Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 93.3 %

Procedure:
50.0 g. (251mmoles) of α-bromoacetophenone (Compound CI) and 65.9 g. (251 mmoles) of triphenylphosphine are stirred in 500 ml. of toluene at 20°-25° C. under nitrogen for 16 hours, and the resulting solid is collected by filtration, rinsed with toluene and rinsed with diethyl ether to obtain the product as a white powder (107.98 g. (93%)).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C)C=CC=CC=1.[CH2:14]([O:25][C:26]1C=[CH:33][CH:32]=[CH:31][C:27]=1C(O)=O)[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:25][C:26]1[CH:27]=[CH:31][CH:32]=[CH:33][C:1]=1[C:2]([Cl:4])=[O:3])[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC/C=C\CCCOc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCC/C=C\CCCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
800 μL of oxalyl chloride (9.17 mmol) and two drops of anhydrous DMF are added under argon to 76 mg of toluene-dried acid 30 (262 μmol) dissolved in 15 mL of anhydrous DCM. The medium is stirred at room temperature for two hours and then concentrated to give 80 mg of a yellow oil, i.e. a yield of 99%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][Cl:24])=[O:21]>C(OCC)C>[C:20](=[O:21])([O:22][CH2:23][Cl:24])[O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOCc1ccccc1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCl)OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(benzyloxy)propanol (synthesized by a procedure described in Wei et al., J. Org. Chem, 54, 5768-5774 (1989):15.1 g) and pyridine (7.18 g) in diethyl ether (150 ml), a solution of chloromethyl chloroformate (11.7 g) in diethyl ether (50 ml) was added dropwise under ice cooling over the period of 20 minutes. After stirring at room temperature for 15 hours, the resulting solid was removed off by filtration and washed with ethyl acetate (100 ml). The filtrate and the washings were combined, and washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (50 ml). After drying the solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 200 g, eluent: ethyl acetate-hexane=1:4) to obtain [3-(benzyloxy)propyl] chloromethyl carbonate (21.0 g) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 58.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (44 mg, 58.4%) as an orange solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:27]C(OC(Cl)C)=O>C(Cl)Cl>[ClH:27].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:12][CH2:13]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1cccc2ccccc12
Solvent: ClCCl
Product: Cl
Product: O=C(NC1CCNCC1)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of N-(1-benzylpiperidin-4-yl)napth-1-yl carboxamide (1.38 g, 4.0 mmol) in dry CH2Cl2 (15 ml) was cooled to 0° C. and added α-chloroethyl chloroformate (1.14 g, 8.0 mmol) and stirred for 30 minutes. The mixture was evaporated in vacuo, added MeOH (15 ml) and heated under reflux for 1 h. The reaction mixture was evaporated in vacuo and the residue recrystallized from acetonitrile to give the product as a white powder (1.01 g, 86.8%).
Reaction SMILES: [Cl:1][Pt-2:2](Cl)(Cl)Cl.[K+].[K+].[CH:8]([C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)=[CH2:9].[ClH:23]>O>[Cl:23][C:15]1[C:10]([CH:8]=[CH2:9])=[C:11]([Cl:1])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:13][C:14]=1[CH3:16].[Pt:2]
Reactant: C=Cc1cc(C)nc(-c2ccccn2)c1
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Reactant: Cl
Agent: [K+]
Solvent: O
Product: C=Cc1c(Cl)c(C)nc(-c2ccccn2)c1Cl
Product: [Pt]
Reaction time: 0.5 h

Procedure:
A mixture of 0.830 g (2×10-3 mol) of potassium tetrachloroplatinate in 100 ml of water, 0.432 g (2.2×10-3 mol) of 4-vinyl-6-methyl-2,2'-bipyridine and 4 ml of 2 N hydrochloric acid is boiled for 30 minutes. After cooling, the yellow crystals which have precipitated are filtered off with suction. After concentration of the filtrate, further product is obtained. The product is recrystallised from N,N-dimethylacetamide/water.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([OH:16])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1(=[O:24])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(=O)C>[C:8]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:17]1=[O:24])(=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1CCCCCN1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1NCCCCC1C(=O)c1ccccc1

Procedure:
heating acetic anhydride, benzoic acid, and caprolactam at a temperature of about 130° to about 170° C. to form volatile acetic acid and benzoyl caprolactam;
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(O)[CH2:6][CH3:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[H][H]>CC1CCCO1.[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:5]([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:18])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC1CCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 5 °C
Yield: 97.9 %

