Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH2:29][CH2:30][CH:31]([OH:33])[CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:29][CH2:30][CH:31]([OH:33])[CH3:32])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(O)CN
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CC(O)CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 1-aminopropan-2-ol were reacted by a procedure similar to that to prepare 137 in Example 47 to give 227. MS: (ESI+) 471.1
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:33]=[CH:32][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1>CO.O>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:33]=[CH:32][C:12]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[N:6][N:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@@H]2CCN(C)C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nnc(-c2ccc(Oc3cc(O[C@@H]4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Yield: 71.5 %

Procedure:
Sodium hydroxide (pallets, 0.35 g) was added To a stirring mixture of (R)-(+)-Methyl 3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]-5-[(1-methyl-2-oxo-pyrrolidin-3-yl) oxy]benzoate (1.1 g) (Intermediate 19) in MeOH:H2O (1:1) at room temperature. The reaction was monitored by TLC. After completion, methanol was evaporated from the reaction mixture and water was added. The aqueous layer was washed with EtOAc, acidified with dil. HCl (0.05 N) to obtain solid. The solid obtained was filtered, washed with water, dried under suction or vacuum to get pure white solid (0.76 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCN(Cc2ccccc2)CC1)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h
Yield: 108.3 %

Procedure:
A stirred solution of 6.9 g (0.03 mole) of 3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 60 ml of methylene chloride was treated with 10.8 g (0.06 mole) of 1-benzylpiperazine, added dropwise. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and stirred for an additional 1 hr. The methylene chloride portion was separated and the aqueous portion was extracted with 2×25 ml of methylene chloride. The methylene chloride portions were combined, dried and concentrated in vacuo, yielding 12 g of oil residue. This oil solidified when triturated with ligroin and was recrystallized from benzene/ligroin to yield 10.1 (91%) of tan crystals. A 500 mg portion was recrystallized from benzene/ligroin to yield 250 mg of fine white crystals, m.p. 109°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11](C)[C:10](=[O:13])[O:9][C:8](=O)[C:7]=2[CH:15]=1.COC1C(OC)=CC2[NH:28][C:27](=O)OC(=O)C=2C=1>>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[NH:11][C:10](=[O:13])[CH2:27][NH:28][C:8](=[O:9])[C:7]=2[CH:15]=1
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Product: COc1cc2c(cc1OC)C(=O)NCC(=O)N2
Yield: 54 %

Procedure:
By replacing 6,7-dimethoxy-1-methyl-11,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XVI) in example XVIIaa by 6,7-dimethoxy-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XV) and proceeding in the same manner, the abovenamed product is obtained. Yield: 54%. 1H-NMR (DMSO, 300 MHz): d 3.55 (d, J=5.3, 2H, CH2), 3.77 (s, 6H, 2×OCH3), 6.16 (s, 1H Ar), 6.67 (s, 1H Ar), 8.34 (t, J=5.3, 1H, NH), 10.07 (s, 1H, NH).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]([OH:29])[CH:13]([CH2:16][CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[F:40][C:41]1[CH:54]=[CH:53][C:44]([C:45]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])=[CH:43][CH:42]=1>CN(C=O)C>[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:17][CH2:16][CH:13]3[CH:12]([OH:29])[C:11]4[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][O:9][C:10]=4[CH2:15][CH2:14]3)[CH2:49][CH2:48]2)=[O:46])=[CH:53][CH:54]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3onc(-c4ccccc4)c3C2O)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCC2CCc3onc(-c4ccccc4)c3C2O)CC1
Temperature: 80 °C
Yield: 15 %

Procedure:
To a solution consisting of 3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (8.0 g) and DMF (100 ml) was added diisopropylethyl amine (6.7 ml) and 4-(4-fluorobenzoyl)piperidine hydrochloride (7.1 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 4.5 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 1.3 g of 5-[2-(4-(4-fluorobenzoyl)-1-piperidinyl)-ethyl]-3-phenyl-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 79 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and benzylamine: yield 79%.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15](=[O:36])[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15](=[O:36])[CH2:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[O:25])[CH2:22][CH2:23]2)[N:10]=[N:9]1
Reactant: [H][H]
Reactant: O=C(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCc1cn(Cc2ccccc2)nn1
Solvent: CCO
Product: O=C(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCc1c[nH]nn1

