Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(CCCC)(CCCC)CCCC.O[C:34]1[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:34]3[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=3)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of 1-(4′-chloro-4-biphenylyl)-1-pentanol (140 mg, 0.51 mmol) in dry THF (15 mL) under nitrogen at 0° C. (ice/water bath) was added nBu3P (250 μL, 1.02 mmol), followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (110 mg, 0.52 mmol) and ADDP (260 mg, 1.03 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed under vacuum. The residue was partitioned between water and EtOAc and extracted with EtOAc (3×30 mL). The organic extract was separated and dried (MgSO4) and the solvent removed under vacuum. Purification by flash chromatography (silica) eluting with cyclohexane:EtOAc (9:1) afforded the title compound as a colourless gum (150 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:6]=1)(=O)=O.[CH:31]1([CH2:34][OH:35])[CH2:33][CH2:32]1>>[CH:31]1([CH2:34][O:35][C:5]2[N:10]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:7]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:6]=2)[CH2:33][CH2:32]1
Reactant: OCC1CC1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(N2CCCC2)n1
Product: Clc1ccc(-c2c(-c3ccc(Cl)cc3Cl)nc(OCC3CC3)nc2N2CCCC2)cc1

Procedure:
2-(Methylsulfonyl)-4-(N-pyrrolidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 36, Step A, 48 mg, 0.1 mmol) was treated with cyclopropyl methanol by the same general procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 70/30 hexanes/ethyl acetate) afforded the title compound. HPLC: Rt=3.46 min. 1H-NMR 500 MHz (CDCl3): δ 0.37 (d, J=4 Hz, 2H), 0.61 (dd, J=8 Hz, J=1 Hz, 2H), 1.38 (m, 1H), 1.80 (bs, 4H), 3.2 (bs, 4H), 4.17 (m, 1H), 4.25 (m, 1H), 6.85 (d, J=8 Hz, 1H), 7.08 (d over bs, J=8 Hz, 3H), 7.12 (d, J=8 Hz, 2H) 7.24 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Br:8])[Br:7])[CH:3]1[C:9](Cl)=[O:10].N1C=CC=CC=1.[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]([OH:32])[CH:30]=[CH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOCC>[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]([O:32][C:9]([CH:3]1[CH:4]([CH:5]=[C:6]([Br:7])[Br:8])[C:2]1([CH3:12])[CH3:1])=[O:10])[CH:30]=[CH2:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=CC(OC(=O)C1C(C=C(Br)Br)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
15.8 g (0.05 mole) of 2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropanecarboxylic acid chloride are added dropwise, whilst stirring, to 5.1 g (0.05 mole) of pyridine, 100 ml of absolute ether and 11.4 g (0.05 mole) of 3-phenoxy-α-vinyl-benzyl alcohol at 0°-5° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH:7]([C:13]1[C:18](I)=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:21]([O:23][C:24]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[C:25]#[CH:26])[CH3:22]>C(#N)C.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>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:26]#[C:25][C:24]([O:27][CH2:28][CH3:29])([O:23][CH2:21][CH3:22])[O:30][CH2:31][CH3:32])[C:13]=1[C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C#CC(OCC)(OCC)OCC
Reactant: CCOC(=O)C(CCOCCBr)c1c(Cl)cccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2c(Cl)cccc2C#CC(OCC)(OCC)OCC)CCOCC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of ethyl 4-(2-bromoethoxy)-2-(2-chloro-6-iodophenyl)butanoate (5.8 g, 12 mmol) and TEA (15 mL, 110 mmol) in 24 mL ACN was degassed by vacuum and back filled with nitrogen 3 times. The mixture was treated with 3,3,3-triethoxyprop-1-yne (2.7 g, 16 mmol), dichlorobis(triphenylphosphine)palladium(ii) (0.17 g, 0.24 mmol) and copper(I) iodide (0.12 g, 0.61 mmol). The mixture was stirred at 55° C. for 2 hours. The mixture was cooled to room temperature, diluted with 100 mL EtOAc, and washed with water (3×20 mL) and then with 20 mL saturated NaCl. The organic layers were dried and concentrated. The crude product was evaporated from 50 mL toluene and dissolved in 50 mL DMF. The mixture was treated with 0.7 g NaH. The mixture was stirred at room temperature for 15 hours. The mixture was quenched with 50 mL water and neutralized with 10% HCl to pH=5. The mixture was then extracted with ether (3×100 mL). The combined organic layers were washed with water (3×20 mL) and saturated NaCl (20 mL), and then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (10% EtOAc/hexane) to give 2.42 g yellow oil. MS m/e: (M+H)+ 487.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10](OCC)=O)[C:5]([O:7]CC)=[O:6].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:3][CH:4]([CH2:10][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1nc(-c2ccccc2)cc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Sodium hydride (2.1 g, 60% strength in oil) and anhydrous tetrahydrofuran (50 cc) are placed under nitrogen. A solution of diethyl methylmalonate (9.1 g) in anhydrous tetrahydrofuran (50 cc) is added dropwise. Stirring is continued for 1 hour at room temperature (approximately 20° C.) and a solution of 1-bromomethyl-3-phenylisoquinoline (10.4 g) in anhydrous tetrahydrofuran (100 cc) is added. After 20 hours of contact, water (200 cc) is added and the aqueous phase extracted with ethyl acetate (3×50 cc). After removal of the solvents under reduced pressure, the product (19 g) recovered is brought to boiling for 20 hours in concentrated hydrochloric acid (70 cc) and acetic acid (70 cc). After being cooled, the mixture is poured into water (1000 cc) and alkalinised to pH 10 with sodium hydroxide solution, and the aqueous phase is washed with ethyl acetate (100 cc) acidified with hydrochloric acid and extracted with chloroform (3×200 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. α-Methyl-3-phenyl-1isoquinolinepropanoic acid (7.4 g), m.p. 184° C., is obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12i and 4-bromoanisole
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([C:11]1[C:12]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[N:13][N:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([OH:25])=[O:24])=[C:16]([F:30])[C:15]=12)=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:16]1[C:15]2[N:14]([N:13]=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:11]=2[C:9](=[O:10])[NH:8][CH3:6])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12