Procedure:
A solution of compound (4) (50.3 g) dissolved in 2-methyltetrahydrofuran (120 ml) was stirred and cooled to 5° C. Then trifluoroacetic anhydride (30.6 ml) was added slowly over a period of 10 minutes while the temperature of the reaction mixture was kept below 20° C. After addition, the reaction mixture was allowed to stir for 1 hour at 20° C. b) Palladium 10% on activated carbon (50% wetted) (2.52 g) was added and the reaction mixture was stirred at 800 rpm and pressurized to 2 atmosphere (202.65 kPa) with hydrogen gas. The reaction mixture was heated to 40° C. and stirred for 4 hours at 40° C. The mixture was allowed to cool to 20° C. and filtered under nitrogen atmosphere. The filter was washed with 2-methyltetrahydrofuran (10 ml). Water (160 ml) was added to the filtrate and the mixture was stirred, then an aqueous NaOH solution (28.6 ml, 50% w/w) was added over a period of 10 minutes while the temperature was kept below 20° C. The organic and water layer were allowed to separate, the organic layer was isolated and washed with water (50 ml), and concentrated under reduced pressure to dryness, yielding (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethyl-pentanamine (5) as a colourless oil (46.10 g).
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:17][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4]1=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc(C(F)(F)F)cc21

Procedure:
A solution of 3-methylthio-5-trifluoromethyloxindole (1.40 g, 0.0057 mol) and N-chlorosuccinimide (800 mg, 0.006 mol) in 100 ml of carbon tetrachloride was stirred at room temperature for 1 hour. The precipitated succinimide was removed by filtration, and the filtrate was evaporated to give 3-chloro-3-methylthio-5-trifluoromethyl oxindole as a yellow solid which was dissolved in 30 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.30 g, 5.8 mmol) and boron trifluoride etherate (860 mg, 5.8 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. The resulting mixture was stirred for 2 hours at room temperature, filtered through a pad of Celite and the filtrate was extracted with four 100-ml portions of methylene chloride. The methylene chloride extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed on silica gel. Elution with methylene chloride gave 5-trifluoromethylisatin as yellow needles (860 mg, 73%), mp 191°-193° (recrystallized from benzene); ir (KBr) 3200 (NH), 1750 (C=O), 1710 cm-1 (C=O); nmr (DMSO-d6), π-1.20 (b s, 1H, NH), 2.15 (d, 1H, H6), 2.30 (s, 1H, H4), 2.90 (d, 1H, J6,7 =8 Hz, H7); mass spectrum m/e obs. 215.0196 (calc. 215.0194).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:20][CH3:21])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C.CO>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:20][CH3:21])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCN(c1cccc(C(C)=O)c1)S(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
1.05 g (3.46 mmol) of N-(3-acetyl-phenyl)-N-ethyl-benzenesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.2 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide as a yellowish-white solid were obtained (yield 96%).
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].S(Cl)([Cl:22])=O.[CH3:24]O>>[NH2:1][C@H:2]([C:17]([O:19][CH3:24])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[ClH:22]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Product: Cl

Procedure:
To a solution of H-Orn(Z)—OH (1.00 μg, 3.76 mmol) in anhydrous MeOH (25 mL) at 0° C. was slowly added thionyl chloride (1.37 mL, 2.24 g, 18.8 mmol) as to maintain the internal reaction temperature below 10° C. After the addition was complete, the cold bath was removed, and stirring was continued for at rt 18 hours. The reaction was then concentrated under reduced pressure to afford a yellowish solid. Recrystallization with MeOH:EtOAc (1:6) afforded the desired product xliv as a white solid (600 mg, 0.190 mmol). The filtrate and EtOAc washings were cooled for 48 h at −20° C. to provide additional product xliv (177 mg, 0.56 1 mmol). The two batches (total: 777 mg, 2.46 mmol, 65%) were combined for further use.
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([CH2:7]Br)[CH:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCc1cc(Br)sn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1cc(CN2CCCCC2)ns1
Yield: 76.1 %

