Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)(=[O:9])=[O:8])[C:5]#[N:6].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:24]=1[NH:34][NH2:35].O>C(O)C>[NH2:6][C:5]1[N:34]([C:24]2[C:23]([Cl:22])=[CH:28][C:27]([C:29]([F:30])([F:32])[F:31])=[CH:26][C:25]=2[Cl:33])[N:35]=[C:3]([S:2][CH3:1])[C:4]=1[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CSC(SC)=C(C#N)S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A suspension of 0.50 g (1.42 mmol) of 3,3-bis-methylthio-2-(3-trifluoromethylphenylsulfonyl)acrylonitrile and 0.35 g (1.42 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol was heated at reflux for 2.5 hours, solution occurring as the reaction mixture was warmed. The mixture was stirred overnight at room temperature and was then poured into cold water. The product was extracted into ethyl acetate and the extracts were dried with magnesium sulfate and evaporated. The residues were crystallized from ether, and the product was filtered off and air dried to give 314 mg (40%) of the desired product, m.p. 201°-203° C. Anal. Calcd. for C18H11O2N3S2Cl2F6 : C, 39.28; H, 2.02; N, 7.64. Found: C, 39.35; H, 2.19; N, 7.48.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].C1C=CN=CC=1.[FH:34]>ClCCl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[F:34])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](F)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C

Procedure:
Mannose pentaacetate (100 g) was stirred with dichloromethane (10 mL) in a FEP Erlenmeyer. Cold HF-pyridine (100 g) was added and the resulting solution stirred at 40° C., sealed, overnight. The solution was poured into a FEP separating funnel containing water and chloroform and shaken. The chloroform layer was washed once with water and once with saturated sodium bicarbonate. The aqueous layers were neutralized with sodium hydroxide. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by plug chromatography (silica, eluent hexane/EtOAc). Yield 74.06 g, 80%.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.C([Si](C(C)C)(C(C)C)[O:21][CH2:22][C:23](=O)[CH2:24]O[Si](C(C)C)(C(C)C)C(C)C)(C)C.Cl>O1CCCC1.C(OC(=O)C)C>[OH:21][CH2:22][C:23]1[C:10]2[O:9][CH:13]=[CH:12][C:11]=2[C:14](=[O:16])[O:15][CH:24]=1
Reactant: O=C(O)c1ccoc1
Reactant: CC(C)[Si](OCC(=O)CO[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1occ(CO)c2occc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Add lithium diisopropylamine (0.454 mole) as a solution in tetrahydrofuran (100) mL to a solution of 3-furoic acid (23.36 g, 0.208 mole) at −78° C. over 30 minutes and stir for 1 hour at −78° C. To the resulting di-anion add 1,3-Bis-triisopropylsilanyloxy-propan-2-one as a solution in tetrahydrofuran (250 mL)over 30 minutes and stir at −78° C. for 1 hour and allow to warm to room temperature overnight. Quench the reaction with saturated aqueous ammonium chloride, pour into ethylacetate (1 L), add 1N HCL (1L) and separate the two layers. Wash the organic layer with 1N HCl, water, and brine, dry over magnesium sulfate, filter and concentrate to an oil. Dissolve the crude oil in 50% tetrahydrofuran and 50% 3N HCl (1L) and heat a reflux over night. Distill off tetrahydrofuran, concentrate under reduced pressure and, add acetonitrile remove it under reduced pressure to azeotrope off the remaining water. Dissolve the resulting crude oil in acetonitrile (250 mL) and add the solution to a solution of toluene containing a catalytic amount of p-toluenesulfonic acid at reflux that is fitted with a Dean Stark trap over 30 minutes. Toluene was added to replace the acetonitrile and water removed by distillation and azetroping (500 mL). Heat the solution at reflux until it appears no futher water is being removed. The hot solution was poured into an erlenmeyer flask and allowed to cool. Triturate the brown remaining residue with ethylacetate and methanol and combine it with the toluene solution and concentrate. Dilute with ethylacetate and wash with saturated aqueous sodium bicarbonate and brine, dry over magnesium sulfate and concentrate to an off white solid. Purification by flash chromatography eluting with hexane:ethylacetate gives 13.27 g (42%) of the tide compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[C:13]4=[CH:12][C:11]=3[O:10][CH2:9][C:8]=2[CH:22]=1)(=[O:3])[CH3:2].C(Cl)Cl.CO.[Br-:28].[Br-:29].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CCOC(C)=O>[Br:28][CH:19]1[CH2:18][CH2:17][C:14]2=[CH:15][C:16]3[C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:29])=[CH:22][C:8]=4[CH2:9][O:10][C:11]=3[CH:12]=[C:13]2[C:20]1=[O:21]
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
