Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[N+:16]([O-:51])[CH:17]=[C:18]([Cl:50])[C:19]=1[CH2:20][C@@H:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:22][C:23](OC1C=CC([N+]([O-])=O)=CC=1)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:50][C:18]1[CH:17]=[N+:16]([O-:51])[CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:20][C@@H:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:22][C:23]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:3]=1)=[O:24]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Nc1cccc(S)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(SC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a suspension of N-(3-mercaptophenyl)methanesulfonamide (97 mg, 0.478 mmol) in DCM (15 ml), under nitrogen atmosphere, (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)-carbonyloxy)ethyl)pyridine 1-oxide (prepared with an analogous procedure to that described in Scheme 3, Step 1) (200 mg, 0.342 mmol), and DMAP (20.87 mg, 0.171 mmol) were added, and the reaction mixture was stirred at RT for 3 hours. The organic solution was washed with K2CO3 dil. aq., dried over Na2SO4, filtered and evaporated. The crude was triturated with EtOH affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(methylsulfonamido) phenylthio)carbonyloxy)ethyl)pyridine 1-oxide (162.9 mg, 0.251 mmol, 73.4% yield, MS/ESI+ 649.04 [MH]+, [αD]=−93.81, c=0.53 in DCM).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].N12CCCN=C1CCCCC2.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>C(#N)C>[NH2:1][C@@H:2]([CH2:3][CH2:4][O:5][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-Homoserine (1 g, 8.4 mmol) in acetonitrile (10 ml) at 0° C. was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.32 ml, 8.8 mmol). Tert-butyl-dimethyl-silyl chloride (1.33 g, 8.8 mmol) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. A white precipitate had formed which was filtered off and washed with acetonitrile before drying under vacuum. The title compound was isolated as a white solid (1.8 g, 92%). 1H NMR (300 MHz, DMSO), δ: 7.50 (1H, bs), 3.70 (1H, m), 3.35 (4H, bm), 1.95 (1H, m), 1.70 (1H, m), 0.90 (9H, s), 0.10 (6H, s).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.S1[CH2:17][CH2:16][C:15](=[O:18])NC1=O.[OH-].C[N+:22](C)(C)C.CS(O)(=O)=O>>[CH:5]1[N:6]=[CH:7][NH:8][C:4]=1[CH2:3][C@H:2]([NH:1][C:15]([CH2:16][CH2:17][NH2:22])=[O:18])[C:9]([OH:11])=[O:10]
Reactant: C[N+](C)(C)C
Reactant: O=C1CCSC(=O)N1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CS(=O)(=O)O
Agent: [OH-]
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Yield: 50 %

Procedure:
Starting with 1.55 g. (10 mmol) of L-histidine, 2.62 g. (20 mmol) of tetrahydro-1,3-thiazin-2,4-dione, 20% aqueous tetramethylammonium hydroxide solution to raise the pH and methanesulfonic acid to lower the pH, and following the procedure of Example 1, there was isolated 1.13 g. (50% yield) of L-carnosine.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]I>O1CCCC1>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:2][CH3:1]
Reactant: CN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Solvent: C1CCOC1
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
5.1 g of methylamine is condensed in a solution of 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one in 35 ml of anhydrous tetrahydrofuran at −78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.7 g of 11β-fluoro-3-hydroxy-7α-[5-(methyl-amino)-pentyl]-estra-1,3,5(10)-trien-17-one is obtained as a crude product.