Procedure:
3,5-dichlorobenzyl 4-(3-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-3-oxopropyl)piperidine-1-carboxylate (51 mg, 0.096 mmol) was dissolved in ethanol (4 ml). The solution was then submitted to continuous flow hydrogenation using H-cube hydrogenation apparatus, at 70° C. and 30 bar hydrogen pressure. After 90 mins the solution was concentrated and the residue purified using preparative LC-MS. Product fractions were collected, concentrated under reduced pressure, diluted with ethyl acetate, and extracted with water. The organics were separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:37])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].[CH3:48][O:49][C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)=[O:51].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:37])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[C:16]([C:55]1[CH:56]=[CH:57][C:52]([C:50]([O:49][CH3:48])=[O:51])=[CH:53][CH:54]=1)=[CH:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)OCc6ccccc6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 90 °C
Yield: 88.9 %

Procedure:
A mixture of (1S,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl 1-isopropyl-5a,5b,8,8,11a-pentamethyl-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.5 g, 5.16 mmol), 4-(methoxycarbonyl)phenylboronic acid (1.206 g, 6.70 mmol), Pd(Ph3P)4 (0.179 g, 0.155 mmol) and sodium carbonate (1.639 g, 15.47 mmol) in dioxane (20 mL) and water (20 mL) was heated up at 90° C. for 2 h. TLC indicated starting material was consumed and a new spot was present. The reaction mixture was purified by biotage with 0-10% ethyl acetate/hexanes to provide the title compound as white solid (3.05 g, 89%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.24 Hz, 2H), 7.48-7.28 (m, 5H), 7.19 (d, J=7.93 Hz, 2H), 5.28 (dd, J=6.26, 1.68 Hz, 1H), 5.19-5.00 (m, 2H), 3.90 (s, 3H), 2.38-2.20 (m, 3H), 2.11 (dd, J=17.09, 6.41 Hz, 1H), 1.89-1.75 (m, 2H), 1.72-1.61 (m, 2H), 1.53-1.07 (m, 16H), 0.95 (s, 6H), 0.92 (s, 3H), 0.90 (s, 3H), 0.85 (d, J=6.71 Hz, 3H), 0.80 (s, 3H), 0.75 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[C:5]([NH2:8])=[N:6][CH:7]=1.I[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]([CH3:25])[CH:13]=1>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH3:25])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#Cc1cc(Cl)cnc1N
Reactant: COc1cc2c(I)cn(C)c2cc1OC
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(C#Cc3cc(Cl)cnc3N)cn(C)c2cc1OC
Temperature: 20 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A suspension of 0.43 g of 5-chloro-3-ethynylpyridin-2-ylamine, 0.6 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole (example 103-f), and 0.072 g of copper iodide, in a mixture of 60 ml of triethylamine and 30 ml of dimethylformamide, is degassed with argon for 15 minutes. 0.066 g of bis(triphenylphosphine) palladium(II) chloride is added to the above suspension. The mixture is agitated at around 20° C. for approximately 6 hours; 0.075 g of 5-chloro-3-ethynylpyridin-2-ylamine is added and the mixture is agitated at this same temperature for 2 days. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 100 ml of water and extracted with three times 100 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (50/50 by volume)]. 0.44 g of 5-chloro-3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)pyridin-2-ylamine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.C[Si]([C:26]#[C:27][Sn](CCCC)(CCCC)CCCC)(C)C>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:26]#[CH:27]
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C#Cc1cc(-c2ccc(O)c(F)c2)nc2c(Cl)cc(O)cc12
Yield: 73 %

