Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].C1(C)C=CC=CC=1>C(O)C>[Br:1][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)Cc1ccc(C(=O)CBr)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Bromine (1.25 ml; 25 mmol) is added dropwise to a solution of 4′-isobutylacetophenone (3.52 g; 20 mmol) in 60 ml of ethanol cooled down to approximately 5° C. After stirring the reaction mixture for 30 minutes at this temperature, stirring is continued for one hour at ambient temperature. The reaction medium, to which small portions of toluene are added, is concentrated to dryness. After purification on a silica column (eluent: ethyl-heptane acetate: 5-95), a colourless oil is obtained with a yield of 57%.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][NH2:5].O=C1[NH:12][C:11]2[C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=[CH:16][C:10]=2[C:9](=[O:20])[O:8]1.Cl>O>[NH2:12][C:11]1[C:13]([C:17](=[O:18])[NH:5][CH3:4])=[CH:14][CH:15]=[CH:16][C:10]=1[C:9]([OH:8])=[O:20]
Reactant: CN
Reactant: O=C(O)c1cccc2c(=O)oc(=O)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(=O)c1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
Aq NaOH (23.4 mL, 46.8 mmol) was added to a solution of methylamine hydrochloride (3.52 g, 53.7 mmol) in H2O (37 mL). 2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-8-carboxylic acid 29 (3.23 g, 15.6 mmol) was in portions. After addition was complete, the solution was stirred at ambient temperature for 1.5 h. 6M HCl was added until pH=3. The resulting precipitate was collected by filtration, rinsed with H2O and dried to give 31 (2.60 g, 86% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][CH:7]=1.[Si:21]([O:28][C@H:29]([C@H:31]1[NH:36][C:35]([CH3:38])([CH3:37])[CH2:34][CH:33]([OH:39])[CH2:32]1)[CH3:30])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CC(C)([O-])C.[K+]>CN(C=O)C>[Si:21]([O:28][C@H:29]([C@H:31]1[NH:36][C:35]([CH3:38])([CH3:37])[CH2:34][CH:33]([O:39][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)=[CH:10][C:9]=3[O:19][CH3:20])=[CH:6][CH:7]=2)[CH2:32]1)[CH3:30])([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(C)(C)N1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2C[C@@H]([C@H](C)O[Si](C)(C)C(C)(C)C)NC(C)(C)C2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (32 mg, 0.11 mmol) and (6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol (Intermediate 4-1, 32 mg, 0.11 mmol) in DMF (1 mL) was added potassium tert-butoxide (1 M in THF, 0.45 mL, 0.45 mmol) at 0° C. The reaction mixture was stirred for 1 h at RT. The mixture was then quenched with saturated ammonium chloride solution (10 mL) and extracted with 10% MeOH in dichloromethane (20 mL). The extract was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 56 mg (94%) of 3-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine: LCMS (m/z, MH+): 538.5; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J=8.1 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.54-6.47 (m, 1H), 5.79-5.87 (m, 1H), 3.96 (s, 3H), 3.83-3.93 (m, 1H), 3.07-3.17 (m, 1H), 2.13-2.22 (m, 1H), 2.05-2.12 (m, 1H), 1.43-1.57 (m, 2H), 1.27 (s, 3H), 1.16 (d, J=6.6 Hz, 3H), 1.14 (s, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]1[CH2:31][CH2:30][C:29]2[N:25]([C:26]3[N:45]=[CH:44][N:43]=[C:42]([NH2:46])[C:27]=3[C:28]=2[C:32]2[CH:33]=[N:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24]1)=[N+]=[N-]>C1COCC1.O>[N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[C:32]([C:28]2[C:27]3[C:42]([NH2:46])=[N:43][CH:44]=[N:45][C:26]=3[N:25]3[C:29]=2[CH2:30][CH2:31][CH:23]([NH2:20])[CH2:24]3)[CH:33]=1
Reactant: [N-]=[N+]=NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Yield: 72.6 %

Procedure:
Polymer-supported triphenylphosphine (˜3.0 mmol/g, 1.42 g) was added to a solution of 8-azido-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-4-amine (508 mg) obtained in Step 10 in THF (10 ml) and water (1 ml) at room temperature. The reaction mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was filtered through Celite, washed with ethanol, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a yellow solid (342 mg). ESI-MS m/z 331 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7]([N:10]1[CH2:15][CH2:14][N:13]([C@@H:16]([CH2:21][NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([O:30]COCCOC)=[CH:26][CH:25]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]1)(=[O:9])=[O:8].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][C@H:16]([N:13]2[CH2:12][CH2:11][N:10]([S:7]([CH3:6])(=[O:9])=[O:8])[CH2:15][CH2:14]2)[C:17]([O:19][CH3:20])=[O:18])=[O:37])=[CH:25][CH:26]=1