Reaction SMILES: [Br-].CN([CH:5]=[N:6][C:7]1[S:8][C:9]2[CH2:20][CH2:19][CH2:18][C:10]=2[N+:11]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C1CCN2C(=NCCC2)CC1.C(O)(=O)C>CN(C=O)C>[CH2:16]([O:15][C:13]([C:12]1[N:11]2[C:7]([S:8][C:9]3[CH2:20][CH2:19][CH2:18][C:10]=32)=[N:6][CH:5]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C[n+]1c(N=CN(C)C)sc2c1CCC2
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2sc3c(n12)CCC3

Procedure:
A suspension of 2-[[(Dimethylamino)methylene]amino]-3-(2-ethoxy-2-oxoethyl)-5,6-dihydro-4H-cyclopentathiazolium bromide (Formula E-3) (4.0 g) in DMF (20 mL) dissolved on addition of DBU (2.48 mL). The solution was reacted at 25° for 18 hours, poured into cold 10% acetic acid solution, and precipitated 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Formula E-4) (1.95 g) was filtered. Crystallization of an aliquot from isopropanol gave pure 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Formula E-4), m.p. 101-102°.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(C)C)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(C)C)c2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O)c2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)-phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 60.0 mg (0.114 mmol) in 1.0 ml of THF at room temperature was added 91.5 mg (0.35 ml, 0.35 mmol) of tetrabutylamonium flouride (1M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=7.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.39-7.21 (4H, m), 6.93 (1H, d, J=7.5 Hz), 6.84 (1H, d, 7.1 Hz), 6.83 (1H, s), 6.01 1H, t, J=4.7 Hz), 4.91 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [N:1]([C:4]1C=CC(C(OC)=O)=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:14]1[C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH2:16][NH:15]1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)CN1>>[C:31]1([CH2:23][CH2:6][CH2:5][CH2:4][NH:1][C:2]([N:15]2[CH2:14][C:22]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[CH2:16]2)=[O:3])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: c1ccc2c(c1)CNC2
Reactant: c1cc2c(cn1)CNC2
Product: O=C(NCCCCc1ccccc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 1A, substituting (4-isocyanatobutyl)benzene for methyl 4-isocyanatobenzoate and 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine for isoindoline. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.46 (d, J=5.0 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.32-7.22 (m, 2H), 7.23-7.11 (m, 3H), 6.38 (t, J=5.6 Hz, 1H), 4.63-4.57 (m, 4H), 3.10-3.07 (m, 2H), 2.59 (t, J=7.5 Hz, 2H), 1.66-1.39 (m, 4H); MS (ESI(+)) m/e 296 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CCC>[CH3:13][O:12][C:9]1[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:20][CH2:21]3)[C:11]=2[N:10]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
4-Chloro-6-methoxy-8-methylpteridin-7(8H)-one (4.00 g, 17.7 mmol, 1 equiv) and 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (3.83 g, 17.7 mmol, 1 equiv) were suspended in anhydrous n-butanol (40 mL) in a 250 mL one-necked round-bottomed flask. Triethylamine (35.30 mmol, 3.57 g, 4.92 mL, 2 equiv) was added to the flask, and the stirred reaction mixture was heated to 80° C. The reaction was monitored by LC/MS and was complete after 6 hours. The resulting tan colored suspension was cooled to room temperature and filtered. The collected solid was washed with n-butanol (10 mL) and anhydrous ether (25 mL). The solid was air-dried to give the desired material, 6-methoxy-8-methyl-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one as a pale yellow colored solid (5.69 g, 79% yield.). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (broad s, 1H), 8.33 (s, 1H), 7.13 (m, 1H), 6.93 (m, 3H), 5.30 (d, 1H), 4.54 (1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.20 (t, 2H), 2.42 (dq, 2H), 1.82 (d, 2H). MS (EI) for C20H21N7O3: 408 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:9]1[CH2:10][CH2:11][O:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:17]
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3,3-dimethyl-butyryl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing the 3,3-dimethyl-1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 438 mg of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1.[CH3:36][Zn]C>O1CCOCC1.C1(C)C=CC=CC=1.[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9]([CH3:36])[CH:10]=1
Reactant: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: C[Zn]C
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(CC(=O)O)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by treating the product from step (ii) (0.25 g) in dry dioxane (10 ml) with bisdiphenylphosphinoferrocene palladium (0.02 g) and 2.0M dimethylzinc in toluene (0.40 ml). The mixture was heated to reflux for 3 h, partitioned between water and ethyl acetate, the organics separated, dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in methanol (10 ml), 2M NaOH (10 ml) added and stirred at RT overnight. The mixture was diluted with water, extracted with ether (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an oil, which was purified by RPHPLC to give a white solid (0.085 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)(O)=[O:2].C(Cl)(=O)C([Cl:27])=O>CN(C)C=O.C(Cl)Cl>[ClH:22].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:9]1[C:8]2[CH:23]=[C:4]([C:1]([Cl:27])=[O:2])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH:12]1[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1ccc2nc(C3CC3)n(Cc3ccccc3Cl)c2c1
Reaction time: 2 h

Procedure:
A suspension is prepared by adding 6-carboxy-1-(2-chlorobenzyl)-2-cyclopropylbenzimidazole (390 mg) to methylene chloride (10 ml) which includes N,N-dimethylformamide (one drop). Oxalyl chloride (0.208 ml) is dripped into the suspension over a period of a few minutes at room temperature. After stirring for two hours at the same temperature, the mixed material is concentrated under reduced pressure. Isopropyl ether is added to the residue, which is then turned into powder. Thus, white powder of 1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole hydrochloride (450 mg) is obtained. Because this material is unstable, it is used as a source material for the next process without purification.
