7); m/z (ES+) 418 (100%, [MH]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:18])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:18][Br:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(F)cc2)nc1CBr
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.95 g, 7.35 mmol), N-bromosuccinimide (1.37 g, 7.71 mol) and benzoyl peroxide (89 mg, 0.37 mmol) in carbon tetrachloride (20 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (2.38 g); MS: (+) m/z 343.93, 345.96 (M+1, 79Br/81Br).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.NC(N)=[S:16]>C(O)C>[SH:16][C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(nn1)CCCCCC2
Reactant: NC(N)=S
Solvent: CCO
Product: Sc1cc2c(nn1)CCCCCC2
Reaction time: 20 h

Procedure:
59.1 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine and 25.2 g of thiourea are heated at reflux in 250 cc of absolute ethanol while stirring for 20 hours. The reaction mixture is subsequently concentrated and divided between chloroform and water. After concentrating the chloroform phase, crude 3-mercapto-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine is obtained and is recrystallized from 250 cc of absolute ethanol with the addition of carbon.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[N-]1C=CN=C1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:19][C:20]2[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CNc1ncc(C(=O)OC)cc1N
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CNc1ncc(C(=O)OC)cc1NC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.6 g (15 mmol) of 3-(4-cyanophenyl)propionic acid in 25 mL of absolute tetrahydrofuran was mixed with 2.4 g (15 mmol) of N,N′-carbonyldiimidazole and stirred for 20 minutes at room temperature. Then the imidazolide was mixed with a solution of 2.3 g (13 mmol) of methyl 5-amino-6-methylaminonicotinate in 25 mL of dimethyfformamide and heated for 3 hours to 100° C. After the removal of the solvent in vacuo, the crude product obtained was taken up in ethyl acetate, the organic phase was washed with water and after drying over sodium sulfate it was again freed from solvent. The residue obtained was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol=19:1). Yield: 2.1 g (50% of theory) of beige solid; Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).