Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]2[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1.[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[F:19][C:20]([F:30])([F:31])[C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]3[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=3)[CH2:2]2)=[O:28])[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ncccc1OCC1CCNC1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OCC1CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-(pyrrolidin-3-ylmethoxy)picolinate (EXAMPLE 92, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:27]#[C:26][CH2:25][CH2:24][OH:28])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: C#CCCO
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (17.0 g, 60.7 mmol; Intermediate 1), Pd(PPh3)2Cl2 (5.80 g, 6.07 mmol), CuI (1.20 g, 6.07 mmol), and triethylamine (170 mL) was added but-3-yn-1-ol (6.80 g, 97.2 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and washed with water (3×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30˜50% EtOAc in petroleum ether) affording the title compound (8.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 5.84 (dd, 1H), 4.90 (br, 1H), 3.91-3.87 (m, 1H), 3.77-3.70 (m, 1H), 3.60 (t, 2H), 2.56 (t, 2H), 2.48-2.33 (m, 1H), 2.04-1.94 (m, 2H), 1.76-1.69 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 271 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:14]([C:16]1[O:20][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)=[N:18][C:17]=1[CH2:32][CH2:33]O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[CH2:14]([C:16]1[O:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=2)=[N:18][C:17]=1[CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])[CH3:15]
Reactant: COC(=O)Cc1ccc(C)c(O)c1
Reactant: CCc1oc(-c2ccc(OC(F)(F)F)cc2)nc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1oc(-c2ccc(OC(F)(F)F)cc2)nc1CCOc1cc(CC(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Under atmosphere of argon, a solution of methyl (3-hydroxy-4-methylphenyl)acetate (1.00 g) in methylene chloride (22 mL) was added by 2-{5-ethyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-4-yl}ethanol (2.00 g), triphenylphosphine (2.18 g) and 1,1′-(azodicarbonyl)dipiperidine (2.10 g) and stirred overnight at room temperature. The reaction mixture was concentrated and the obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (2.38 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([O:24][C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]=2[Cl:13])[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:5]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)cc(Cl)n1
Temperature: 120 °C

Procedure:
A mixture consisting of 2.06 gm (0.01 mol) of methyl 4,6-dichloro-picolinate, 2.15 gm (0.011 mol) of 2-chloro-4-trifluoromethyl-phenol, 1.5 gm of pulverized potassium carbonate and 5 ml of dimethylformamide was heated at 120° C. for one hour, while stirring. The mixture solidified. The solid mass was stirred and decanted several times with ice water, then acidified with acetic acid, and finally extracted with ethyl acetate. The organic phase was separated, washed with water and dried with sodium sulfate. The solvent was distilled off, and the residual oil was purified by chromatography on 40 gm of silicagel (eluant: Diisopropyl ether). 1.4 gm (38% of theory) of the title compound were obtained as a virtually colorless oil. Rf -value: 0.48 (prepared thin-layer chromatography plates manufactured by E. Merck, Darmstadt, Germany, with silicagel 60-F-254. Eluant: Acetone/diisopropyl ether 1:2; the spots are visible in ultraviolet light at 254 μm).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[O:10][CH3:11].[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(#N)C>[C:12]([O:16][C:17](=[O:18])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: COc1cc(CN)ccc1O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-3-methoxybenzylamine (1.0 g, 5.27 mmol) in acetonitrile (30 mL) was added tert-butyldicarbonate (1.27 g, 5.80 mmol) and di-isopropylethylamine (1.84 mL, 10.54 mmol). The reaction was stirred at room temperature for 16 h before being partitioned between EtOAc (60 mL) and water (30 mL). The aqueous phase was separated and re-extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO4, filtered and concentrated. Purification by flash chromatography (40% EtOAc/hexanes) gave tert-Butyl(4-hydroxy-3-methoxybenzyl)carbamate. LCMS 275.9 (M+1)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([OH:15])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[Cs+].[Cs+].CC#N>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Temperature: 80 °C
Yield: 98.9 %