Procedure:
This compound was prepared from 45a following a combination of method J using (trimethylsilylethynyl)tributyltin and method L. Yellow solid; Yield: 73%; mp 210° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.06 (s, 1H), 7.09 (dd, J=8.9, 8.8 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 8.00 (dd, J=8.5, 1.7 Hz, 1H), 8.12 (dd, J=12.9, 2.2 Hz, 1H), 8.26 (s, 1H), 10.34 (s, 1H), 10.60 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.30 (dd, J=13.2, 9.3 Hz); MS (ESI) m/z 312/314 ([M−H]−), 314/316 ([M+H]+); Anal. Calcd for C17H9ClFNO2: C: 65.09, H: 2.89, N: 4.46. Found: C: 64.86, H: 3.14, N: 4.05.
Reaction SMILES: [Na].[CH3:2][N:3]1[S:7](=[O:9])(=[O:8])[NH:6][C:5](=[O:10])[CH:4]1[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[N:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[C:18]=1[F:26].C1OCCOCCOCCOCCOC1>C(#N)C>[F:23][C:21]1[C:20]([F:24])=[C:19]([N:6]2[C:5](=[O:10])[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:3]([CH3:2])[S:7]2(=[O:9])=[O:8])[C:18]([F:26])=[C:17]([F:16])[N:22]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Product: CC(C)CCC1C(=O)N(c2c(F)c(F)nc(F)c2F)S(=O)(=O)N1C
Yield: 40.6 %

Procedure:
To a mixture of the sodium salt of 5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.13 mmol, prepared by treatment with sodium methoxide), pentafluoropyridine (0.54 ml, 4.97 mmol), and 0.91 g (4.13 mmol) of 15-Crown-5 suspended in 30 ml of acetonitrile was refluxed for 17 hours. The mixture was cooled, concentrated in vacuo, and the residue extracted with methylene chloride, and the organic layer was washed with water (3×) and brine. After drying over sodium sulfate, the organic layer was concentrated in vacuo and a crude product was purified by flash chromatography (10% ethyl acetate in hexane) to afford 0.62 g (41%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide. (Formula I: R1 =(CH2)2 CH(CH3)2 ; R2 =H; R3 =CH3), as a solid, m.p. 80.5°-81.5° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16]Cl>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[CH:6][C:5]=1[C:11]1([C:12]#[N:13])[CH2:16][CH2:15]1
Reactant: N#CCc1cnc(Cl)cc1Cl
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2cnc(Cl)cc2Cl)CC1

Procedure:
Sodium hydride (60% in mineral oil, 0.128 g, 3.21 mmol) was suspended in 0.5 ml THF. At 0° C. a solution of 2-(4,6-dichloro-3-pyridyl)acetonitrile (0.200 g, 1.07 mmol) in 1.7 ml THF was added drop wise. The reaction mixture was stirred until no gas evolution was detectable. It was then a red suspension. At 0° C. 1-Bromo-2-chloro-ethane (0.355 mL, 4.28 mmol) was added drop wise. The reaction mixture was stirred 30 min at 0° C. then overnight at rt. It was quenched with aq NH4Cl. The organic layer was separated and dried with Na2SO4 then filtrated. The filtrate was concentrated. The residue was a brown gum (260 mg). The crude product was purified by flash chromatography (Solvent: Cyclohexane/EtOAc 3/1). The desired product was isolated as a white solid (135 mg).
Reaction SMILES: CC(C1C=C(S[C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])C=C(C(C)(C)C)C=1O)(C)C.C(OC1[O:43][C@@H:42]([CH2:44][OH:45])[C@@H:41]([CH2:46]O)[O:40]1)C>>[C:32]([C:23]1[CH:22]=[C:21]([SH:20]([CH:17]([CH3:18])[CH3:19])[S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)[CH:26]=[C:25]([C:27]([CH3:30])([CH3:28])[CH3:29])[C:24]=1[O:31][CH2:46][C@H:41]([OH:40])[C@H:42]([OH:43])[CH2:44][OH:45])([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCOC1O[C@@H](CO)[C@@H](CO)O1
Product: CC(C)[SH](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC[C@H](O)[C@H](O)CO)c(C(C)(C)C)c1

Procedure:
The title compounds can be prepared using the same procedure as described in Ex-1 starting from probucol and 2-ethoxy-1,3-dioxolane-4(S),5(R)-dimethanol and performing a chiral separation.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[CH:13])[CH:7]=1.[F:15][CH:16]([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=1[CH3:25]>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.CN(C=O)C>[F:15][CH:16]([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:13]#[C:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([F:14])[F:1])[CH:7]=2)=[CH:20][C:19]=1[CH3:25]
Reactant: Cc1cc(I)ccc1OC(F)F
Reactant: C#Cc1cccc(OCCC(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2cccc(OCCC(F)F)c2)ccc1OC(F)F