Procedure:
To a solution containing 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.070 g, 0.13 mmol) and dichloromethane (8.0 mL) was added TFA (0.84 mL, 10.9 mmol) at room temperature. The solution was maintained for 15 min and concentrated to dryness to afford 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as an off white solid which was used without further purification. LCMS retention time: 1.825 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 444 (MNa−).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C>[NH:1]([C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1)[C:15]([CH3:16])=[O:17]
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)O)c2c1OCCO2
Yield: 84 %

Procedure:
43 g of 8-amino-1,4-benzodioxane-5-carboxylic acid and 72 ml of acetic acid wee introduced into a balloon flask and then 24.5 ml of acetic anhydride were added in portions. The mixture was heated to 60°-70° C. and then cooled. The precipitate was dried off, washed with acetic acid and water and dried. 44 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 233° C.; yield: 84%).
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1)[CH3:13].COCCO>O>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)=[CH:17][N:16]=1)[CH3:13]
Reactant: CCOc1ccc(N)cn1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Solvent: O
Solvent: COCCO
Product: CCOc1ccc(Nc2nc3nc[nH]c3c(=O)[nH]2)cn1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 2-bromohypoxanthine (6.3 g; 29.3 mmol), 2-ethoxy-5-aminopyridine (12.1 g; 87.9 mmol), 2-methoxyethanol (90 mL), and water (15 mL) is heated under reflux for 3 h. The reaction mixture is cooled to room temperature, the precipitate collected by filtration and washed with water and methanol to afford N2-(2-Ethoxypyridin-5-yl)guanine (6.4 g), m.p. >350° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]=[CH:5][C:6]=1[NH:7]/[C:8](/[CH3:15])=[CH:9]\[C:10]([O:12]CC)=O.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[O:12]=[C:10]1[CH:9]=[C:8]([CH3:15])[NH:7][C:6]2=[C:2]([CH3:1])[N:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:4]=[C:5]12
Reactant: CCOC(=O)/C=C(/C)Nc1cnn(-c2ccccc2)c1C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(=O)c2nn(-c3ccccc3)c(C)c2[nH]1