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
0.5 ml of 98% sulphuric acid are added to a solution of 1.6 g (3.4 mmol) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methoxyethoxymethoxy)benzoyl-amino]propanoate in 15 ml of tetrahydrofuran and 15 ml of methanol. After stirring for 18 h at ambient temperature, the reaction medium is hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate then extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. 1.1 g (85%) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methane-sulphonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:19]3[C:14](=[C:15]([O:20]C)[N:16]=[CH:17][CH:18]=3)[N:13]([CH3:22])[CH:12]=2)=[CH:9][C:8]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:7][N:6]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:19]3[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=3[N:13]([CH3:22])[CH:12]=2)=[CH:9][C:8]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:7][N:6]=1
Reactant: COc1nccc2c(-c3cc(CS(C)(=O)=O)cnc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(CS(C)(=O)=O)cnc2Oc2ccc(F)cc2F)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 81.9 %

Procedure:
The product from Example 60F (0.097 g, 0.211 mmol) and 4 M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined and heated at 70° C. for 18 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and water adjusting the pH to 7. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated. Purification by trituration (1:1 dichloromethane/heptane) afforded the title compound (0.077 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.03 (d, J=5.43 Hz, 1H) 8.02 (d, J=2.37 Hz, 1H) 7.95 (d, J=2.37 Hz, 1H) 7.75 (s, 1H) 7.39-7.50 (m, 2H) 7.10-7.19 (m, 1H) 6.93-6.97 (m, 1H) 6.66 (d, J=6.44 Hz, 1H) 4.57 (s, 2H) 4.14 (s, 3H) 2.98 (s, 3H). MS (ESI+) m/z 446 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25]C)=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Li+].[Br-].Cl>CC#N.O>[CH2:14]([O:13][C:11](=[O:12])[C:10]([CH3:22])([CH3:21])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:23]([OH:25])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-benzyl 1-methyl N-(tert-butoxycarbonyl)-3,3-dimethyl-L-aspartate (Preparation 45, 2 g, 5.47 mmol) in MeCN (30 mL) and water (0.6 mL) was added triethylamine (2.3 mL, 16.41 mmol) followed by LiBr (4.75 g, 54.73 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step (1.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=4[C:20]=3[CH3:29])(=[O:18])=[O:17])[C:11]2=[O:30])[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:31]I>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([CH3:31])[S:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=4[C:20]=3[CH3:29])(=[O:17])=[O:18])[C:11]2=[O:30])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CI
Reactant: Cc1c(S(=O)(=O)N[C@H]2CCN(Cc3ccnc(C#N)c3)C2=O)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)N(C)[C@H]2CCN(Cc3ccnc(C#N)c3)C2=O)sc2ccc(Cl)cc12

Procedure:
The title compound is prepared from 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [1-(2-cyanopyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using methyl iodide in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.[Cl-].[Na+].O>[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc2c(c1)OCC2=O)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-benzofuran-3-one (1.01 g, 6.73 mmol) in dry dichloromethane (18 mL) was added imidazole (0.458 g, 6.727 mmol) followed by tert-butyldiphenylchlorosilane (1.72 mL, 6.73 mmol) at room temperature. The mixture was stirred overnight and poured into brine. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, evaporated in vacuo and the residue was purified by column chromatography (ethylacetate:hexane; 1:9) to give the 6-(tert-butyl-diphenyl-silanyloxy)-benzofuran-3-one as slightly yellow oil (1.34 g, 52%). 1H NMR (CDCl3, 400 MHz) 1.21 (s, 9H), 4.54 (s, 2H), 6.40 (s, 1H), 6.55 (dd, J=1.6, 8.0 Hz, 1H), 7.38-7.50 (m, 7H), 7.67 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6][CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(N=Cc2cccc(OC)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a stirred mixture solution of 4-[(3-methoxy-benzylidene)-amino]-benzoic acid methyl ester (2.7 g, 10.0 mmol) and ytterbium(III) triflate hydrate (620.3 mg, 1.0 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.93 mL, 10.2 mmol) and water (0.2 mL, 10.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (3.4 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H23NO4 (M+H)+: 342.41, observed: 324.2 & 342.2.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]1[C:12](N=C=S)=[CH:11][C:10]2[C:16]([O:18][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=4[O:27][C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]3=4)[C:9]=2[CH:8]=1)=[O:17]>P([O-])([O-])([O-])=O.CC(C)=O>[CH:7]1[CH:12]=[CH:11][C:10]([C:16]([OH:18])=[O:17])=[C:9]([C:19]2[C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[O:27][C:28]3[C:29]=2[CH:30]=[CH:31][C:32]([CH:33]=3)=[O:34])[CH:8]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
