Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1.[CH2:20](OCCOCC)[CH3:21]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[O:9][C:10]3[C:2]([CH:20]=[CH2:21])=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Oc1cc(Br)c2oc(-c3ccc(O)c(F)c3)nc2c1
Reactant: CCOCCOCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 115 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.87 g, 1.1 mmol) was added into a mixture of 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol (7.16 g, 22.1 mmol) tributyl(vinyl)tin (10.5 g, 33.25 mmol) and ethylene glycol diethyl ether (65 mL). The reaction mixture was stirred at 115° C. for 48 h, cooled to room temperature and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography, on acidic silica gel (hexanes/EtOAc/CH2Cl2 1/1/1), gave a white solid (4.35 g, 72% yield, m.p. 250-252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[S:2].C(Cl)(Cl)Cl.[CH:9]1([SH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>O>[Cl:3][CH:1]([S:2][S:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[Cl:4]
Reactant: SC1CCCCC1
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: ClC(Cl)SSC1CCCCC1
Yield: 67.2 %

Procedure:
To a solution of 20.0 g (0.17 mole) of thiophosgene in 100 ml. of chloroform cooled to 0° C. was added dropwise with stirring 20.2 g (0.17 mole) of cyclohexyl mercaptan. To this mixture was added dropwise a solution of 2.5 g of sodium hydroxide in 25 ml. of water at such a rate as to keep the temperature less than 8° C. When the addition was complete, the chloroform layer was separated and dried over calcium chloride. The solvent was evaporated, and the residue was distilled under reduced pressure to give 26.4 g of yellow cyclohexyl dichloromethyl disulfide, b.p. 118°-125° C. (5 Torr.)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1>>[CH3:17][C:16]1[C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccnc1F
Reactant: N#Cc1cccc(O)c1
Product: Cc1cccnc1Oc1cccc(C#N)c1

Procedure:
3-Hydroxy-benzonitrile was reacted with 2-fluoro-3-methylpyridine according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 211 (M+1)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:37])[CH:28]([F:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C(Cl)=O.CS(C)=O>>[C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:27](=[O:37])[CH:28]([F:36])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(F)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(=O)C(F)Cc1ccccc1

Procedure:
According to the procedure of Thaisrivongs et. al. (J. Med. Chem. 1986, 29, 2080), the resultant compound of Example 128 was oxidized with oxalyl chloride/dimethyl sulfoxide to provide the desired compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19](Br)=[CH:20][N:21]=2)[N:18]=1)[CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH:24]1([B-](F)(F)F)[CH2:26][CH2:25]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.N#N>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:1]([O:4][C:5](=[O:23])[N:6]([CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][N:21]=2)[N:18]=1)[CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(CCNc1ccc2ncc(Br)n2n1)C(C)C
Reactant: F[B-](F)(F)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N(CCNc1ccc2ncc(C3CC3)n2n1)C(C)C
Yield: 9 %

Procedure:
A solution of 10% (v/v) water in THF (25 mL) was added to a mixture of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-isopropyl-carbamic acid isopropyl ester (515.1 mg, 1.34 mmol), potassium cyclopropyltrifluoroborate [1065010-87-1] (396.8 mg, 2.7 mmol), cesium carbonate [534-17-8] (1.3 g, 4.0 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (110.4 mg, 0.1 mmol) contained in a 50 mL round bottomed flask. The reaction pot was fitted to a reflux condenser and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated reflux for 4d then cooled and filtered. The filtrate was partitioned between brine and ethyl acetate and the phase separated organic extract dried (MgSO4) and evaporated to give a black oil which was purified by preparatory RP-HPLC to provide 41.6 mg of [2-(3-cyclopropyl-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-isopropyl-carbamic acid isopropyl ester as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.77-0.84 (m, 2H) 0.98-1.06 (m, 2H) 1.20-1.32 (m, 14H) 2.08-2.19 (m, 1H) 3.43-3.50 (m, 2H) 3.50-3.59 (m, 2H) 6.61 (d, J=9.70 Hz, 1H) 7.08 (s, 1H) 7.52 (d, J=9.70 Hz, 1H). LRMS (ESI) m/z 346.2 [(M+H)]+, calc'd for C18H27N6O2: 345.45.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][CH:17]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:18][C:13]=2[C:12]=1[CH3:30])=[O:10])C1C=CC=CC=1.[H][H].C(Cl)(Cl)Cl>C(Cl)Cl.[Pd]>[C:22]([SiH2:21][O:20][C:19]([CH3:27])([CH3:26])[CH:17]1[CH2:16][O:15][C:14]2[CH:28]=[CH:29][C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:30])[C:13]=2[O:18]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(C(=O)OCc2ccccc2)ccc2c1OC(C(C)(C)O[SiH2]C(C)(C)C)CO2
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)O)ccc2c1OC(C(C)(C)O[SiH2]C(C)(C)C)CO2
Reaction time: 3 h
Yield: 85.1 %