Procedure:
This compound was made in a similar manner to Example 89 Step 4 using 1-(3,3-difluoropropoxy)-3-ethynylbenzene (650 mg, 3.13 mmol) from the previous step, 1-(difluoromethoxy)-4-iodo-2-methylbenzene (818 mg, 2.88 mmol), TEA (1.45 g, 2.0 mL, 14.5 mmol), PdCl2(PPh3)2 (101 mg, 0.144 mmol), and CuI (16.4 mg, 0.0864 mmol), and DMF (4.4 mL) to provide the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19](F)[CH:18]=2)[N:3]=1.O.[NH2:27][NH2:28]>C(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:17]2[CH:18]=[C:19]3[C:20]([C:23]([NH2:24])=[N:27][NH:28]3)=[CH:21][CH:22]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOCC3C(N)=O)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NC(=O)C1COCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of 4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-morpholinecarboxamide (360 mg, 1.05 mmol) and hydrazine monohydrate (2.58 mL, 52.6 mmol) in ethanol (10 mL) was stirred at 90° C. in a sealed tube for 16 hours. The mixture was cooled and diluted with water. Attempts to extract the product from the water using 90/10 CH2Cl2/IPA were unsuccessful, so the aqueous phase was combined with the residue from the concentrated CH2Cl2/IPA extractions and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (68 g SiO2, CHCl3 to 80/20/2 CHCl3/CH3OH/NH4OH gradient with a 10 minute hold at 90/10/1 CHCl3/CH3OH/NH4OH) to give the title compound (40 mg) as an off-white solid. LC-MS (ES) m/z=355 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.29-3.41 (m, 1H), 3.41-3.50 (m, 1H), 3.61 (dd, J=11.6, 3.5 Hz, 1H), 3.85-3.93 (m, 1H), 3.99-4.18 (bs, 1H), 4.35 (d, J=11.6 Hz, 1H), 4.82-5.08 (bs, 1H), 5.39 (s, 2H), 6.12 (s, 2H), 6.55 (s, 1H), 7.19 (s, 1H), 7.35 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:5][C:4]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)([C:6](O)=[O:7])[CH2:3]1.C1C=C2[N:21]=[N:22]N(O)C2=CC=1.O.O.NN>C(#N)C>[CH3:1][C:2]1([CH3:14])[CH2:5][C:4]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)([C:6]([NH:21][NH2:22])=[O:7])[CH2:3]1
Reactant: CC1(C)CC(C(=O)O)(c2cccs2)C1
Reactant: On1nnc2ccccc21
Agent: NN
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(C(=O)NN)(c2cccs2)C1

Procedure:
3,3-Dimethyl-1-(2-thienyl)cyclobutanecarboxylic acid was reacted with HOBt monohydrate and WSC monohydrochloride in acetonitrile at room temperature. The above reaction solution was added dropwise to an acetonitrile solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 3,3-dimethyl-1-(2-thienyl)cyclobutanecarbohydrazide.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.O.NN>C1COCC1>[CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2nnnn2C)c1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (5.22 g, 11 mmol) in dry THF (130 mL) was added hydrazine hydrate (2.63 mL, 54 mmol). The reaction mixture was stirred at room temperature for 6 h, then insolubles were removed by filtration and washed with ethyl acetate. The filtrates were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with water (2×100 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine as an orange solid [3.56 g, yield 89%; HPLC/MS:m/z=353 (M+H); log P(HCOOH)=1.19].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12](=O)[CH:13]([F:15])[F:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:24]([C:23]4[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=4)[N:25]=[C:12]([CH:13]([F:15])[F:14])[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccc3c(c2)OCO3)cc1
Yield: 83.9 %

Procedure:
1-(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione from Step 1 (2.4 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (3.3 g, 84%): mp 214°-218° C.; 1H NMR (D6 -DMSO): 7.86 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.49 (brs, 2H), 7.3-6.7 (m, 5H), 6.06(s, 2H). Anal. Calc'd for C17H13N3SO4 F2 : C, 51.91; H, 3.33; N, 10.68. Found: C, 51.90; H, 3.25; N, 10.65.