Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)[N:21]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (57.0 mg, 0.176 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (37.0 mg, 0.193 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a tan foam (0.037 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (s, 1H), 8.11 (d, J=6.1 Hz, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.57-7.45 (m, 4H), 7.11 (t, J=7.3 Hz, 1H), 6.96 (d, J=7.7 Hz, 2H), 6.78 (t, J=7.0 Hz, 1H), 6.67 (s, 1H), 3.18-3.12 (m, 7H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[O:17][C:16]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][N:23]=2)=[N:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[Br:1][C:22]1[N:23]=[C:18]([C:16]2[O:17][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[N:14][N:15]=2)[C:19]([NH2:24])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1nnc(-c2nccnc2N)o1
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc(-c2nc(Br)cnc2N)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
1-Bromopyrrolidine-2,5-dione (18.57 g, 104.36 mmol) was added portionwise to a solution of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (20.8 g, 94.87 mmol) in THF (320 mL) and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was dissolved in dichloromethane (300 mL), washed with water (2×150 mL), brine, dried over magnesium sulfate and concentrated. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel, eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (25.5 g, 90%) as a beige solid: 1H NMR Spectrum; (CDCl3) 1.52 (9H, s), 8.23 (1H, s); Mass Spectrum [M+H]+=300.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Ca+2].[OH-].Br[CH:13]([CH3:22])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:15]>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:13]([CH3:22])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCOC(=O)C(C)Br
Agent: [Ca+2]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
264 g (2.4 moles) of hydroquinone were dissolved in 800 ml of anhydrous dimethylsulfoxide, and 89 g (1.2 moles) of calcium hydroxide were added. The mixture was stirred for 30 minutes at room temperature, after which it was cooled to 10° C. 268 g (1.2 moles) of n-pentyl 2-bromopropionate were added dropwise in the course of 3 hours, while maintaining this temperature. Thereafter, the mixture was left to warm up to room temperature, and stirred for 20 hours at this temperature. Finally, the mixture was worked up as described in Example 1. 214 g (0.85 mole) of n-pentyl 2-(4-hydroxyphenoxy)-propionate were obtained. Yield: 70.8%; bp.=149°-150° C./0.2 mbar. ##STR6##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH3:10])[C:11](=[O:13])[O:12][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: C[C@H]1C(=O)OCN1C(=O)OC(C)(C)C

Procedure:
(4S)-N-tert-Butyloxycarbonyl4-methyl-1,3-oxazolidin-5-one (2) was prepared from N-tert-butyloxycarbonyl-(L)-alanine (1.89 g, 10.0 mM) and para-toluenesulfonic acid (30 mg) following general procedure A and obtained as fine white needles after crystallisation from chloroform (1.49 g, 74%): [α]D20 +78.1 (c 1, CHCl3); mp 64-67° C.; IR (KBr) 1795, 1705 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 5.40 (d, J=2 Hz, 1H), 5.20 (d, J=2 Hz, 1H), 4.50 (q, J=7 Hz, 1H), 1.55 (d, J=7 Hz, 3H), 1.45 s (s, 9H); 13C NMR (50.3 MHz, CDCl3): δ 173.5, 152.0, 81.4, 77.3, 50.3, 27.8, 16.3; LRMS (NH3): 219 (MNH4+). Anal. Calcd for C9H15NO4 : C, 53.72; H, 7.51; N, 6.96; found: C, 53.58; H, 7.71; N, 6.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.C=O.C1C[O:31][CH2:30]C1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:30][OH:31])=[C:9]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:16][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: C1CCOC1
Reactant: Clc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Agent: C=O
Solvent: O
Product: OCc1c(CN2CCN(c3ccc(Cl)cc3Cl)CC2)nc2ccc(Cl)cn12
Reaction time: 1.5 h

Procedure:
A mixture of 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]-methyl]imidazo[1,2-a]pyridine (Example 31, Step 2; 0.125 g), 37% formaldehyde in water (2 mL), and THF (2 mL) is stirred at 85° C. for 50 min, at which time an additional 1 mL of 37% formaldehyde in water is added. A third addition of 37% formaldehyde in water (1 mL) is made 1.5 h later. After the mixture has stirred for a total of 22 h, the heat is turned off and the mixture is allowed to stir at room temperature an additional 12 h. The mixture is then partitioned between dichloromethane and aq. sodium bicarbonate. Chromatography on silica gel using methanol/dichloromethane (3/97) gives 0.132 g of product, which after crystallization from dichloromethane/hexane gives 0.125 g of the title compound; mp 165-166° C.; MS m/z 424, 426; IR (mineral oil) 1479, 792, 1021, 816, 1502 cm-1. 1H NMR (CDCl3) δ2.79, 3.05, 3.90, 4.93, 6.1, 6.92, 7.17, 7.35, 7.52, 8.04.
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1.CCCCC.C(OC(C)C)(C)C>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)ccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cc(F)ccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 46.1 %