Procedure:
9.63 g of 3-(tert-Butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid benzyl ester was dissolved in ca. 125 mL of dry CH2Cl2. The solution was transferred to a Parr hydrogenation bottle, and 5 g of 5% Pd on carbon were added. The bottle was charged with hydrogen and shaken on a Pair hydrogenation apparatus for 3 hours; hydrogen uptake ceased after 2 hours, as indicated by pressure monitoring. 100 mL CHCl3 were added, and the Pd/C was filtered off after adding MgSO4 as an aid to increase particle size. The CH2Cl2-CHCl3 phase was washed with 200 mL of 0.1N HCl to remove the by-product benzyl alcohol. The organic layer was dried and evaporated to give 6.47 g 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid, after trace solvent removal in a vacuum oven. TLC Rf=0.55 (1:1 ethyl acetate:hexane). Note: (a) Pd catalyzed hydrogenation is a far superior method to triethylsilane/palladium diacetate for this benzyl ester cleavage, (b) washing product with weak aqueous acid is a good way to remove benzyl alcohol. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.55 (d, 1H), 6.7 (d, 1H), 4.3 (d, 1H), 4.17 (m, 1H), 4.02 (dd, 1H), 3.82 (dd, 1H), 3.75 (dd, 1H), (2.45 (s, 3H), 0.8 (s, 9H), 0.01 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A reaction mixture of methyl 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.13 g, 0.24 mmol), lithium hydroxide monohydrate (0.025 g, 0.60 mmol) in methanol (4.0 mL), THF (2.0 mL) and water (1.0 mL) was stirred at 40° C. for 3 h. The mixture was adjusted to pH=4 with 2.0 N HCl aqueous solution, and concentrated under reduced pressure to remove MeOH and THF. The precipitate formed was filtered, washed with water and ether, and dried in vacuum to afford the desired product (0.100 g, 79%). LCMS (M+H)+: m/z=531.4.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:23])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:23])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a stirred solution of 7-[2-(2-amino-4-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxylic acid (520 mg) in methanol (15 ml) was added sodium borohydride (100 mg) under ice-cooling, and stirred at the same temperature for 3 hours. Methanol was distilled off under reduced pressure from the reaction mixture, and the residue was dissolved in water (3 ml) and adjusted to pH 3 with 6 N-hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-amino-4-thiazolyl)-2-hydroxyacetamido]-3-cephem-4-carboxylic acid (290 mg).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Br:8][CH2:9][CH2:10]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:8][CH2:9][CH2:10][N:3]1[C:4](=[O:6])[CH2:5][S:1][C:2]1=[O:7]
Reactant: O=C1CSC(=O)N1
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CSC(=O)N1CCBr
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-thiazolidine-2,4-dione (10 g, 85.38 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), 2-bromoethan-1-ol (10.6 g, 84.82 mmol, 1.00 equiv), triphenylphosphane (27 g, 102.94 mmol, 1.20 equiv). This was followed by the addition of a solution of DIAD (21 g, 103.96 mmol, 1.20 equiv) in tetrahydrofuran (30 mL) dropwise with stirring at 0-10° C. in 30 min. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/50) to give 9 g (47%) of 3-(2-bromoethyl)-1,3-thiazolidine-2,4-dione as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:20])[N:4]=1.[C:21](=N)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCCl>[C:21](=[N:1][CH2:2][C:3]1[N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11](=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:20])[N:4]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cccc2nc(CN)n(-c3ccccc3)c(=O)c12
Solvent: ClCCCl
Product: Cc1cccc2nc(CN=C(c3ccccc3)c3ccccc3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-aminomethyl-5-methyl-3-phenyl-3H-quinazolin-4-one (2.91 g, 11.0 mmol), benzhydrylideneamine (2.39 g, 13.2 mmol), and 1,2-dichloroethane (15 mL). The reaction mixture was heated at reflux for 4 h under nitrogen atmosphere and then cooled to ambient temperature. Concentration under reduced pressure followed by purification by column chromatography afforded the compound 162 as an orange solid. m.p. 49° C. (dec); 1H NMR (DMSO-d6) δ (ppm) 7.22-7.78 (m, 17H), 6.74 (m, 1H), 4.17 (s, 2H), 2.74 (s, 3H); m/z=430 (M+H). The reaction described above and compound 162 are shown below.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].CS.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([O:35][CH3:36])=[O:34])=[CH:23][CH:22]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)c(C(=O)OCC)[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CS
Product: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 69.3 %

