Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)=[O:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[C:19]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]([NH:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[C:19]([CH:29]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:18]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Reactant: COc1ccc2nc(C=Cc3ccccn3)nc(Cl)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2nc(C=Cc3ccccn3)nc(N[C@H]3CC[C@@H](CNC(=O)C(F)(F)F)CC3)c2c1

Procedure:
A solution of 140 mg of cis-4-trifluoroacetylaminomethylcyclohexylamine in 15 mL of toluene was combined with 180 mg of 4-chloro-6-methoxy-2-[2-(2-pyridyl)ethenyl]quinazoline, 500 mg of triethylamine and 20 mg of 4-dimethylaminopyridine, and heated under reflux for 15 hours. After the reaction solution was distilled off, the residue was combined with water, and extracted with chloroform. After drying over magnesium sulfate and concentrating, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 140 mg of the desirable compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][N:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[N:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][N:22]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(=O)[nH]n3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(-c2ccc(OC3CCNCC3)nc2)n[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 111.3 %

Procedure:
To 4-[5-(6-oxo-1,6-dihydro-pyridazin-3-yl)-pyridin-2-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 13.2 mmol) in dioxane (30 mL) was added 4N HCl/dioxane (6.6 mL, 3 mmol). After overnight stirring at 60° C., the reaction was concentrated under vacuum to obtain 4 g of product as the HCl salt (quantitative); MS m/z 327 (M+H).
Reaction SMILES: O1CCC[CH2:2]1.[C:6]([O:9][N:10]([C:17]([O:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])(=[O:8])[CH3:7].[H-].[Na+].IC>O>[C:6]([O:9][N:10]([C:17]([O:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:2])(=[O:8])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(=O)ON(CCOCCO)C(=O)OC(C)(C)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCOCCN(OC(C)=O)C(=O)OC(C)(C)CCc1ccccc1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Under an argon gas atmosphere, a tetrahydrofuran (20 mL) solution of benzyl{tert-butoxycarbonyl-[2-(2-hydroxyethoxy)ethyl]amino} acetate (5.83 g, 16.5 mmol) was added dropwise to a tetrahydrofuran (10 mL) solution of sodium hydride (1.2 g, 24.8 mmol, 50% in mineral oil) at 0° C. After stirring at the same temperature for 20 minutes, iodomethane (1.6 mL, 24.8 mmol) was added at 0° C. The reaction mixed liquid was stirred at room temperature for 20 hours and then water was added while cooling in an ice bath, thereby terminating the reaction. The reaction liquid was extracted three times with ether and the organic layer was dried, and then the residue was concentrated under reduced pressure and purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=5/1, 3/1) to obtain benzyl{tert-butoxycarbonyl-[2-(2-methoxyethoxy)ethyl]amino} acetate (3.02 g, 8.21 mmol) as a colorless oily product with a yield of 50%.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:34]1[C:42]2[C:37](=[C:38]([C:43]3[CH:44]=[C:45]([NH2:58])[C:46]4[C:50]([CH:51]=3)=[N:49][N:48](C3CCCCO3)[CH:47]=4)[CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:34]1[C:42]2[C:37](=[C:38]([C:43]3[CH:51]=[C:50]4[C:46]([CH:47]=[N:48][NH:49]4)=[C:45]([NH:58][C:7]([C:4]4[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=4)=[O:9])[CH:44]=3)[CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: Cc1cc(C(=O)O)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n[nH]1
Reaction time: 0.08 h