One mg of HIgG (Human IgG) dissolved in 0.4 ml of 0.1 M phosphate buffer pH 7.5, was brought to pH 9.5 with crystalline Na2CO3. A solution (10 μl) of FITC (70 μg) in acetone was added with stirring and mixed for 3 hrs at room temperature. The resulting solution was separated two times on Sephadex G-25(M) column (1×15 cm) equilibrated with 0.05 M phosphate buffer pH 8.0. The eluted FITC-hIgG conjugate solution was 0.58 mg/ml in concentration and had D/P=5.5 (M/M) as determined by the Wells' nomograph.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][N:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH2:2][C:1]([C:4]1[C:12]2[S:11][N:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1cccc2nnsc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccc2nnsc12
Reaction time: 2 h

Procedure:
0.9 g of 7-acetylbenzo-1,2,3-thiadiazole is dissolved in 20 ml of chloroform, and 0.88 g of bromine is added dropwise at room temperature. Stirring is then continued for 2 hours at the same temperature, during which process a yellow precipitate forms. This precipitate is filtered off, washed with hexane and dried. The title compound which is thus obtained melts at 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride (0.42 g) are added. The reaction mixture is heated to 90° C. for 6 h. Water is added and a dark solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-20% MeOH/CHCl3) gave 0.103 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.072 g of the title compound as a solid.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([CH3:20])([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:8]1[CH:7]=[C:6]([CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:4]([F:3])[C:9]=1[OH:10]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(O)c(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(C)(C)Cc1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine solution (12.4 ml, 12.4 mmol, 1.0 M in CCl4) was added a solution of the product of STEP 6 (1.58 g, 6.2 mmol) in 30 ml CCl4 at 0° C. over 5 min. The reaction was stirred at room temperature for 30 min, and quenched with saturated NaHCO3 solution. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed brine, dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/ hexane=1/9) to give a colorless oil in 0.73 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=1)=O)C.[CH3:20][NH:21][NH2:22]>C1(C)C=CC=CC=1>[OH:3][C:4]1[N:21]([CH3:20])[N:22]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC(C)C)c(C)c1
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(O)n(C)n2)ccc1OC(C)C
Yield: 84.3 %

Procedure:
At room temperature, to a mixture of 3-(4-isopropoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester (described in Reference Preparation example 94) 12.1 g and toluene 100 ml was added N-methyl hydrazine 21 g, and the resulting mixture was stirred for twelve hours. The toluene was distilled off under reduced pressure. At room temperature, to the reaction mixture was added water 100 ml and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was stirred for three hours. The precipitates were filtered and were washed with water 400 ml and ethyl acetate 500 ml, and then were dried under reduced pressure to give 5-hydroxy-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 9.5 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:18][N:14]1[CH:15]=[CH:16][C:17]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([F:20])[C:26]=4[F:27])[CH:3]=3)[CH:10]=[N:11][C:12]=2[C:13]1=[O:19]
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Reactant: OB(O)c1cccc(F)c1F
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cccc(F)c3F)c2)c1=O
Yield: 40 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 2,3-difluorobenzeneboronic acid, in the same way as in Example 1, to give 5-methyl-1-(2,2′,3′-trifluorobiphenyl-5-yl)-1,5-dihydroimidazo[4,5-c]pyridin-4-one as an off-white solid (32 mg, 40%): δH(400 MHz, d6-DMSO) 3.54 (3H, s), 6.61 (1H, d, J 7), 7.35-7.41 (1H, m), 7.48 (1H, dd, J 8 and 7), 7.55-7.67 (3H, m), 7.77-7.81 (2H, m), 8.40 (1H, s); m/z (ES+) 356 [MH+].