Procedure:
Ethyl 3-(3-methyl-2-phenylpyrazol-4-ylamino)crotonate (0.200 g) was added to boiling Dowtherm A (5 ml) under nitrogen. The mixture was heated under reflux for 30 mins and then allowed to cool. Petroleum ether (60°-80° C.) was added to the cooled Dowtherm solution and the required pyrazolopyridone precipitated out. The title compound (0.120 g) was filtered off and washed thoroughly with hot petroleum ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccncc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
In a round bottom flask was charged with 4-pyridinepropanol (5 g, 36.45mmol), triethylamine (5.7 mL, 72.9 mmol), methylene chloride (80 mL). The solution was cooled down to 0° C. and mesyl chloride (5.7 mL, 72.9 mmol) in methylene chloride (20 mL) was slowly added. The ice bath was removed, and the mixture was stirred at room temperature overnight before being concentrated. The residue was diluted with ethyl acetate, and the organic was washed with water (2×) and brine (1×). It was dried over anhydrous sodium sulfate and concentrated to give methanesulfonic acid 3-pyridin-4-yl-propyl ester as a dark oil (6.52 g).
Reaction SMILES: [F:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].CO>C([O-])(O)=O.[Na+].[Fe]>[NH2:14][C:10]1[CH:9]=[C:8]([C:2]([F:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(F)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(F)c1cccc(N)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Methyl 2-fluoro-2-(3-nitrophenyl)propanoate (1.0 g, 4.5 mmol) was added by portion to a suspension of Fe in a mixture of 1:5:0.05H2O/MeOH/37% HCl (50 ml). The solution was refluxed for 1 hour. After cooling at room temperature, the reaction mixture was diluted with a saturated solution of NaHCO3 (50 ml), trasferred into a separator funnel and extracted with EtOAc (3×100 mL), dried over Na2SO4 and evaporated under vacuum to give pure methyl 2-(3-aminophenyl)-2-fluoropropanoate as a yellow oil (0.81 g, yield 91%). 1H-NMR (CDCl3) δ 7.15 (t, 1H, J=7 Hz), 6.85-6.75 (m, 2H), 6.75 (t, 1H, J=7 Hz), 3.80 (bs, 3H+NH2), 1.95 (d, 3H, J=23 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH:14]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Cl>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][C:14]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:17][NH:16][C:15]1=[O:18]
Reactant: CCOC(=O)C1C(=O)NCC1c1ccc(OC)c(OC)c1
Reactant: COc1ccc(CCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=O)NCC1c1ccc(OC)c(OC)c1
Reaction time: 1 h
Yield: 77 %

Procedure:
5.3 g of a 50% suspension of sodium hydride in mineral oil is added to a solution of 29.3 g of ethyl 4-(3,4-dimethoxyphenyl)-2-oxo-3-pyrrolidinecarboxylate in 180 ml of anhydrous dimethylformamide at 0°-5°C with stirring. The resulting mixture is held at 0°-5°C with stirring for 30 minutes and then at room temperature for an additional one hour. To the mixture is added 20.5 g of 3,4-dimethoxybenzyl chloride at 0°-5°C, and the whole mixture is stirred at room temperature for one hour. The reaction mixture is then concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oil is crystallized with ethanol to give 34.1 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)-2-oxo-3-pyrrolidinecarboxylate as white crystals, melting at 146°-149°C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.204 g, 0.74 mmol) in dry DCM (20 mL) were added 4-(aminooxy)tetrahydro-2H-pyran 31 (0.131 g, 1.11 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.142 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.11 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 32 (0.26 g, 93%) as a clear thick oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al]([C:21]#[N:22])(CC)CC>C1COCC1>[OH:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[C:21]#[N:22]
Reactant: CC[Al](C#N)CC
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: N#CC(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-(phenylmethyl)-4-piperidinecarbaldehyde (2.35 g, 11.6 mmol)[prepared according to Alfaro-Lopez, J.; et al. J. Med. Chem. 1999, 42, 5359] in THF (160 mL) at 0° C. was added dropwise Et2AlCN (25 mL, 1 M solution in toluene). After 1 h, the solution was partitioned between NaHCO3(sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated yielding the title compound as a yellow oil which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>CCCCCC>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([Cl:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Yield: 32.6 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (0.5 mL, 6.46 mmol), and 3-chloroaniline (5.4 mL, 51.05 mmol). The reduction was performed as described but using DMF as the solvent to afford the product (2.29 g) after trituration in hexane; m.p. 144-146° C. after recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]([F:9])([F:8])[C:5]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:4]=2[O:3]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:14][C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([F:16])([F:1])[O:7][C:6]([F:9])([F:8])[C:5]=2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Product: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1

Procedure:
A mixture of (2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-methanol (6.5 g) in thionyl chloride (75 mL) was heated at reflux overnight. The resulting mixture was concentrated under vacuum. The residue was basified with aqueous saturated NaHCO3. The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried over Na2SO4, filtrated, and concentrated under reduced pressure to give 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g), which was used directly in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.65 (s, 1 H), 7.61 (dd, J=2.1, 8.7 Hz, 1 H), 7.15 (d, J=8.4 Hz, 1 H), 4.60 (s, 2 H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Nc1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
DIPEA (1.631 mL, 9.36 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.389 g, 6.24 mmol) and 4-(piperidin-4-yl)aniline (1.21 g, 6.86 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash chromatography on silica gel, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to give 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]aniline (1.910 g, 84%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:31][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1

Procedure:
A mixture of 4-(4-Chloromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (700 m g, 2.20 mmol), 4-methanesulfonyl-phenol (417 mg, 1.1 eq.) and K2CO3 (609 mg, 2 eq.) in acetone (30 mL) was heated to reflux overnight. After cooling, the solid was filtered off through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as an off-white solid. 1H NMR (CDCl3): δ 7.87 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.59 (1H, s), 5.05 (2H, s), 3.56 (4H, m), 3.48 (4H, m), 3.04 (3H, s), 1.49 (9H, s).