Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)=O.CC(C)=O.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24].S(=O)(=O)(O)O>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
24.3 g of magnesium turnings are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride are added and, when the reaction has started up, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether is added dropwise, vigorous reflux being observed. After the reaction has moderated, the mixture is heated to boiling for 2 hours, then cooled down to -5° C. to -10° C. with dry ice/acetone and, at this temperature, a solution of 227.5 g of 2,4-dichloro-5-fluorobenzoyl chloride (1) in 100 ml of absolute ether is slowly added dropwise. The mixture is stirred at 0° to -5° C. for 1 hour, allowed to reach room temperature overnight and, while cooling in ice, a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid is allowed to run in. The phases are separated and the aqueous phase is extracted twice more with ether. The combined ether solutions are washed with saturated NaCl solution, dried with Na2SO4 and the solvent is removed in vacuo. 349.5 g of diethyl 2,4-dichloro-5-fluorobenzoylmalonate (3) are obtained as a reaction product.
Reaction SMILES: CC([O-])(C)C.[K+].O.Cl[C:9]([C:20]1[C:24]([CH3:25])=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:22]([CH3:33])[N:21]=1)=[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)C=O.C(=O)(O)[O-]>C1COCC1>[Cl:19][C:15]1[CH:14]=[C:13]([C:10]#[C:9][C:20]2[C:24]([CH3:25])=[C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[N:22]([CH3:33])[N:21]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1c(C(Cl)=C(C=O)c2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C#Cc2ccnc(Cl)c2)nn(C)c1-c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 11 ml of THF cooled to 0° C. were added 0.26 g of Potassium tert-butylate and 20 μl of water. Then a solution of 0.40 g 3-Chloro-2-(2-chloro-pyridin-4-yl)-3-[5-(4-fluoro-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-propenal in 7 ml of THF was added at 0°. After stirring for 1 h at 5° C., 10 ml of 5% Bicarbonate solution were added and the aqueous phase was extracted twice with Ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product (0.28 g, yellow oil) was purified by chromatography on silica gel (Heptane/Ethyl acetate 4:1). The desired product was obtained as a white solid (0.275 g, 82%), MS: m/e=326.0 (M+).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N12CCN(CC1)CC2.C(N(C(C)C)CC)(C)C.Cl[C:28]1[N:33]2[N:34]=[C:35]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[Cl:50])[C:36]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)=[C:32]2[N:31]=[C:30]([CH3:51])[N:29]=1>O1CCCC1>[C:1]([N:5]1[CH2:8][CH:7]([O:9][C:28]2[N:33]3[N:34]=[C:35]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[Cl:50])[C:36]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)=[C:32]3[N:31]=[C:30]([CH3:51])[N:29]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: C1CN2CCN1CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(OC2CN(C(C)(C)C)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 48 h

Procedure:
To a solution of 1-tert-butylazetidin-3-ol (19 mg, 0.15 mmol), 1,4-diazabicyclo[2.2.2]octane (11 mg, 0.10 mmol), and diisopropylethylamine (0.026 ml, 0.15 mmol) in tetrahydrofuran (1 ml) was added 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 39 mg, 0.10 mmol), portionwise. After stirring for 2 days, the reaction was concentrated, in vacuo, and the residue purified on a Biotage™ Flash 12S column using 20-40% ethyl acetate in hexanes to afford 11A-1 (25 mg, 52%) as a solid: +APcI MS (M+1) 482.3; 1H NMR (400 MHz, CD3OD) δ 7.52-7.42 (m, 4H), 7.39 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 5.58 (quintet, J=6.2 Hz, 1H), 3.80-3.75 (m, 2H), 3.63-3.58 (m, 2H), 2.60 (s, 3H), 1.04 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Product: COC(=O)CCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (70.0 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(pyridin-3-yloxy)propanamide (30.3 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH:11]1([C:14](=O)[CH2:15][CH2:16][C:17](O)=[O:18])[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH:11]1([C@@:14]23[CH2:15][CH2:16][C:17](=[O:18])[N:1]2[C@@H:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]3)[CH2:13][CH2:12]1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)CCC(=O)C1CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CC[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of (S)-2-amino-2-phenylethanol (2.28 g, 16.6 mmol) and 4-cyclopropyl-4-oxobutanoic acid (1.97 g, 13.8 mmol) in toluene (35 mL) was heated at reflux for about 6 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with aqueous HCl (1.0 N), saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a Biotage silica gel column eluting with heptane/EtOAc (3:2) to afford (3S,7aS)-7a-cyclopropyl-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (2.54 g, 10.4 mmol) as a bright yellow needle-like solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 244.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[F:22].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1c(Cl)cccc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cccc(Cl)c2F)C1=O
Yield: 3.1 %