Procedure:
5-Bromo-3-bromomethylisothiazole (1.92 g, 7.5 mmol), triethylamine (1.57 mL, 11.2 mmol) and piperidine (1.5 mL, 15.0 mmol) in DCM (10 mL) were stirred for 16 h at ambient temperature. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (1.49 g, 97%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.25 (s, 1H), 3.59 (s, 2H), 2.46-2.33 (m, 4H), 1.62-1.53 (m, 4H), 1.48-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Cl)[C:11]=1O)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.[OH-].[Li+].Cl>CO.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(O)c(Cl)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
A solution of the ester from Step 2 (0.20 g, 0.56 mmole) was dissolved in 3 mL mixture of MeOH/ACN/H2O=1/1/1, treated with lithium hydroxide (81 mg, 3.36 mmole) and stirred at room temperature for 2 days. The reaction mixture was acidified with 1.0 N HCl to pH=1 and was extracted with EtOAc. The organic layer was washed with water,dried over anhydrous MgSO4, and filtered. The filtrate was evaporated and dried in vacuo to afford the title compound as a yellow solid (0.11 g, 60%): ESHRMS m/z 326.9438 (M−H, C11H4O4F3Cl2, Calc'd 326.9433). 1H NMR (acetone-d6/400 MHz) 7.82 (s, 1H), 7.46(s, 1H), 6.00 (q, 1H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH:22]3[OH:27])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]([CH2:25][CH2:24][CH:23]=[O:26])[CH:22]=[O:27])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2CCC(O)C2O)C1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C=O)CCC=O)C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 102, Step F) (110 mg, 0.223 mmol) in THF (3 mL) and water (3 mL) was added sodium periodate (134 mg, 0.626 mmol) at room temperature. The reaction mixture was stirred at room temperature for 45 min and was diluted with EtOAc and the layers were separated. The organic layer was washed with sat. aq. Na2S2O3 solution, sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:16]2[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2cc(-c3ccccc3)nc(Cl)n2)[nH]n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
To a solution of 2,4-dichloro-6-phenyl-pyrimidine (300 mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added triethylamine (195 μL, 1.40 mmol) followed by sodium iodide (200 mg, 1.33 mmol) and the reaction mixture is stirred for 15 hours at 90° C. The resulting solution is partitioned between ethyl acetate and water and the organic phase washed with brine, dried over MgSO4 then concentrated in vacuo. The residue is triturated in methanol and the resulting white solid collected by filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (236 mg, 62%).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: OC1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (395 mg, 1.29 mmol) was added dropwise to a solution of Intermediate 24c (254 mg, 1.07 mmol) and Et3N (0.20 mL, 1.40 mmol) in DMF (3 mL) at RT under N2. The mixture was stirred for 1 h then Et3N (0.10 ml, 0.70 mmol) and triisopropylsilyl trifluoromethanesulfonate (200 mg, 0.65 mmol) were added sequentially, and the mixture stirred for 1 h. The solvent was evaporated, the residue applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left the title compound (339 mg, 80%). LCMS (Method 1): Rt 4.74 min, m/z 393 [MH+].
Reaction SMILES: [C:1]1([S:7][CH:8]=[C:9]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22]O.C1(C)C=CC=CC=1.O>C(O)(=O)C>[C:1]1([S:7]([CH:8]=[C:9]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:10]([F:13])([F:11])[F:12])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: FC(F)(F)C(=CSc1ccccc1)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=S(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
2-(3,5-Dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfide (1.00 g, 94% purity, 2.69 mmol) was dissolved in glacial acetic acid (5 mL) and hydrogen peroxide (0.54 mL, 35% in water, 6:19 mml) was added in one portion. The reaction mixture was heated to 50° C. and stirred for three hours at that temperature. After cooling, toluene and water were added and the phases were separated. The aqueous phase was extracted with toluene and the combined organic phases were washed two times with saturated sodium bicarbonate solution and once with sodium metabisulfite solution (30% w/w solution in water). Drying over sodium sulfate, filtration and evaporation yielded 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide (950 mg, 94% purity, 91% yield, E/Z=93/7).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Br[CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C=O.C(OCC)C>[CH:8]1([S:1][CH2:2][CH2:3][OH:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrC1CCCCCC1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: OCCSC1CCCCCC1
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
2.32 g of 2-mercaptoethanol, dissolved beforehand in 10 cm3 of dimethylformamide, were slowly added, under an inert atmosphere and at a temperature in the region of 20° C., to a stirred suspension of 0.91 g of 60% sodium hydride in 10 cm3 of anhydrous dimethylformamide. After stirring for 20 minutes, 3.5 g of bromocycloheptane, dissolved in 10 cm3 of dimethylformamide, were added. The reaction was brought to completion by stirring at a temperature in the region of 20° C. for 1 hour 30 minutes. The reaction mixture was poured onto 150 cm3 of water to which have been added 100 cm3 of diethyl ether. The ethereal phase was separated by settling and the aqueous phase was extracted once with 50 cm3 of diethyl ether. The organic phases were combined and then washed with 2 times 100 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 3.2 g of 2-hydroxyethyl cycloheptyl sulfide were obtained in the form of an oil with a yellow color.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>ClCCl>[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:1](=[O:3])[CH3:2])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OCCN)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OCCNC(C)=O)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (10.2 μl) was added dropwise to a mixture of the product of example 31 (50 mg) and DIPEA (55 μl) in dichloromethane (2 ml). After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0→100% acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10]([N:25]=[N+:26]=[N-:27])[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A mixture of (4S)-1-(tert-butyloxycarbonyl)-4-(methanesulfonyloxy)-L-proline tert-butyl ester (250 mg, 0.684 mmol) and sodium azide (222 mg, 3.42 mmol) in N,N-dimethylformamide (1.5 mL) was stirred for 18 hours at 55° C. under a nitrogen atmosphere. The cooled reaction mixture was evaporated and partitioned between diluted ethyl acetate and water. The organic layer was washed with water, 0.1N hydrochloric acid, water, saturated brine solution, dried (Na2SO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting with 10% ethyl acetate/hexane. The desired azide was obtained as a colorless oil; yield 196 mg (92%). 400 MHz 1H NMR (CDCl3): δ1.42-1.45 (3s, 18H); 2.11 (m, 1H); 2.22-2.36 (m, 1H); 3.68 (m, 1H); 4.12 (m, 1H).