Reaction SMILES: C(NCC=O)(OC[CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)C2C1=CC=CC=2)=O.[H-].[Na+].S(N1[CH:38]=[CH:37][N:36]=[CH:35]1)(C1C=CC(C)=CC=1)(=O)=O.[O:39]1CCC[CH2:40]1>>[CH2:5]([N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:35]1)[C:17]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
A solution of N-benzyl diol 4 (1.54 g, 4.02 mmol, 1.0 equiv) in 40.0 mL tetrahydrofuran was stirred at 0° C. for 10 min and was then added via cannula to sodium hydride (254.2 mg, 10.06 mmol, 2.5 equiv). The resulting white suspension was stirred vigorously at 0° C. for 5 min before removing the cooling bath. After 1 hr at 23° C., the reaction suspension was returned to a 0° C. bath for 10 min and N-tosylimidazole (894.5 mg, 4.02 mmol. 1.0 equiv) added in 3 portions over 12 min (gas evolution was observed subsequent to the addition of each portion). After stirring the resulting reaction solution for a further 10 min at 0° C., the cooling bath was again removed. After 1 hr at 23° C., excess sodium hydride was CAREFULLY quenched by the slow addition of 30 mL saturated aqueous ammonium chloride to the reaction suspension at 0° C. The reaction mixture was then partitioned between 340 mL ammounium chloride (sat., aq.) and 370 mL diethyl ether and the organic layer separated and washed further with 1×300 mL water and 1×200 mL brine. The aqueous washes were combined and extracted with 2×200 mL diethyl ether. All of the organic extracts were then combined and dried over sodium sulfate. Concentration of the extracts in vacuo provided a yellow oil, which was purified by flash column chromatography (SiO2, 20% ethyl acetate-hexanes), affording the N-benzyl morpholine product as a yellow oil (926.6 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:43]1([NH:42][C:8]([C:5]2[C:4]([N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:28])[F:26])[CH:19]=3)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)Nc1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (0.5 mL) at room temperature. The reaction was heated at reflux for 1 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and aniline (93 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL) and water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid phenylamide. MS m/z 556.1 (M+Na); 502.1 (M+H-MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[CH3:12][CH:13]([S-:15])[CH3:14].[Na+].CN(C=[O:21])C>>[CH:13]([S:15]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1)=[O:21])([CH3:14])[CH3:12]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC(C)[S-]
Agent: [Na+]
Product: CC(C)S(=O)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 250 mL round bottom flask was added methyl 5-bromopyridine-2-carboxylate (5 g, 23.14 mmol), DMF (50 mL) and sodium propane-2-thiolate (5.678 g, 57.85 mmol). The reaction was placed in a pre-heated 65° C. oil bath and was stirred for 3 h. The reaction was allowed to cool to 25° C. and the reaction was quenched with brine. The reaction was extracted with ethyl acetate. The two layers were separated in a reparatory funnel. The aqueous layer was kept and collected in a 1 L Erlenmeyer flask. The organic layer was discarded. The aqueous layer was then treated with 24 mL of Clorox bleach drop-wise over 1 h and allowed to stir overnight. By LCMS, the reaction showed a small amount of sulfone, and about a 50:50 mixture of sulfoxide and thio ether. The reaction was then acidified to pH 2 with HCl. The reaction mixture was then extracted with ethyl acetate 3 times, separated, and the organic layers were collected. The organic layers were then washed with brine 3 times to remove DMF. The aqueous layer was then evaporated to dryness to give 5-(isopropylsulfinyl)picolinic acid (2.10 g) as a white solid; ESI-MS m/z talc. 213.0, found 214.2 (M+1)+; Retention time: 0.87 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[C:3](O)=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:4]=1