A 20 mL vial with a stirbar was charged with 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (100 mg, 0.366 mmol), 9:1 CH2Cl2/MeOH (3.4 mL) and pyridinium tribromide (246 mg, 0.769 mmol). The solution was heated to 35° C. After 30 minutes, the reaction was judged complete. The mixture was cooled to ambient temperature, diluted with EtOAc (50 mL) and sequentially washed with saturated aqueous Na2S2O3 (20 mL), 2% aqueous NaHCO3 (20 mL), water (20 mL), and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure resulting in 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (68 mg, 41%): 400 MHz 1H NMR (CDCl3) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m, 1H), 2.59-2.46 (m, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]([CH3:31])[CH2:14][CH2:15][N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][CH:13]([CH:12]=[O:11])[CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(CO)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C=O)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 34.3 %

Procedure:
Dimethyl sulfoxide (5.17 mL) was added to a solution of oxalyl chloride (3.12 mL) in methylene chloride (70 mL) with stirring at −78° C., and the mixture was stirred at the same temperature for 5 minutes. Then, a solution of the crude product of di-tert-butyl (4-hydroxy-3-methylbutyl)imidodicarbonate (19.8 g) in methylene chloride (50 mL) was added thereto. The mixture was stirred at the same temperature for 15 minutes. Then, triethylamine (13.4 mL) was added thereto, and the mixture was heated to room temperature and stirred. The reaction solution was separated into aqueous and organic layers by the addition of water. The organic layer was washed with water and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (6.75 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:11])=[CH:4][N:3]=1.C[N+]1([O-])CC[O:16]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH2:28]>CC(C)=O.O=[Os](=O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([CH3:10])[CH2:9][OH:28])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: O
Reactant: C=C(C)c1cc(Br)ncc1F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)(CO)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-bromo-5-fluoro-4-isopropenyl-pyridine (17.1 g, 79 mmol) in acetone (50 mL) and H2O (100 mL) was added N-methylmorpholine oxide (10.51 g, 87 mmol) and OsO4 (4.97 mL, 4.02 g, 0.396 mmol). The biphasic mixture was stirred at rt for 17 h. The reaction mixture was quenched with sodium hydrosulfite (1.516 g, 8.71 mmol) in H2O (50 ml) and stirred at rt for 20 min. The reaction mixture was filtered through celite and the celite pad was washed three times with acetone. The combined filtrates were evaporated and the residue was taken up with EtOAc and 1N aq. NaOH soln. The phases were separated and the aq. phase was reextracted with EtOAc. The combined org. phases were dried over Na2SO4, filtered and concentrated to yield the title compound as a light purple solid. HPLC RtH4=0.60 min; ESIMS: 250, 252 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, 1H), 7.71 (d, 1H), 5.57 (s, 1H), 4.89 (t, 1H), 3.65-3.57 (m, 1H), 3.53-3.45 (m, 1H), 1.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([NH2:13])=[O:12])[C:8]2[C:4](=[CH:5][N:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[N:7]=2)[CH:3]=1.[BH4-].[Na+].[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34][O:35][C:36](Cl)=[O:37])=[CH:30][CH:29]=1>CO>[NH2:13][C:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:36]([O:35][CH2:34][C:31]5[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=5)=[O:37])[CH2:21]4)=[CH:18][CH:19]=3)[N:7]=2)[CH:3]=[C:2]([F:1])[CH:10]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)c1cc(F)cc2cn(-c3ccc(-c4cccnc4)cc3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(F)cc2cn(-c3ccc(C4CCCN(C(=O)OCc5ccccc5)C4)cc3)nc12

Procedure:
To a stirred solution of (D4) in dry MeOH (0.2 M), NaBH4 (1.2 eq) was added and then dropwise Cbz-Cl (1.2 eq) at −65° C. The reaction was allowed to reach RT O/N, and then quenched with H2O. MeOH was concentrated under reduced pressure and EtOAc was added. The organic phase was washed with sat. aq. NaHCO3 solution, dried (Na2SO4). Evaporation of the solvent gave (D5) which was used in the next step without further purification. MS (ES) C27H25FN4O3 requires: 472. Found: 473 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:19][CH:18]([C:20]#[N:21])[CH2:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[NH:7][C@@H:3]([C:4]([N:16]1[CH2:19][CH:18]([C:20]#[N:21])[CH2:17]1)=[O:6])[CH2:2][CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
In a round-bottomed flask Boc-D-2-aminobutyric acid (400 mg, 1.97 mmol) and azetidine-3-carbonitrile hydrochloride (373 mg, 3.15 mmol) were dissolved in DMF (9 ml). N,N-Diisopropylethylamine (1.0 ml, 5.73 mmol) was added followed by HATU (823 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to provide 410 mg (70%) of [(R)-1-(3-cyano-azetidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(F)ccc1C