Procedure:
To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 19; 500 mg, 1.2 mmol) was added MeCN (30 ml), tetrabutylammonium bromide (30 mg, 0.08 mmol), anhydrous sodium carbonate (500 mg, 4.7 mmol), ethyl bromoacetate (0.14 ml, 1.26 mmol) and caesium carbonate (20 mg, 0.06 mmol). This reaction mixture was then stirred over night at 80° C. Then the solvent was removed under reduced pressure, water and DCM were added and the aqueous phase was extracted three times with DCM. The combined organic phases were then dried, concentrated and purified by flash chromatography [DCM:EtOAc, 1:0, 9:1] to give the title compound 600 mg (99%). NMR (300 MHz) 0.8–1.0 (m, 6H), 1.0–1.8 (m, 11H), 2.2 (s, 3H), 3.2 (q, 2H) 3.75 (brq, 2H), 4.3 (q, 2H), 4.75 (s, 1H), 6.7 (s, 1H), 6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.3 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28]=[C:29]=[S:30])[CH3:27]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:29]([NH:28][CH2:26][CH3:27])=[S:30])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCN=C=S
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CCNC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 52 μl (2 molar equivalents) of ethyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 92 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=73%) which was characterized as follows:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1)=[O:5].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([CH2:26][CH2:27][NH:28][CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:9][CH:8]=2)=[O:5])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCC(c2ccc(NC(=O)CCCl)cc2)=NN1
Reactant: NCCc1ccccc1
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)CCNCCc3ccccc3)cc2)=NN1
Yield: 36.4 %

Procedure:
11.18 g (40 millimoles) of 6-[p-(3-chloropropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone in 250 ml of ethanol were initially taken and 26.5 g (220 millimoles) of 2-phenylethylamine were added dropwise, after which the mixture was refluxed for 6 hours. Insoluble material was filtered off, the solvent was stripped off and the mother liquor was then crystallized by adding acetone. The product was recrystallized twice from methanol to give 5.3 g of 6-{p-[3-(2-phenylethylamino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.HCl of melting point 269°-270° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C.Cl>CCOCC>[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:15]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CC(F)=C(F)F)Oc1ccc([N+](=O)[O-])cc1
Yield: 92.1 %

Procedure:
A solution of 4-nitrophenol (1.10 g, 0.0079 mole) and 3,4,4-trifluoro-3-butenoyl chloride (1.85 g, 0.0116 mole) in dry ether (15 mL) is treated dropwise with triethylamine (1.01 g, 0.01 mole) at -78° C. with stirring. The mixture is stirred at -78° C. for 10 min and allowed to reach room temperature. The reaction mixture is diluted with ether (20 mL), stirred with 15 mL of 2N HCl. The organic layer is successively washed with water, 5% sodium bicarbonate, brine, and dried. The dark brown residue obtained after evaporation of the solvent was purified by passing through a short column of silica gel to give 1.9 g of the product as a brown solid, a 91% yield. m.p. 58°-62° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]2[CH2:18][C:17]3[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=3[O:19][CH3:20])[CH2:11]2)=[CH:30][CH:29]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.4 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (830 mg), 4-chlorophenol (269 mg), and potassium carbonate (481 mg) in DMF (8 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (776 mg) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[C:23](Cl)(=O)[CH2:24][CH3:25]>>[Cl:21][C:19]1[C:18]([Cl:22])=[CH:17][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=3)[C:23]([CH2:24][CH3:25])=[N:1][C:2]=2[CH:20]=1
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)c(Cl)cc2N)cc1
Product: CCOC(=O)Cc1ccc(-n2c(CC)nc3cc(Cl)c(Cl)cc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from ethyl [4-(2-amino-4,5-dichloroanilino)phenyl]acetate (step 2) and propionyl chloride.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(C2=CCC3(CC2)OCCO3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CC=C(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Intermediate 3B (1.00 g, 3.52 mmol) in DCM (5 mL) was added TFA (2.5 mL, 32. mmol). The reaction was stirred at rt for 2 h. The reaction mixture was concentrated and purified on a 24 g silica gel column eluted from 0 to 100% EtOAc in hexanes over 15 minutes to Intermediate 3C (650 mg, 2.71 mmol, 77.0% yield). LCMS=241 [M+1], RT=3.59 min (Method A).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:43][C:44]1[C:45]([CH2:50]Cl)=[N:46][CH:47]=[CH:48][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:50][C:45]3[C:44]([Cl:43])=[CH:49][CH:48]=[CH:47][N:46]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: ClCc1ncccc1Cl
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3ncccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro-2-(chloromethyl)pyridine and isolated as light-brown gum. MS(m/e): 400.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Yield: 30.4 %