Procedure:
A mixture of 0.874 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 8.8 cm3 of dioxane to which had been added 1.37 cm3 of 5N aqueous sodium hydroxide solution was stirred for 17 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μ; diameter 3 cm; 25 g), elution was carried out with a dichloromethane/methanol (85/15 by volume) mixture, first a fraction of 100 cm3 was collected and then 50-cm3 fractions were collected. Fractions 3 and 4 were combined and concentrated as above. The evaporation residue was taken up in dichloromethane and filtered. The filtrate was concentrated as under the above conditions and then the product obtained was taken up with stirring in 40 cm3 of a pentane/diisopropyl ether (50/50 by volume) mixture for 16 hours at a temperature in the region of 20° C. The crystals obtained were filtered off and washed with 2 times 10 cm3 of the same mixture as above and then 3 times 20 cm3 of pentane. 0.392 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a pale yellow solid melting at 109° C. which was a mixture of two diastereoisomers.
Reaction SMILES: Br[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(=O)CC>[O:28]([CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:5][CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(COc2ccccc2)cc1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
A suspension of 3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (30 mg, 0.086 mmol, prepared according to procedure 4), phenol (10 mg, 0.1 mmol), potassium carbonate (25 mg, 0.18 mmol), potassium iodide (3 mg, 0.008 mmol) and 2-butanone was heated at 80° C. overnight. The reaction mixture was allowed to cool down to RT, mixed with water (5 mL), organic phase was separated and the aq. phase was extracted with ethyl acetate (3×8 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to get the product. Purification by chromatography on silica gel, eluting with 5-20% ethyl acetate in hexanes yielded the title compound (22 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.38 (m, 11H), 6.99 (m, 3H), 5.50 (t, 1H), 5.08 (s, 2H), 4.59 (d, 1H), 4.44 (d, 1H), 3.80 (m, 1H), 3.34 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][N:27]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])[C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:32][CH2:31][CH2:30][CH2:29][C:28](=[O:34])[N:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
N-(tert-Butoxycarbonyl)-O-benzylhydroxylamine (4.2 g, 18.8 mmol) was dissolved in DMF (120 mL) and cooled to 0° C. Sodium hydride (80%, 0.564 g, 18.8 mmol) was added, and the mixture was stirred at 0° C. for 30 minutes. A solution of (3) (6.0 g, 18.6 mmol) in DMF (30 mL) was slowly added to the cold solution which was then allowed to stir at room temperature for 20 minutes and at 80° C. overnight. The DMF was removed under high vacuum, and the reside was quenched with H2O (50 mL) and extracted with CH2Cl2 (3×70 mL). Organic extracts were washed with saturated sodium chloride, and the solvent was removed by rotary evaporation. Silica gel column chromatography, eluting with 2:1 hexane/EtOAc produced 7.29 g (77%) of (4) as an oil: NMR δ 1.50 (s, 9H), 1.40-1.90 (m, 8H), 2.30 (t, 2H, J=6), 2.40 (t, 2H, J=6), 3.40 (t, 2H, J=6), 3.63 (t, 2H, J=6), 4.77 (s, 2H), 4.80 (s, 2H), 7.33 (s, 10H) . Anal. (C29H39N3O5), C, H, N.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[O:22][N:21]=1>>[F:31][C:29]1[CH:30]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:4]3[C:5]4[C:10](=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH2:1][CH3:2])[N:24]=2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: MS (ESI): m/z 433 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[N:4]([CH3:5])[C:23](=[O:24])[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(=O)Cc1ccccc1
Yield: 60.3 %