Procedure:
5-Methyl-1H-pyrazole-3-carboxylic acid (10 mg) in DMF (0.2 ml) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (27 mg) in DMF (0.2 ml) and DIPEA (0.03 ml). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg) in DMF (0.2 ml). The reaction mixture was shaken for five min and left to stand at 22° C. for 18 h. The solvent was removed in vacuo and the product re-dissolved in methanol (1 ml) prior to application on to an SCX SPE cartridge (1 g). The product was eluted after 1 h with 2M ammonia in methanol (2×3 ml), the fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.C([O:19][B:20]([O-])[O-:21])CCC>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:21])[OH:19])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCCCOB([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a solution of 4-bromoanisole (100 g, 0.53 mol) in dry THF (1 L), BuLi (494 ml-, 0.64 mol) was added slowly at −78° C. and stirred for 2 h. To this was added n-butylborate (147 g, 0.64 mol) slowly over 30 min and stirred at RT for 12 h. After completion, the reaction mixture was quenched with water (400 ml), acidified with 1.5N HCl and filtered off the solid precipitate. The solid was washed with water and dried to give 4-methoxyphenylboronic acid (75 g, 92%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:30])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)CN(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), isobutyl(methyl)amine (38 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 54 mg (58% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.91 (d, J=6.64 Hz, 6 H), 1.46-1.61 (m, 4 H), 1.64 (s, 9 H), 1.82-1.95 (m, 1 H), 2.25-2.45 (m, 1 H), 2.69 (s, 3 H), 2.74 (d, J=7.42 Hz, 2 H), 3.29-3.40 (m, 2 H), 3.87-4.00 (m, 2 H), 4.49 (d, J=7.42 Hz, 2 H), 7.82 (dd, J=8.69, 1.66 Hz, 1 H), 7.98 (d, J=8.79 Hz, 1 H), 8.08 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=422.0; Anal. Calcd for C22H35N3O3S+0.90 TFA+0.20 EtOAc (541.85): C, 54.53; H, 6.98; N, 7.75. Found: C, 54.53; H, 6.99; N, 7.77.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C1C=CC=CC=1.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: ClCCCl
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.00 g) in 1,2-dichloroethane (10 ml) was added rhodium(II) octanoate (10 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in benzene (5 ml) and evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate. The compound obtained was dissolved in acetonitrile (10 ml) and cooled to 0°~2° C. under atmosphere of nitrogen. To this solution were added diphenyl phosphorochloridate (0.56 ml) and N,N-diisopropyl-N-ethylamine (0.49 ml) successively and the mixture was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl}-methylpyrrolidine (1.62 g) in acetonitrile (5 ml) and N,N-diisopropyl-N-ethylamine (0.77 ml) with stirring at 0°~2° C. and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added ethyl acetate (80 ml) and the solution was washed with water and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone 1, V/V). The fractions containing the desired compound were collected and concentrated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S) -1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl}methyl pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (0.79 g).
Reaction SMILES: N#N.Cl.Cl.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=[O:32]>ClCCl>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:31]([NH:30][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 0 °C
Yield: 6.2 %

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride (934.9 mg, 2.6 mmol) and Hunig's base [7087-68-5] (1.8 mL, 10.6 mmol) in dichloromethane (26 mL) was added 2-isocyanato-2-methylpropane [1609-86-5] (340 μL, 2.9 mmol). The suspension was permitted to stir and warm to ambient temperature over 17 h and was then partitioned between brine and ethyl acetate. The organic phase was reduced in volume to precipitate product as 442.1 mg of yellow solid. A 129.3 mg aliquot was purified by preparative RP-HPLC to yield 61.8 mg of 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N-(tert-butyl)piperazine-1-carboxamide as a white powder, mp. 199-200° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 8H) 2.51 (s, 1H) 3.30 (s, 1H) 3.39-3.46 (m, 4H) 3.48-3.54 (m, 4H) 7.26 (d, J=10.11 Hz, 1H) 7.61 (s, 1H) 7.88 (d, J=10.11 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.15, 43.05, 45.27, 49.94, 99.27, 110.77, 126.00, 131.50, 136.54, 155.16, 156.93. LRMS (ESI) m/z 381.1/383.1 [(M+H)]+, calc'd for C15H21BrN6O: 381.28.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:26][C:27](=[O:29])[CH3:28])[CH:5]=[CH:6][C:7]=1[O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(NC(C)C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[C:27]([O:26][C:4]1[CH:5]=[CH:6][C:7]([O:8][Si:9]([C:22]([CH3:25])([CH3:23])[CH3:24])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:3]=1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N)c1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(NS(C)(=O)=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Acetic acid 3-amino-4-(t-butyl-diphenyl-silanyloxy)-phenyl ester (3.5 g, 8.6 mmol) was dissolved in anhydrous dichloromethane (150 mL) and anhydrous N,N-diisoproplyamine (1.5 mL) added. The solution was cooled to −78° C. and methanesulfonyl chloride (1.08 g, 9.05 mmol) added. The solution was stirred for 30 minutes and allowed to come to room temperature. The solution was stirred overnight. The reaction mixture was washed with water. The organic solvent was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield the title compound as a solid (2.8 g, 5.7 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:32][CH:31]=3)[N:26]=2)[CH:3]=1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[5-methyl-1-(4-{[tris(1-methylethyl)silyl]oxy}benzyl)-1H-pyrazol-3-yl]-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole (Step 1, 500 mg, 0.873 mmol) in THF (20 mL) was added a solution of tetrabutylammonium fluoride (1M in THF, 960 μl, 0.96 mmol) at a temperature of 0° C. The cooling bath was removed, and the reaction mixture was stirred at rt for 1 h. After the addition of water (100 μL), most of the organic solvent was removed in vacuo and replaced by methanol (1 mL). The crude mixture was subjected to preparative HPLC to afford the title compound in pure form (416 mg, 67%): 1H NMR (400 MHz, CDCl3) 8.24 (d, 2H), 7.32 (d, 2H), 7.07 (d, 2H), 6.79 (d, 2H), 6.78 (s, 1H), 5.61 (broad, 1H), 5.35 (s, 2H), 2.28 (s, 3H); ES-MS m/z 417, HPLC RT (Method J) 4.78 min.
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F-:12].[K+].O>CC#N>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([F:12])(=[O:9])=[O:8]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1S(=O)(=O)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/l; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:28]3[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.30 g, 13.20 mmol) in DMF (10 mL) was treated with cesium carbonate (13.30 g, 40.82 mmol) at 0° C. followed by 2,4-dichloropyrimidine (3.90 g, 26.20 mmol). The mixture was stirred at room temperature for 24 hours. The suspension was quenched with ice water, acidified with 2N HCl and extracted with ethyl acetate. The extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane; 1:1 then MeOH/CH2Cl2; 1:99 gradient) to give [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester as a yellow foam (3.00 g, 63%). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=5.85 Hz, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.98 (d, J=5.85 Hz, 1H), 5.65 (dd, J=8.20, 2.73 Hz, 1H), 4.14-4.07 (m, 2H), 3.18 (dd, J=15.22, 2.73 Hz, 1H), 2.52 (dd, J=15.22, 8.20 Hz, 1H), 2.39 (s, 3H), 1.19 (t, J=7.03 Hz, 3H).
Reaction SMILES: [N+](=[CH:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[N-].[SH2:38]>ClCCl>[SH:38][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C@H:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11]
Reactant: [N-]=[N+]=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: S
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS)CS[C@H]12