Procedure:
Using the same reaction conditions as described in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.15 g, 0.847 mmol) was reacted with 1-bromo-3-chloro-2-fluoro-benzene (0.211 g, 1.016 mmol), 1,4-dioxane (20 mL), copper iodide (0.015 g, 0.084 mmol), trans-1,2-diamino cyclohexane (0.028 g, 0.254 mmol) and potassium phosphate (0.445 g, 2.1 mmol) to afford 8 mg of the product (0.03% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+]>C1COCC1>[O:14]1[C:10]2=[CH:9][CH:8]=[CH:7][C:6]([CH:4]=[O:5])=[C:11]2[CH:12]=[CH:13]1
Reactant: CON(C)C(=O)c1cccc2occc12
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cccc2occc12
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A solution of N-methoxy-N-methyl-benzofuran-4-carboxamide (3.2 g, 16.6 mmol) in THF (100 mL) was cooled to -45° C. and then LAH (0.7 g, 18.7 mmol) was added. The mixture was stirred for 15 min, allowed to warm to -5° C., and then recooled to -45° C. Saturated KHSO4 (25 mL) was added with vigorous stirring, and the mixture was allowed to warm to room temperature. The precipitate was filtered and washed with acetone. The filtrate was concentrated in vacuo to give an oil (2.3 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18][F:19])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:20])([CH3:21])[CH2:18][F:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CF)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CF)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Yield: 91.6 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-((3-fluoro-2,2-dimethylpropanamido)methyl)benzoate (100 mg, 0.30 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (24 mg, 0.60 mmol) to afford 84 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.30 (t, 1H), 7.39-7.29 (m, 2H), 4.47-4.28 (m, 4H), 1.14 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:32]([C:35]1[C:40](=[O:41])[NH:39][C:38](=[O:42])[NH:37][C:36]=1[C:43]([C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][C:54]#[N:55])[CH:48]=[C:49]([CH3:51])[CH:50]=1)=[O:44])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:37]2[C:36]([C:43]([C:45]3[CH:46]=[C:47]([CH:52]=[CH:53][C:54]#[N:55])[CH:48]=[C:49]([CH3:51])[CH:50]=3)=[O:44])=[C:35]([CH:32]([CH3:33])[CH3:34])[C:40](=[O:41])[NH:39][C:38]2=[O:42])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Reactant: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reaction time: 1.5 h
Yield: 54.4 %