Procedure:
The operation is carried out as in Example 5, starting with 0.6 g of ethyl 2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate (prepared as indicated in Stages C and D of Preparation 1, replacing the ethanethiol with methanethiol), using 907 mg of methyl 4'-(bromomethyl)-(1,1'-biphenyl)-2 -carboxylate. After chromatography on silica (eluant: methylene chloride--ethyl acetate (97-3)), 0.8 g of the desired product is obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27].O>CN1C(=O)CCC1>[CH2:25]([NH:29][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: CC(C)CN
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)CNc1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) and isobutylamine(0.52 ml) in NMP (10 ml) was stirred at ambient temperature for 18 h. Water (100 ml) was then added and the resulting precipitate was collected by filtration and dried (0.85 g). Trituration of this material with ether/cyclohexane gave the title compound as a colourless solid (0.62 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3n2)c(N)c1
Temperature: 80 °C
Yield: 18.5 %

Procedure:
To a mixture of compound 2-chloro-6-methoxyquinoline (1.70 g, 8.78 mmol), 2-amino-4-(methoxycarbonyl)phenylboronic acid (2.05 g, 10.5 mmol), and K2CO3 (2.43 g, 17.6 mmol) in ethylene glycol monomethyl ether/H2O (35 mL/5 mL) was added Pd(dppf)Cl2 (158 mg, 0.193 mmol) under N2 atmosphere. Then the mixture was heated to 80° C. for 3 hours. After aqueous workup with EtOAc extraction, the resulting crude product was purified by silica gel column (PE/EtOAc=15/1 to 3/1) to give the product (500 mg, yield 19%) as a yellow solid.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C(C1C=CN=CC=1)#N.[CH2:27]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1C=CC=CC=1.B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[C:39]1([C:35]2[N:34]=[CH:27][C:38]([C:12]3[NH:8][C:9]([C:13]4[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=4)=[N:10][CH:11]=3)=[CH:37][N:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(Cn2ccnc2-c2ccncc2)cc1
Reactant: c1ccc(Cn2ccnc2-c2ccccc2)cc1
Agent: N#Cc1ccncc1
Agent: OB(O)c1cccc(F)c1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2ncc(-c3cnc(-c4ccncc4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, except that 4-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to Example 8, Step A, except that commercially available 4-cyanopyridine was used instead of 3-fluorobenzonitrile) was used in place of the 1-benzyl-2-phenyl-1H-imidazole in Step C; Rf 0.26 with 95:5 v/v dichloromethane-methanol; melting point 300° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.40 (s, 2H), 8.73 (d, 2H), 8.50-8.45 (m, 2H), 8.25 (bs, 1H), 8.00 (d, 2H), 7.62-7.55 (m, 4H); MS (ESI+) m/z 300.0 (M+1); H-PGDS FPBA IC50: 0.125 μM; H-PGDS inhibitor EIA IC50: 0.075 μM.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Mg].[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[C:13]([F:24])[C:12]=1[F:25])[CH3:9].C(OC1C=CC=C(F)C=1F)C.C([Li])CCC.O1C2(CCC(=O)CC2)OCC1>C1COCC1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][C:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([OH:23])[CH2:21][CH2:22]2)=[C:13]([F:24])[C:12]=1[F:25])[CH3:9]
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: CCCCCBr
Agent: CCOc1cccc(F)c1F
Agent: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC1(O)CCC(c2ccc(OCC)c(F)c2F)CC1