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:1]([O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCCCCC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 6-heptenoic acid (4.71 g, 36.75 mmol) in AcOEt (80 mL) at 0° C. were successively added triethylamine (15.3 mL, 110.24 mmol), benzyl bromide (13.1 mL, 110.24 mmol) and Bu4NI (6.79 g, 18.37 mmol). The reaction mixture was stirred at 0° C. for 2 H and concentrated in vacuo. The residue is taken up in AcOEt, the organic phase was washed with a saturated aqueous NaHCO3 and H2O. The organic phase was dried over MgSO4 and the solvent removed in vacuo. Flash chromatography of the residue on silica gel (n-heptane/EtOAc, 9:1) provided compound C-9 (6.00 g; 75%) as a colorless oil. 13C-NMR (62.89 MHz, CDCl3): 24.42, 28.34, 33.37, 34.13, 66.08, 114.73, 128.19, 128.55, 136.16, 138.37, 173.43.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH2:29][CH3:30])([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([CH3:28])[CH:15]=2)[CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:4].N1C=CN=C1.CN(C=O)C.[CH3:41][C:42]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CCOCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([O:27][Si:45]([C:42]([CH3:44])([CH3:43])[CH3:41])([CH3:47])[CH3:46])[C:23]([CH3:24])([CH3:25])[CH3:26])=[C:16]([CH3:28])[CH:15]=2)([CH2:12][CH3:13])[CH2:29][CH3:30])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (Example 2) (1.15 g, 2.66 mmol), imidazole (0.27 g, 4.00 mmol), and DMF (15 mL) is added TBSCl (0.54 g, 2.80 mmol). The reaction is stirred for 24 h. The reaction is diluted with Et2O (120 mL) and washed with 0.1 M HCl (3×40 ml). The organic layer is MgSO4 dried and concentrated. The resulting residue is chromatographed to give the title compound (0.94 g, 64%). 1H NMR (CDCl3), δ 0.01 (s, 3H), 0.06 (s, 3H), 0.65 (t, J=7.4 Hz, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 2.00-2.14 (m, 4H), 2.14 (s, 3H), 2.43 (s, 3H), 3.67 (dd, J=5.8, 3.4 Hz, 1H), 3.74 (s, 3H), 3.85 (dd, J=9.8, 5.8 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 6.56 (s, 1H), 6.68 (d, J=8.3 Hz, 1H), 6.96-7.03 (m, 2H). LC/MS (m/z): calcd for C31H51O4SSi (M+H)+: 547.9; found: 547.2.
Reaction SMILES: COC[O:4][CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.CO.Cl.[OH-].[Na+]>O>[OH:4][CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1
Reactant: COCOCCc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1ccc(CCO)cc1
Temperature: 60 °C
Reaction time: 17.5 h
Yield: 99.6 %

Procedure:
Next, a mixture of 4-(2-methoxymethoxyethyl)benzaldehyde (8.2 g, 42.1 mmol), methanol (160 mL), water (6 mL) and concentrated hydrochloric acid (4 mL) was stirred at 60° C. for 17.5 hours. After cooling to room temperature, the reaction mixture was neutralized with aqueous sodium hydroxide and evaporated under reduced pressure to remove methanol. The residue was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 50:50) to give 4-(2-hydroxyethyl)benzaldehyde (6.3 g).