Procedure:
1.15-1.55 (3H, m), 3.19 (3H, s), 3.93-4.50 (4H, m), 6.49 (1H, d, J=12.0 Hz), 8.76-9.07 (2H, m). 2) By using 1.00 g of N-(5-fluoro-4-methylsulfonyl-2-nitrophenyl)glycine ethyl ester, 0.85 g of imidazole and 5 ml of DMF, 0.35 g (67%) of N-[5-(1H-imidazol-1-yl)-4-methylsulfonyl-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2.10 g, 5.29 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.87 g, 8.46 mmol) in DMF (30 mL) was added EDCI hydrochloride (1.31 g, 6.90 mmol), HOBt (0.93 g, 6.90 mmol) and DIPEA (1.17 mL, 6.90 mmol). The reaction mixture was stirred at room temperature for 5 hours before being concentrated in vacuo. The resultant residue was dissolved in 1:1 tert-butylmethylether:ethyl acetate (20 mL) and aqueous saturated sodium hydrogen carbonate solution (20 mL) was added. The resultant mixture was sonicated until a precipitate formed, the precipitate was collected by filtration and dried in vacuo at 45° C. to yield the title compound as a tan solid (1.55 g, 60%). LCMS (Method B): RT=2.80 min, M+H+=483.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1
Reactant: OCc1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(F)cc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(4-fluorophenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[N:41]([CH:43]=[CH:44][N:45]=2)[N:42]=1.C([O-])(O)=O.[Na+].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].O1CCOCC1>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]4[N:41]([CH:43]=[CH:44][N:45]=4)[N:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Clc1ccc2nccn2n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc3nccn3n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 64.8 %

Procedure:
A microwave vial equipped with a flea stir bar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.042 mmol), 6-chloroimidazo[1,2-b]pyridazine (13 mg, 0.083 mmol), NaHCO3 (7 mg, 0.083 mmol), PdCl2(dppf) (3 mg, 0.004 mmol), H2O (0.1 mL) and dry dioxane (1.0 mL). The mixture was sparged with nitrogen for 10 min and heated at 110° C. for 30 min in the microwave. The mixture was diluted with glacial HOAc (0.1 mL) and methanol (0.6 mL), and filtered. The filtrate was purified directly by prep HPLC to afford the title compound (12.8 mg, 65%) as an oil. LC-MS Method 1 tR=1.28 min, m/z=471; 1H NMR (CD3OD) 0.97 (s, 3H), 1.26 (s, 3H), 1.59 (d, 3H), 2.17 (s, 2H), 2.29 (m, 1H), 2.50 (2H), 3.11 (m, 1H), 5.61 (q, 1H), 7.19 (d, 2H), 7.25-7.40 (5H), 7.93 (d, 2H), 8.19 (s, 1H), 8.27 (d, 1H), 8.42 (d, 1H), 8.54 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])C)=[O:9])[CH2:4][CH2:3]1.CN(C)CCN(C)C.C([Li])(CC)C.[CH2:28]([N:35]1[CH2:40]CC(=O)C[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:28]([N:35]1[CH2:40][CH2:13][C:11]2([CH:6]3[CH2:7][N:2]([CH3:1])[CH2:3][CH2:4][N:5]3[C:8](=[O:9])[O:10]2)[CH2:14][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CN1CCN2C(=O)OC3(CCN(Cc4ccccc4)CC3)C2C1
Temperature: -78 °C
Yield: 46.2 %

Procedure:
A mixture of tert-butyl 4-methylpiperazine-1-carboxylate (24.2 g), N,N,N′,N′-tetramethylethane-1,2-diamine (21 g) and tetrahydrofuran (500 mL) was cooled to −78° C. under a nitrogen atmosphere, and sec-butyllithium (184 mL, 1.3M cyclohexane solution) was added dropwise over 1.5 hr while stirring. Furthermore, the mixture was stirred at the same temperature for 2 hr, the reaction system was heated to 30° C., and the mixture was stirred for 1.5 hr. Thereafter, the reaction system was cooled again to −78° C., and a solution of 1-benzylpiperidin-4-one (28.3 g) in tetrahydrofuran (50 ml) was added dropwise over 1 hr. The reaction system was stirred at room temperature overnight, and the mixture was cooled to 0° C. Saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (300 mL), and the extract was washed with water (300 mL) and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (17.6 g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[N+:31]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reaction time: 1 h

Procedure:
1.35 g of tert-butyl(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}phenyl)carbamate (2.3 mmol, 1 eq.) were dissolved in 43 mL THF and heated to 50° C. upon which a solution of 6.8 g sodium dithionite (39 mmol, 17 eq.) in 35 mL water was added and stirring was continued at that temperature for 1 h. The layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product (1.5 g) was used without further purification.