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (5.9 g) was added at room temperature diethyl malonate (14.0 g), and then added little by little 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g), and the mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (46 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (46 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (8.6 g) as colorless crystals.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: S=C(NN=Cc1ccccc1)NC1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.4 %

Procedure:
To a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.55 mmol) and benzaldehyde (56 μl, 0.55 mmol) in ethanol (5 mL) was added a solution of sodium acetate (45 mg, 0.55 mmol) in water (1 mL) and the mixture was stirred at room temperature for 24 h. The mixture was diluted with water (1.5 mL) and the resultant precipitate was collected by filtration and isolated as a white solid (14 mg, 9%). 1H NMR (CDCl3): 9.84 (s, 1H), 7.88 (s, 1H), 7.64-7.61 (m, 2H), 7.50 (d, J=7.5 Hz, 1H), 7.42-7.40 (m, 3H), 6.24-6.14 (m, 2H), 4.314.26 (m, 1H), 3.06 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=9.3 Hz, 1H), 1.52 (d, J=9.0 Hz, 1H), 1.46-1.39 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1[C:38]2[CH:39]=[CH:40][C:41]([OH:43])=[CH:42][C:37]=2OC1.[F:44][C:45]([F:54])([F:53])C1C(O)=CC=CC=1>>[OH:17][C:4]1([C:40]2[CH:39]=[C:38]([C:45]([F:54])([F:53])[F:44])[CH:37]=[CH:42][C:41]=2[OH:43])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=2)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]1=[O:16]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Product: CCCCCN1C(=O)C(O)(c2cc(C(F)(F)F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with α,α,α-trifluorocresol, the title compound was obtained (46%): 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.50-7.39 (m, 3H), 7.21 (td, 1H), 7.10-7.02 (m, 2H), 6.96 (d, 1H), 4.26 (s, 1H), 3.82-3.59 (m, 2H), 1.77-1.63 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 362 (M−17), 402 (M+23).
Reaction SMILES: [CH3:1][N:2]1[C:6](SC)=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[O-][Mn](=O)(=O)=O.[K+].[S:21]([O-:24])(O)=[O:22].[Na+].[C:26](O)(=O)C>O>[CH3:26][S:21]([C:6]1[N:2]([CH3:1])[C:3]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4][N:5]=1)(=[O:24])=[O:22]
Reactant: CC(=O)O
Reactant: CSc1nnc(-c2ccncc2)n1C
Reactant: O=S([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 4-(4-Methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine (1000 mg, 4.85 mmol) in acetic acid, added a solution of KMnO4 (1.15 g, 7.28 mmol) in H2O (50 mL) drop-wise. Stirred at RT for 3 hours. Added sodium hydrogen sulfite until purple colour was discharged. Extracted into chloroform (3×100 mL). Washed organic layer with saturated sodium bicarbonate (50 mL). Dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield title compound (1.01 g, 87% yield). 1H-NMR (CDCl3) δ (ppm): 8.89 (d, 2H), 7.64 (d, 2H), 4.05 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@H:24]([CH3:25])[C@H:23](O)[CH2:22][C@H:21]([C:27]([O:29][CH3:30])=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1C(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O.O>[C:27]([C@@H:21]1[CH2:20][C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:24]([CH3:25])=[CH:23][CH2:22]1)([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H]1C[C@@H](O)[C@@H](C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC=C(C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.8 %

Procedure:
To a solution of 2.2.c (R=Me, P=TBDPS, A=COOCH3) (167 mg, 0.392 mmol), picolinic acid (257 mg, 2.092 mmol) and triphenylphosphine (548 mg, 2.092 mmol) in THF at −38° C. was added dropwise DIAD (diisopropyl azodicarboxylate; 412 μL, 2.092 mmol) over 4 min. The reaction solution was stirred for 4.5 h and warmed to room temperature overnight. The mixture was poured into water and EtOAc (50 ml:50 ml). The organic phase was separated, the aqueous layer was extracted with EtOAc (3×50 ml) and dried over MgSO4. The residue was separated by HPLC (isooctane/EtOAc 98:2), affording (4S,6S)-4-carbomethoxy-6-t-butyldiphenylsilyloxy-1-methylcyclohexene (142 mg, 88.8%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](O)=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C=O)C.C(Cl)(=O)C([Cl:41])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([Cl:41])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cl)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (1.0 g) in THF (10 ml) was added DMF (0.1 ml), and oxalyl chloride (0.4 ml) was added dropwise under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for 30 min., and concentrated under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound (1.0 g).