Procedure:
To a stirred solution of 2-fluoro-6-(p-methoxybenzylamino)-4-pyridine-methanol (262 mg, 1 mmol) in chloroform (10 ml) at 0° C. (ice bath), was added triethylamine (210 μl, 1.5 mmol) followed by methanesulfonyl chloride (90 μl, 1.2 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (98) (323 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), lithium iodide (134 mg, 1 mmol). Anhydrous DMF (5 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through celite pad, and evaporated in vacuo to give a light yellow foam. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.16 was collected.) to afford 309 mg (59%) of a pale yellow foam.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:57][CH2:56][C:38]3([O:43][C:42]([F:45])([F:44])[CH2:41][N:40]([C:46]([C:48]4[N:49]=[C:50]([CH:53]([CH3:55])[CH3:54])[S:51][CH:52]=4)=[O:47])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1)(C(C)(C)C)(C)C>C1COCC1>[F:45][C:42]1([F:44])[CH2:41][N:40]([C:46]([C:48]2[N:49]=[C:50]([CH:53]([CH3:54])[CH3:55])[S:51][CH:52]=2)=[O:47])[CH2:39][C:38]2([CH2:56][CH2:57][N:35]([CH2:34][C:31]3[S:32][CH:33]=[C:29]([CH2:28][CH2:27][OH:26])[CH:30]=3)[CH2:36][CH2:37]2)[O:43]1
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cc(CCO)cs4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
TBAF (1M in THF, 1.5 mL) was added to a stirred solution of (9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 51, step a) (0.30 g) in THF (3 mL). After 1 h, the reaction was evaporated in vacuo to a gum. Purification by silica gel chromatography eluting with ethyl acetate:triethylamine, 20:1 gave the subtitled compound as a gum. Yield 0.2 g.
Reaction SMILES: [N:1]1[C:9]2[C:4](=NC=C[CH:8]=2)N(O)N=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(N)CC1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH:9]1([NH:1][C:20](=[O:22])[CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (7.77 g, 57.1 mmol), 2-(tert-butoxycarbonylamino)acetic acid (10 g, 57.1 mmol), cyclopropanamine (3.91 g, 68.5 mmol) and DMAP (8.37 g, 68.5 mmol) in DMF (28 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrogen chloride salt and the mixture stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with 0.1N aqueous HCl, aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl 2-(cyclopropylamino)-2-oxoethylcarbamate (8.90 g, 41.5 mmol, 72.8%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 6.18 (s, 1H), 3.74 (d, J=5.9 Hz, 2H), 2.71 (m, 1H), 1.45 (s, 9H); 0.84-0.7 (m, 2H), 0.56-0.43 (m, 2H); EIMS m/z 214 ([M]+). To a solution of tert-butyl 2-(cyclopropylamino)-2-oxoethylcarbamate (8.5 g, 39.7 mmol) in dioxane (20 mL) was added HCl (100 mmol, 25 mL 4 M in dioxane) and the mixture stirred at 10° C. for 3 h. The mixture was diluted with hexanes and filtered under vacuum to give 2-amino-N-cyclopropylacetamide, HCl salt as a white solid (5.2 g, 83%): mp 139-142° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (bs, 1H), 8.19 (bs, 3H), 3.46 (s, 2H), 2.73-2.60 (m, 1H), 0.71-0.60 (m, 2H), 0.48-0.36 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]([NH2:15])=[O:14])(=[O:11])=[O:10].[NH:16]1[CH2:20][CH2:19][CH:18]=N1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]([N:15]1[CH2:18][CH2:19][CH:20]=[N:16]1)=[O:14])(=[O:11])=[O:10]
Reactant: C1=NNCC1
Reactant: NC(=O)NS(=O)(=O)c1c(F)cccc1F
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1c(F)cccc1F)N1CCC=N1

Procedure:
N-(2,6-difluorophenylsulphonyl)urea in an amount of 2.36 and 1.40 g of 2-pyrazoline in 20 ml of dioxane are refluxed for 4 hours. After evaporation of the solvent at reduced pressure, the remaining solid is dissolved in 20 ml of water. This solution is filtrated and acidified with conc. hydrochloric acid. The precipitate is sucked off, washed with water and dried, yielding the title product, viz. 1-(2,6-difluorophenylsulphonylcarbamoyl)-2-pyrazoline in a yield of 1.87 g; melting point 183° C.
Reaction SMILES: [H-].[Na+].COC(CP(OC)(OC)=O)=O.C(OC1C(C)=C2C(=C(C)C=1C)OC(O)(C)CC2)(=O)C.C([O:36][C:37]1[C:38]([CH3:55])=[C:39]2[C:44](=[C:45]([CH3:48])[C:46]=1[CH3:47])[O:43][C:42]([CH2:50][C:51]([O:53]C)=[O:52])([CH3:49])[CH2:41][CH2:40]2)(=O)C.[OH-].[Na+]>O1CCCC1.O.C(O)C>[OH:36][C:37]1[C:38]([CH3:55])=[C:39]2[C:44](=[C:45]([CH3:48])[C:46]=1[CH3:47])[O:43][C:42]([CH2:50][C:51]([OH:53])=[O:52])([CH3:49])[CH2:41][CH2:40]2
Reactant: COC(=O)CC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Agent: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Reaction time: 0.25 h

Procedure:
In a dried flask under N2, a suspension of 47.2 (1.10 mol) of 56 percent by weight sodium hydride in mineral oil in 1000 ml of tetrahydrofuran was stirred as 209.4 g (1.15 mol) of trimethyl phosphonoacetate was added over 2.25 hr. The white paste was stirred for 0.25 hr and then a solution of 132.2 g (0.50 mol) of (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman in 1000 ml of tetrahydrofuran was added over 0.50 hr. The pale yellow suspension was stirred at 23°C for 18 hours and then heated at reflux for 4.0 hours. The cooled solutions from two such reactions were stripped of solvent and worked up and dried by the procedure given in Example 1 to give a cloudy red-brown oil containing (±)-methyl (6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetate. To a solution of this material in 2000 ml. of ethanol, there was added 2000 ml. of H2O and 240 g. (6.0 mol.) of NaOH. The solution was stirred at 23°C. for 4 hours, washed with petroleum ether (b.p. 30°-60°C.), diluted with 6000 ml. of ice-H2O and acidified by the dropwise addition over 0.50 hour of 600 ml. of concentrated aqueous HCl. The solid was removed by filtration, washed with H2O and crystallized from ethanol-H2O to give (±) -(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid as a light tan powder: m.p. 168°-171°C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH:2]=1.NN>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][O:12][NH2:13])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cnc2ccccc2c1
Agent: NN
Solvent: CCO
Product: NOCc1cnc2ccccc2c1
Reaction time: 8 h
Yield: 106.3 %