Procedure:
To a mixture of S,N-dimethyl-N'-nitroisothiourea (0.5 g), CH3CN (20 ml) and potassium carbonate (0.93 g) was added a solution of phenylacetyl chloride (1.04 g) in CH3CN (2 ml) dropwise at room temperature over 10 minutes under stirring. After stirring for 3 hours, insolubles were filtered off and the filtrate was concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexaneacetone (2:1) to afford 0.54 g of S,N-dimethyl-N'-nitro-N-phenylacetylisothiourea as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC1CNCCC1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-dimethylethyl 3-[(methyloxy)methyl]-4-[(phenylcarbonyl)amino]-1-piperidinecarboxylate D34 (0.8 g) was dissolved in dichloromethane (25 ml). Trifluoroacetic acid (10 ml) was then added dropwise at room temperature. The reaction mixture was then stirred at room temperature for 3 hours, solvent was removed. A light yellow oil was obtained of desired product D35 in 0.6 g. LCMS [M+H] 249.1@1.20 min (5 min run)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Cc1cnn2cc(Cl)nc(O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C)c34)CC2=O)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
A mixture of 6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-ol 5.52 (48 mg, 0.262 mmol), (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (135 mg, 0.394 mmol), and cesium carbonate (136 mg, 0.417 mmol) in DMF (2 mL) was heated at 90° C. After 5 hours, reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate. Combined organics were washed with 50% brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate/hexanes) to yield (R)-4-((R)-1-((6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 5.53 (37 mg).
Reaction SMILES: [NH4+].[Cl-].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[O:16][C:17]([F:20])([F:19])[F:18])[CH:4]=[CH2:5]>CCO.O.C1COCC1.[Fe]>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[O:16][C:17]([F:18])([F:19])[F:20])[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1OC(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(N)cc1OC(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
To a solution of NH4Cl (3.3 g, 61.7 mmol) in EtOH (30.0 mL) and H2O (15.0 mL) at 90° C., was added a solution of 1-allyloxy-4-nitro-2-trifluoromethoxybenzene (1.6 g, 6.08 mmol) in THF (5.0 mL) followed by the addition of iron (1.02 g, 17.9 mmol, 3.0 equi) in two portions with 5 minutes interval. The resulting suspension was stirred at 90° C. for two hours then filtered through a pad of celite and the celite washed with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc (3×70 mL). The combined organic layer was washed with aq. Na2CO3 (2×100 mL), brine (200 mL), dried over Na2SO4, and concentrated in vacuo to afford 4-allyloxy-3-trifluoromethoxyaniline (1.6 g). The product was used in the subsequent Step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=3)[CH:19]=[CH:20][N:21]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[CH:19]=[CH:20][N:21]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1nccn1Cc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1nccn1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-imidazol-2-yl]butyl}thiophene-2-sulfonamide (250 mg, 0.534 mmol) in CH2Cl2 (5 mL) at −78° C. was added a solution of boron tribromide (IM in CH2Cl2, 0.80 mL, 0.80 mmol) dropwise. After 4 h, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was then slowly poured into H2O, extracted 3 times with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by column chromatography (SiO2, CHCl3, then 2% MeOH/CHCl3) to yield a clear oil in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([OH:14])=[N:12][S:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br.O>C(#N)C>[Br:21][CH2:22][CH2:23][O:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][S:11][N:12]=1
Reactant: BrCCBr
Reactant: Oc1nsnc1-c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1cccc(Cl)c1-c1nsnc1OCCBr
Yield: 148.1 %

Procedure:
In acetonitrile, were mixed and stirred 0.49 g of 3-(2,6-dichlorophenyl)-4-hydroxy-1,2,5-thiadiazole, 0.3 g of potassium carbonate, and 1.9 g of 1,2-dibromoethane at 80° C. for one hour. After spontaneous cooling, the reaction mixture was poured into water, and was extracted with diethyl ether. The diethyl ether layer was washed with dilute hydrochloric acid, 10% sodium hydrogencarbonate, and water successively,dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography to obtain 1.04 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]>CC(O)=O>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][OH:38])[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Agent: *CC(*)C
Solvent: CC(=O)O
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a mixture of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (11) (150 mg, 0.19 mmol) and anhydrous AcOH (2.8 mL) in dry THF (17 mL) hydrogenfluoride-pyridine complex (2 mL) was added in a polypropylene container. The reaction mixture was kept at room temperature overnight, then diluted with EtOAC (100 mL). The resulting solution was washed with saturated sodiumhydrogen carbonate (4×100 mL), saturated brine solution (100 mL), dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography using EtOAC—hexane 2:5 as the mobile phase to give methyl 2-azido-4-O-biphenylcarbonyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (40) (96 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccnc(F)c2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of 1,1-dimethylethyl(4RS,5SR)-5-(2-fluoropyridin-4-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (1.30 g, 2.66 mmol) in methanol (7 ml) was added a solution (6.39 ml, 3.19 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (1.08 g, 88%).