Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:26][C:27]1[CH:28]=[C:29]([Zn]I)[CH:30]=[CH:31][CH:32]=1>O1CCCC1.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>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: Fc1cccc([Zn]I)c1
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Temperature: 60 °C
Yield: 89 %

Procedure:
To a mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.200 g, 0.502 mmol) in tetrahydrofuran (5 mL) was added 0.50 M (3-fluorophenyl)(iodo)zinc in tetrahydrofuran (1.20 mL, 0.602 mmol) with stirring, followed by addition of tetrakis(triphenylphosphine)palladium(0) (29.0 mg, 0.0251 mmol). The reaction mixture was heated at 60° C. overnight. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexane, to give the desired product (154 mg, 89%). LCMS calculated for C18H15ClFN2O2(M+H)+: m/z=345.1; found: 345.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].O.[NH3:14]>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:10])[CH2:11][NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CO1
Reactant: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](O)CN
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-1-Oxiranylmethylcarbamic acid tert-butyl ester (2.26 g, 13.05 mmol) obtained in Step 2 above was dissolved in ethanol (15 ml), and then 28% ammonia water (6 ml) was added thereto at room temperature. After the solution was stirred at room temperature for 1.5 hour, the solvent was distilled off under reduced pressure. After the resulting residue was dissolved in methanol, the solvent was distilled off under reduced pressure to give a crude product of ((S)-3-amino-2-hydroxypropyl)carbamic acid tert-butyl ester (2.38 g) as a yellow oily material.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C:31]([C:34](=[O:39])[NH:35][CH2:36][CH2:37][OH:38])([CH3:33])[CH3:32])=[CH:19][CH:18]=1)#[N:2].CCN(C(C)C)C(C)C.[CH3:49][C:50]([Si:53](Cl)([CH3:55])[CH3:54])([CH3:52])[CH3:51].[OH-].[Na+]>CN(C1C=CN=CC=1)C.C1COCC1>[C:50]([Si:53]([CH3:55])([CH3:54])[O:38][CH2:37][CH2:36][NH:35][C:34]([C:31]([CH3:33])([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:4]2[C:5]3[N:6]([CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11]=3[CH3:12])[N:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)[CH3:32])=[O:39])([CH3:52])([CH3:51])[CH3:49]
Reactant: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO[Si](C)(C)C(C)(C)C)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of 433F (164 mg, 0.31 mmol), DIEA (0.27 ml, 1.55 mmol), DMAP (7.6 mg, 0.062 mmol) and TBSCl (140 mg, 0.93 mmol) in THF (4 ml) was stirred under argon at rt for 2 h. 1N NaOH (0.70 ml, 0.70 mmol) was added. The resulting mixture was stirred at rt for 1 h. Removal of the solvent followed by flash chromatography of the residue of silica gel (2%-5% MeOH—CH2Cl2) gave 433G (75 mg, 38%) as a yellow oil. It has a retention time of 7.43 min (standard LC1 method, 8 min run). MS Found: (M+H)+=644.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ncccc3c2=O)cc1C
Yield: 18.2 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one, and 2-Bromomethyl-6-trifluoromethyl-pyridine 53 mg (0.22 mmol), to give 14 mg of desired compound. LCMS (M+H)+: 454.1.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.CC(C)([O-])C.[K+]>[OH-].[Pd+2].[OH-].C1COCC1>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12

Procedure:
Compound 6 was hydrogenated with palladium hydroxide, THF, and potassium tert-butoxide to produce crude trans racemate, (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (Compound 8). As described in the examples, the preparation of Compound 8, does not require the isolation of crude cis racemate (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (Compound 7). Rather, during the hydrogenation of Compound 6, conditions were modified to effect the isomerization of the resultant Compound 7 in situ. The resulting process provides a means to control key impurities in Compound 8, specifically Compound 6. Specifically, the reaction is carried out in THF solvent, and the catalyst employed is palladium hydroxide. Potassium tert-butoxide is also added to the reaction mixture to promote the isomerization. A detailed description of this process is shown in Example 2.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][CH:7]([C:13](=O)[CH3:14])[C:8]([O:10]CC)=O.Cl.[CH:17]1([C:23](=[NH:25])[NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCO>[CH:17]1([C:23]2[N:25]=[C:8]([OH:10])[C:7]([CH3:6])=[C:13]([CH3:14])[N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N=C(N)C1CCCCC1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C2CCCCC2)nc(O)c1C
Temperature: 25 °C
Yield: 152.3 %