Procedure:
N-(3-quinolyl)methoxy phthalimide (0.69 g) was suspended in 95% EtOH and hydrazine (0.10 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.42 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:23]=[C:22]([C:24]([OH:26])=O)[NH:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8]CC1C=CC(OC)=CC=1.CCN=C=NCCCN(C)C.Cl.OC1C=CC=C[N+]=1[O-].CN1CCOCC1.[C:54]1([CH:60]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:61][CH2:62][NH2:63])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[Cl:18][C:6]1[CH:5]=[C:4]([C:19]2[CH:23]=[C:22]([C:24]([NH:63][CH2:62][CH2:61][CH:60]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:26])[NH:21][N:20]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: COc1ccc(COc2c(Cl)cc(-c3cc(C(=O)O)[nH]n3)cc2Cl)cc1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NCCC(c1ccccc1)c1ccccc1)c1cc(-c2cc(Cl)c(O)c(Cl)c2)n[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.6 %

Procedure:
To a mixture of 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1H-pyrazole-5-carboxylic acid (0.05 g, 1.15 mmol) in a mixture of CH2Cl2 (2 mL) and methanol (0.5 mL) under N2 was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.07 g, 0.35 mmol), 2-hydroxypyridine 1-oxide (0.04 g, 0.35 mmol) and N-methylmorpholine (0.03 mL, 1.15 mmol). The mixture was stirred at room temperature for 30 minutes before addition of 3,3-diphenylpropylamine (48.1 μL, 0.23 mmol). The reaction mixture was then stirred at room temperature for 20 h. The reaction mixture was extracted with water (5 mL) and the organic layer dried via hydrophobic frit washing with CH2Cl2 (2×5 mL). The crude reaction mixture was treated with trifluoroacetic acid (0.5 mL) and stirred at room temperature for 6 h. The solution was concentrated and the residue purified by preparative HPLC to give 0.02 g (32%) of the Compound 3 as a pale brown solid. 1H NMR δ (ppm) (DMSO-d6): 2.30 (2H, q, J=6.80 Hz), 3.16 (2H, q, J=6.80 Hz), 4.03 (1H, t, J=7.59 Hz), 7.15-7.21 (2H, m), 7.26-7.37 (9H, m), 7.78 (2H, s), 8.40 (1H, s), 10.50 (1H, s), 13.50 (1H, s). LCMS (10 cm_ESI_formic_MeOH) tR 4.52 min; m/z 466/468/470 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:20])=[CH:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:20])[CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=CN1CCCCC1)Cc1ccc(C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1

Procedure:
2.9 Kg. of 1-[3-(p-tert.-butyl-phenyl)-2-methyl-1-propenyl]-piperidine are taken up in 1.4 liters of toluene, treated under an atmosphere of nitrogen with 144.8 g. of 5% palladium/carbon and hydrogenated at 35° C. until the hydrogen uptake has been completed. The catalyst is removed by filtration, the toluene is evaporated in vacuo and the residue is distilled. There is obtained pure 1-[3-(p-tert.-butyl-phenyl)-2-methyl-propyl]-piperidine, having a boiling point of 125° C./0.045 Torr.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH3:21])[CH:13]=3)[C:5]([F:24])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:20]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([C:6]3[C:5]([F:24])=[CH:4][N:3]=[C:2]([NH:1][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[C:7]=3[F:8])[C:10](=[O:23])[N:11]2[CH3:22])=[CH:16][N:15]=1)[CH3:21]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N)c1F)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ncc(F)c(-c2cc3cnc(NCC)cc3n(C)c2=O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution 3-(2-Amino-3,5-difluoropyridin-4-yl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (15 mg, 0.05 mmol), triethylamine (3 ml), and DCM (10 mL) was treated with n-propanesulfonyl chloride (0.05 ml, 0.4 mmol) at 0° C. The mixture was allowed to warm to rt and was stirred for 16 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (10 mL) and potassium carbonate (2 g) was added. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate, then the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (2% to 3% methanol in DCM eluant) to provide the title compound.