Reactant: Oc1nc(Cc2ccc(F)cc2)ncc1F
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Cc2ncc(F)c(Cl)n2)cc1
Yield: 90 %

Procedure:
A mixture of 1.93 g (8.7 mmol) of 5-fluoro-2-(4-fluorobenzyl)-4-hydroxypyrimidine, from Step 1, and 15 mL of phosphorus oxychloride was heated in an oil bath at 90° C. for 1.5 hours and then concentrated in vacuo. The residue was triturated with 75 mL of ice water and the aqueous mixture was adjusted to pH 8-9 by the addition of solid sodium bicarbonate. The mixture was extracted with 3×70 mL of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a light brown residue. The residue was purified by flash chromatography on a 230-400 mesh silica gel column (4.8×14.6 cm) eluted with hexane:methylene chloride (1:1 v/v) to afford 1.94 g (90% yield) of the title compound; MS DCI-NH3M/Z: 241 (M+H)+ ; 1H NMR (CDCl3) d 4.22 (s, 2H), 7.00 (m, 2H), 7.30 (m, 2H), 8.48 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][NH:24][CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].[N:30]#[C:31]Br.FC1C(C(F)(F)F)=C(C2CCN(C(N3C4CN(C#N)CC=4C=N3)=O)CC2)C=CC=1F>>[F:2][C:3]1[C:4]([C:26]([F:27])([F:28])[F:29])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][N:24]([C:31]#[N:30])[CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=C(c1n[nH]c2c1CNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: N#CBr
Agent: Cl
Agent: N#CN1Cc2cnn(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1
Product: N#CN1Cc2[nH]nc(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1

Procedure:
Following general procedure GP-J2, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone (38) and cyanogen bromide were converted to -(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile as a white solid (23 mg, 79%): No clear melt observed; 1H NMR (500 MHz, DMSO-d6) δ 13.623-13.172 (m, 1H), 7.850-7.664 (m, 1H), 7.664-7.470 (m, 1H), 5.552-3.846 (m, 6H), 3.271-2.652 (m, 3H), 2.042-1.503 (m, 4H); ESI MS m/z 426 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:30])(=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=3)[N:11]=2)=[CH:8][N:7]=[C:6]1[CH3:31])[CH3:4]>C(O)(=O)C>[Br:1][C:15]1[C:10]([C:9]2[N:5]([CH2:3][CH3:4])[C:6]([CH3:31])=[N:7][CH:8]=2)=[N:11][C:12]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23](=[O:30])(=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)=[N:13][CH:14]=1
Reactant: CCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)cnc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CCn1c(-c2nc(Nc3ccc(S(=O)(=O)NCCOC)cc3)ncc2Br)cnc1C
Temperature: 60 °C
Yield: 57.5 %

Procedure:
Bromine (8 μl, 0.14 mmol) was added to a solution of 4-(1-ethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 71; 52 mg, 0.13 mmol) in glacial acetic acid (2 ml) heated at 60° C. The mixture was heated at 60° C. for 4 hours, then the solvent was removed by evaporated. The residue was dissolved in DCM (20 ml), washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), dried (Chemelut column 1005) and purified by flash chromatography eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 97:3) to yield the title compound (37 mg, 60%) as a white foam NMR 1.25 (t, 3H), 2.50 (s, 3H), 3.15 (q, 2H), 3.26 (s, 3H), 3.42 (t, 2H), 4.33 (q, 2H), 4.92 (t, 1H), 7.40 (s, 1H), 7.71 (d, 2H), 7.82 (m, 3H), 8.61 (s, 1H); m/z 497.