Procedure:
A solution of 54.5 ml of 1-bromopentane in 200 ml of THF was added dropwise to 10.7 g of magnesium turnings under a layer of 100 ml of THF, and the mixture was subsequently refluxed for 1 hour. A solution of 104.5 g of 4-(4-ethoxy-2,3-difluorophenyl)cyclohexanone (obtainable by lithiation of 4-ethoxy-2,3-difluorobenzene using n-butyllithium, reaction with 1,4-dioxaspiro[4.5]decan-8-one, dehydration and hydrogenation of the resultant alkene, followed by removal of the carbonyl protecting group under acidic conditions) in 500 ml of THF was then added dropwise at 40° C., and the mixture was refluxed for 2 hours. Conventional work-up gave 4-(4-ethoxy-2,3-difluoro-phenyl)-1-pentylcyclohexanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH:22]1([CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[CH2:31][NH2:32])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][C@H:27]2[CH2:28][CH2:29][CH2:30][N:26]2[CH2:25][CH:22]2[CH2:24][CH2:23]2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: NC[C@H]1CCCN1CC1CC1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 17] and [(2R)-1-(cyclopropylmethyl)pyrrolidinyl]methylamine [see WO 9839295 A1], to afford the product as a orange oil (100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16](O)=[O:17])[N:13]=[N:12]1.[Cl-].[NH4+:25].C(=O)(O)[O-].[Na+]>C1COCC1>[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16]([NH2:25])=[O:17])[N:13]=[N:12]1
Reactant: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
3.74 ml (45.65 mmol) of oxalyl chloride were added drop wise to a suspension of 10 g (41.8 mmol) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid in ml of anhydrous THF, at 20-25° C. and under nitrogen atmosphere. When the addition of oxalyl chloride was concluded, the mixture was stirred at 20-25° C. for 4 h. Afterwards, the resulting mixture was diluted with 50 ml of anhydrous THF, followed by the distillation of 15 ml at 35-40° C. under vacuum, in order to remove the remaining HCl. The reaction was cooled to 20-25° C. and 8 g (149.57 mmol) of ammonium chloride were added followed by addition of 20 ml of 8% aqueous solution of sodium bicarbonate. After further addition of 8.8 g (104.97 mmol) of sodium bicarbonate, the mixture was left under powerful stirring over 4 h at 20-25° C. To conclude with, the suspension was filtered and washed twice with 50 ml of a saturated aqueous sodium bicarbonate solution and twice with 50 ml of water The solid was dried on a vacuum drier at 50° C. to yield 5.6 g (56.2%) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide as Form R-5.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](O)C(F)(F)F)CC3)ncc1Cl

Procedure:
(S)-3-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-1,1,1-trifluoro-propan-2-ol was prepared from (S)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 328. Product isolated as a white solid (179 mg, 86%). m.p.=170-172° C.; LCMS (m/e) 593 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H, J=8.7 Hz), 8.03 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.32-7.26 (m, 1H), 7.04 (d, 1H, J=8.1 Hz), 6.87 (s, 1H), 6.57 (s, 1H), 6.51 (d, 1H, J=8.7 Hz), 4.50-4.32 (m, 1H), 4.10-4.00 (m, 1H), 3.94 (s, 3H), 3.93-3.89 (m, 4H), 3.21-3.15 (m, 4H), 2.97-2.79 (m, 7H), 2.77-2.67 (m, 3H).