Procedure:
A solution of sodium ethoxide (previously prepared by dissolving sodium (6.36 g, 278 mmol, 3 eq) in EtOH (300 ml)), stirring at RT, was treated with ethyl 2-methyl-3-oxobutanoate (16.94 ml, 120 mmol, 1.3 eq). A slurry of cyclohexanecarboximidamide hydrochloride (15 g, 92 mmol, 1 eq) in EtOH (100 ml) was then added and the RM heated at reflux for 8 h. The RM was concentrated, water added and the pH adjusted to ˜7-8 with 2N HCl. Following acidification a white solid precipitated and this was filtered and dried in the vac-oven to yield 2-cyclohexyl-5,6-dimethylpyrimidin-4-ol as a white solid (28.91 g, 151%). 1H (400 MHz, DMSO) 1.03-1.86 (10H, m), 1.96 (3H, s), 2.16 (3H, s), 2.36-2.57 (1H, m), 12.05 (1H, brs); ES+207.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:16]=[C:15]3[C:10]([O:11][CH2:12][CH:13]=[CH:14]3)=[C:9]([CH3:17])[C:4]=2[O:5][C:6](=[O:8])[CH:7]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][C:2]1[C:3]2[CH:16]=[C:15]3[C:10]([O:11][CH2:12][CH2:13][CH2:14]3)=[C:9]([CH3:17])[C:4]=2[O:5][C:6](=[O:8])[CH:7]=1
Reactant: Cc1cc(=O)oc2c(C)c3c(cc12)C=CCO3
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1cc(=O)oc2c(C)c3c(cc12)CCCO3
Yield: 39.5 %

Procedure:
A mixture of 4,10-dimethyl-2H,8H-benzo[1,2-b;5,4-b']dipyran-2-one (100 mg, 0.44 mmoles), cyclohexene (0.5 ml, 4.94 mmoles) and palladium on activated carbon (10%, 50 mg) in ethanol (25 ml) was refluxed for 5 hr. The mixture was cooled, filtered and the solvent removed under reduced pressure. The residue was recrystallized from benzene/cyclohexene to afford colorless needles of 6,7-dihydro-4,10-dimethyl-2H,8H- benzo[1,2-b;5,4-b']dipyran-2-one (40 mg, 40%), mp 162°-163° C.; 1H NMR 1.93, mult, 2H, H7 ; 2.11, s, 3H, C10 -- Me; 2.24, d, J=1.0 Hz, 3H, C4 --Me; 2.75, t, J=6.5 Hz, 2H, H6 ; 4.20, t, J=5.2 Hz, 2H, H8 ; 5.94, d, J=1.0 Hz, 1H, H3 ; 6.99, s, 1H, H5. 13C NMR 7.88, q, C10 --Me; 18.52, q, C4 --Me; 21.85, 24.86, two t, C6 and C7 ; 66.90, t, C8 ; 111.29, d, C3 ; 112.73, 112.84, two d, C5a and C10 ; 118.31, s, C4a ; 122.078, d, C5 ; 150.92, s, C9a ; 152.55, s, C4 ; 155.74, s, C10a ; 161.54, s, C2.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH2:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][N:5]=1.CC(C)=O>O>[O:6]1[C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:8][C:4]([CH:3]=[O:2])=[N:5]1
Reactant: COC(OC)C1=NOC2(CCCCC2)C1
Solvent: O
Solvent: CC(C)=O
Product: O=CC1=NOC2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
3-Dimethoxymethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene (1.06 g, 4.97 mmol, as prepared in the previous step) was placed in a 50 mL round-bottom flask equipped with a stir bar. Acetone (20 mL), water (0.3 mL), and Amberlyst-15 resin (200 mg) were added. The mixture was stirred at rt for 24 h. The solids were removed by filtration and rinsed with acetone (20 mL), and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/heptane, 0:1 to 3:2, v/v over 30 min, yielding 451 mg (54%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 9.90 (s, 1H), 2.81 (s, 2H), 1.72-1.87 (m, 4H), 1.58-1.69 (m, 2H), 1.40-1.53 (m, 4H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][N:22]=N1)([C:14]1[CH:19]=[CH:18][CH:17]=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:25]([C:29]1N=C(Cl)N(CC2C=CC(C3C(C(O)=O)=CC=CC=3)=CC=2)N=1)[CH2:26][CH2:27]C>>[CH2:29]([C:24]1[N:20]=[C:1]([CH2:14][CH2:19][CH2:18][CH3:17])[NH:22][N:23]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(Cl)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnnn2)cc1
Product: CCCCc1n[nH]c(CCCC)n1