Reaction SMILES: C([NH+](CC)CC)C.[N:8]([C@@H:11]1[C@@H:15]([CH2:16][P:17]([OH:20])(=[O:19])[OH:18])[O:14][C@@H:13]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:12]1)=[N+:9]=[N-:10].C(N1C=CN=C1)(N1C=CN=C1)=O.C([NH+](CCCC)CCCC)CCC.[O-:55][P:56]([NH:59][P:60]([O-])([O-:62])=[O:61])(=[O:58])[O-:57]>CN(P(N(C)C)(N(C)C)=O)C.O.CO>[CH3:28][C:27]1[C:25](=[O:26])[NH:24][C:22](=[O:23])[N:21]([C@@H:13]2[O:14][C@H:15]([CH2:16][P:17]([O:18][P:60]([OH:62])([NH:59][P:56]([OH:58])([OH:57])=[O:55])=[O:61])([OH:20])=[O:19])[C@@H:11]([N:8]=[N+:9]=[N-:10])[CH2:12]2)[CH:29]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CP(=O)(O)O)O2)c(=O)[nH]c1=O
Reactant: O=P([O-])([O-])NP(=O)([O-])[O-]
Agent: CCCC[NH+](CCCC)CCCC
Agent: CC[NH+](CC)CC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CP(=O)(O)OP(=O)(O)NP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 69.4 %

Procedure:
The triethylammonium salt of compound 53 (50.0 mg, 0.09 mmol) was dissolved in HMPA (2 mL) and 1,1′-carbonyldiimidazole (106 mg, 0.66 mmol) was added at room temperature and stirred for 2 h. Methanol (35 μL) was added and stirring was continued for 45 min. The tri-n-butylammonium salt of imidodiphosphate (427 mg, 0.46 mmol) dissolved in HMPA (2 mL) was added with syringe to the solution of activated AZT monophosphate, and the combined solution was stirred at room temperature for 4 h. The reaction mixture was cooled in ice-bath and water (5 mL) was added. Purification by HPLC gave 30.6 mg of the titled compound 57.
Reaction SMILES: CCOCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=O)=[CH:9][CH:8]=1.CCOCC.C1COCC1.[OH-].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][N:16]([CH3:17])[CH3:18])=[CH:11][CH:12]=1
Reactant: CN(C)C(=O)Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN(C)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a suspension of LiAlH4in ether (5 mL) was added a solution of 2-(4-bromophenyl)-N,N-dimethylacetamide (1.1 g, 4.5 mmol) in 5:1 ether/THF (12 mL), giving a small exotherm. The mixture was stirred at room temperature for 3 h, refluxed overnight then cooled to 0° C. Water (0.5 mL) was added dropwise and the mixture stirred vigourously for 3 h, then poured into 1 M NaOH and extracted with ether. The organic phase was washed with brine and dried over MgSO4. Purification by flash chromatography (4% to 8% MeOH/dichloromethane+0.5% ammonium hydroxide) provided 132 mg of 2-(4-bromophenyl)-N,N-dimethylethanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[C:21]([CH3:26])=[CH:22]N(C)C)=[CH:16][CH:15]=3.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:41]([CH2:39][CH3:40])[N:42]=[CH:22][C:21]=1[CH3:26])=[CH:16][CH:15]=3
Reactant: CCNN
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Agent: O=C(O)C(=O)O
Product: CCn1ncc(C)c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in Example 37 above, using 3-(2,4-dichlorophenyl)-6-(3-dimethylamino-2-methylacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from preparation 1.13 above and ethylhydrazine oxalate.