Procedure:
A solution of benzhydryl 3-diazomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (9.0 × 10-4 mole), prepared by the process described in Example 2, in 5 ml. dichloromethane solvent is stirred at room temperature while a slow stream of hydrogen sulfide gas is bubbled in. The excess gas and solvent is removed in vacuo and the residue chromatographed over silica gel with chloroform:acetone (10:1) to give benzhydryl 3-mercaptomethyl-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)[CH:15]=2)[N:8]=[C:7]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:6]=1>C(O)C.O>[OH:18][C:17]([CH3:20])([CH2:16][N:14]1[CH:15]=[C:11]([C:9]2[CH:10]=[C:5]([CH3:4])[CH:6]=[C:7]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=3)[N:8]=2)[CH:12]=[N:13]1)[CH2:19][C:1]#[N:2]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC3(C)CO3)c2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC(C)(O)CC#N)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (113 mg, 2.3 mmol) was added to 4-methyl-6-(1-((2-methyloxiran-2-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (180 mg, 0.46 mmol) in ethanol (5 mL) and water (3 mL), and the mixture was stirred at room temperature for 18 h. The mixture was passed through CELITE, washed with methanol, and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to afford 3-hydroxy-3-methyl-4-(4-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)butanenitrile. The racemic mixture was purified by chiral SFC (Chiralpak column, MeOH+0.25% DMEA) to afford (S or R)-3-hydroxy-3-methyl-4-(4-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)butanenitrile (Isomer 1, first eluting): MS ESI calc'd. for C20H20F3N6O [M+H]+ 417. found 417. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.61 (s, 1H), 8.46 (d, J=5 Hz, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.17 (d, J=5 Hz, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 5.55 (s, 1H), 4.15 (s, 2H), 2.71-2.64 (m, 2H), 2.28 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Chloroaniline (6.697 g, 52 mmol) was dissolved in pyridine (250 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.775 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (6.630 g, 58%), was obtained as a colorless solid, in 97.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:12][C:13]([C@@H:15]1[CH2:20][C@@H:19]2[O:21][C@:18]2([CH3:22])[CH2:17][CH2:16]1)=[CH2:14]>O>[C:1]12([NH:11][C@@H:17]3[CH2:16][C@@H:15]([C:13]([CH3:14])=[CH2:12])[CH2:20][CH2:19][C@@:18]3([CH3:22])[OH:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C=C(C)[C@H]1CC[C@@]2(C)O[C@H]2C1
Solvent: O
Product: C=C(C)[C@H]1CC[C@@](C)(O)[C@H](NC23CC4CC(CC(C4)C2)C3)C1
Reaction time: 744 h
Yield: 39.8 %

Procedure:
A 100-mL, single-neck flask equipped with a magnetic stirring bar and a reflux condenser fitted with a nitrogen bubbler was charged with 7.71 g (0.051 mol) of 1-adamantylamine, 22.83 g (0.150 mol) of (S)-(−)-limonene oxide, and 4.0 mL of deionized water. The mixture was heated to reflux and held there for 31 days. The reaction mixture was filtered to remove some insoluble material. The filter paper was washed with a small amount of n-heptane. Upon cooling, the filtrate solidified to a nearly completely solid mass. The solid was isolated by filtration, washed with a small amount of n-heptane, air dried, and vacuum dried at 40° C. The filtrate was cooled in a freezer to give a second crop of crystals that were isolated and dried in the same manner. The two crops of crystals were combined and recrystallized from 75 mL of n-heptane to give 6.16 g of (1R,2R,4S)-2-(1-adamantylamino)-1-methyl-4-(1-methylethenyl)cyclohexanol as a white solid, mp 94-96° C.