Procedure:
A solution of 64.5 g (0.50 mol) of ethyl iminovalerate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)] in 100 mL of methanol was added slowly to 58.0 g (0.50 mol) of valeric acid hydrazide (Lancaster Synthesis) in 400 mL of methanol at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to ambient temperature and then stir at reflux for 2 days. The solvent was removed in vacuo; purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (80:20) gave 78.9 g (93%) of a colorless solid: mp 50.5°-51.5° C.; NMR (CDCl3) δ 0.88 (t, J=7 Hz, 6H), 1.28-1.33 (m, 4H), 1.63-1.77 (m, 4H), 2.72 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 183 (12%), 182 (100), 181 (3), 180 (6), 152 (8), 139 (4); HRMS. Calcd for M+H: 182.1657. Found: 182.1661.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[S:9])[NH2:8])[CH:2]=1.Br[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:9][CH:11]=[C:12]([OH:13])[N:8]=2)[CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: NC(=S)c1cccnc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1csc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine-3-carbothioamide (20 g, 0.145 mol) was dissolved in a mixture of toluene (145 ml) and DMF (116 ml). Ethyl bromoacetate (24.2 g, 0.145 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hours. The precipitated yellow compound was filtered, washed with water and dried to give 2-(3-pyridyl)thiazol-4-ol as hybromide salt.
Reaction SMILES: CC([N:5]1[C:9]2[N:10]=[C:11](O)[CH:12]=[C:13]([C:14]([O:16][CH2:17]C)=[O:15])[C:8]=2[C:7]([CH3:20])=[N:6]1)(C)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:8]2[C:7]([CH3:20])=[N:6][NH:5][C:9]=2[N:10]=1
Reactant: CCOC(=O)c1cc(O)nc2c1c(C)nn2C(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)nc2[nH]nc(C)c12

Procedure:
Ethyl 1-(1,1-dimethylethyl)-3-methyl-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2 g, 7.21 mmol) and phosphorus oxychloride (10 ml, 107 mmol) were heated at 100° C. for 32 hours. Ice was added and the contents were extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0% to 50% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.20 Hz, 3 H), 2.58 (s, 3 H), 4.44 (q, J=7.16 Hz, 2 H), 7.53 (s, 1 H), 13.82 (br. s., 1 H). LCMS(ES) [M+H]+240.1
Reaction SMILES: [CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]3[N:21]([C:29]4[C:30]5[C@H:37]([CH:38]([CH3:40])[CH3:39])[CH2:36][CH2:35][C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:22][C:23]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[C:16]=23)C(=O)OC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[CH:38]([C@H:37]1[C:30]2[C:29]([N:21]3[C:17]4[C:16](=[C:15]([CH2:14][NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:20]=[CH:19][CH:18]=4)[C:23]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:22]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:35][CH2:36]1)([CH3:40])[CH3:39]
Reactant: CC(C)[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CN(C(=O)OC(C)(C)C)C5CCCC5)cccc43)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNC5CCCC5)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-tert-butyl cyclopentyl((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)carbamate (0.0156 g, 0.0286 mmol) in DCM (2 mL) was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 1 hour and concentrated to yield (S)—N-((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)cyclopentanamine trihydrochloride as a solid. LCMS (APCI+) m/z 446.3 [M+H]+; Rt=3.28 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cn1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1cnc(OC)nc1
Temperature: 130 °C
Yield: 93.6 %

Procedure:
A mixture of 5-bromo-2-(methyloxy)pyrimidine (25.0 g, 132 mmol), methyl 2-propen-oate (13.7 g, 159 mmol), palladium(II) acetate (0.297 g, 1.32 mmol), tri-o-tolylphosphine (0.805 g, 2.65 mmol) and triethylamine (29.4 g, 291 mmol) in DMF (75 mL) was heated at 130° C. under N2 for 3 h, then diluted with water (200 mL) and DCM (200 mL). The organic layer was collected, washed with water (200 mL×4) and brine, dried over sodium sulphate and concentrated to give the title compound as a pale yellow solid (24 g, 81%), which was used without further purification
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][CH2:11]Br.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][C:18]=1[O:20][CH2:11][CH2:10][CH2:9][O:8][CH3:7]
Reactant: COc1ccc(Br)cc1O
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(Br)ccc1OC

Procedure:
66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Re (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.C(N1C=CN=C1)CCC.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:29][CH:28]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[N:3]=[CH:4][C:5]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCn1ccnc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(F)nc2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (900 mg, 4.03 mmol), anhydrous copper acetate (550 mg, 3.03 mmol), 1-butylimidazole (175 mg, 1.41 mmol), N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (418 mg, 2.02 mmol) and pyridine (0.326 ml, 4.03 mmol) were admixed with 25 ml of toluene, and stirred at 100° C. for 15 h, under argon. The reaction mixture was filtered and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 394 mg (32%), M+H+: 303.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[Cl:42])[O:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([N:30]=[C:31]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[N:32]=2)[CH:29]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:42][C:41]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([N:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[CH:21][C:20]=1[NH:19][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)=[O:9]
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Yield: 46.3 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-1H-pyrazole-5-carboxylic acid (46.1 mg, 0.366 mmol), tetrahydrofuran (5 mL), thionyl chloride (63.3 μL, 0.730 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (114 mg, 0.332 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (69.5 mg, 46%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9](Cl)[CH2:10][CH2:11][CH2:12]Cl)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:25].[Na+].[Na+]>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][S:25]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [S-2]
Reactant: CC(C)(C)OC(=O)NCC(Cl)CCCCl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCS1
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A solution of N-tbutoxycarbonyl-2.5-dichloroamylamine 221 (1.75 g, 6.8 mmol) in MeOH (70 mL) was stirred at rt and sodium sulphide nonahydrate (3 g, 12.5 mmol) was added. The mixture was heated at reflux for 1 hour, when TLC indicated that starting material was still present. Further sodium sulphide nonahydrate (1.5 g, 6 mmol) was added and reflux was continued for 5 hours. The MeOH was evaporated and the residue partitioned between water (50 mL) and DCM (100 mL). The layers were separated and the DCM washed with water (20 mL), 0.25 M HCl (20 mL) and brine (20 mL) and dried over MgSO4. Evaporation of the solvents gave 222 as a pale yellow solid (1.48 g, quant.) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 26.2 %

Procedure:
To a mixture of 308 mg (purity: 99.0%; 1.85 mmol) of 4-hydroxy-3,6-dichloropyridazine and 2.72 g (18.1 mmol) of 2-cyclopropyl-6-methylphenol was added 331 mg (5.62 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 134 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 26%) was obtained.
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][NH:15][C:14]2=[O:18])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:39])[C@@H:29](OS(C(F)(F)F)(=O)=O)[CH3:30]>CN1CCCC1=O.[H-].[Na+].O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:39])[C@H:29]([N:15]1[CH:16]=[CH:17][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=2)[C:14]1=[O:18])[CH3:30]
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
1-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (1.42 g) was dissolved in 10 ml of 1-methyl-2-pyrrolidone, to which 60% sodium hydride in oil (0.198 g) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled and added dropwise under nitrogen atmosphere over the period of 10 minutes to a solution of 1.8 g of (2S)-2', 4'-difluoro-2-trifluoromethanesulfonyloxypropiophenone in 50 ml of tetrahydrofuran which was cooled to -40° C. Then, the reaction temperature was raised to -20° C. over the period of 20 minutes and the reaction solution was stirred for 10 minutes. The reaction solution was diluted with 3.5 ml of acetic acid and 70 ml of ethyl acetate, washed with water (40 ml×2), 0.5N-hydrochloric acid (40 ml×2) and 40 ml of a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium chloride. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 300 g, eluent; hexane:ethyl acetate:acetic acid=2:1:0.08) to give 0.94 g of 1-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as a pale yellow viscous substance. The product was crystallized from a mixture of diisopropyl ether and hexane to give colorless powdery crystals.