Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([S:12][CH2:13][CH2:14]O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:5]1([S:12][CH2:13][CH2:14][Cl:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OCCSC1CCCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: ClCCSC1CCCCCC1
Reaction time: 0.25 h

Procedure:
5.11 cm3 of thionyl chloride were added dropwise, with stirring and under an inert atmosphere, at a temperature in the region of 20° C. to a solution of 1.74 g of 2-hydroxyethyl cycloheptyl sulfide in 30 cm3 of chloroform. After the addition, the reaction mixture was first stirred for 15 minutes at the same temperature and then for 1 hour at a temperature in the region of 600° C. The mixture was evaporated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C., then the residue obtained was taken up with 2 times 50 cm3 of water and then 1 times 50 cm3 of a saturated sodium hydrogencarbonate solution. The ethereal solution, separated by settling, was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 400° C. 1.89 g of 2-chloroethyl cycloheptyl sulfide were obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][C:16]=1[O:30][CH3:31])=[O:13])[NH:7]2.Br[C:33]1[N:34]=[C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[N:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=12>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:33]3[N:34]=[C:35]([C@H:43]4[CH2:48][CH2:47][C@H:46]([N:49]5[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)[N:36]4[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=34)=[CH:17][C:16]=1[O:30][CH3:31])=[O:13])[NH:7]2
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2[nH]1
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2[nH]1

Procedure:
Reaction of 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indole-2-carboxamide (32 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indole-2-carboxamide (11 mg)
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1Br)[CH3:7].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:7]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cccc(OC)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cccc(OC)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
2M Aqueous sodium bicarbonate (10 mL) was added to a suspension of 2-bromo-3-methoxybenzoic acid ethyl ester (2.06 g, 7.7 mmol), benzeneboronic acid (1.11 g), and tetrakis(triphenylphosphine)palladium(0) (0.30 g) in toluene (35 mL) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 2 hours, poured into water, and extracted with diethyl ether. The organic layer was evaporated, and the residue was chromatographed, eluting with hexane/acetone (3:1) to give a semisolid oil. Recrystallization from diethyl ether/hexane gave 3-methoxy-2-phenylbenzoic acid ethyl ester as colorless crystals (0.69 g, 34%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][N:3]=1.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CCOC(=O)Cc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccnc(C)c2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.2 g, 10 mmol), ethyl 2-(4-iodophenyl)acetate 26-1 (2.9 g, 10 mmol), Pd(PPh3)4 (0.231 g, 0.2 mmol), toluene (30 mL), ethanol (10 mL) and 2M Na2CO3 (10 mL). The reaction mixture was flushed with nitrogen and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted into 200 mL ethyl acetate and washed with saturated sodium bicarbonate solution and then brine. The organic phase was dried over Na2SO4 and then taken to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(2-methylpyridin-4-yl)phenyl)acetate 26-2 as an oil. MS m/z 256.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][C:5]1[S:6][C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][C@@H:25]4[CH2:27][O:26]4)=[C:18]([CH2:28][CH3:29])[CH:17]=3)[N:12]=2)=[CH:8][C:9]=1[CH3:10])[CH3:2].[NH3:32]>CO>[NH2:32][CH2:27][C@H:25]([OH:26])[CH2:24][O:23][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:7]3[S:6][C:5]([CH2:4][N:3]([CH2:30][CH3:31])[CH2:1][CH3:2])=[C:9]([CH3:10])[CH:8]=3)[O:15][N:14]=2)=[CH:17][C:18]=1[CH2:28][CH3:29]
Reactant: N
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H](O)CN

Procedure:
To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (1.49 g, 3.87 mmol) in isopropanol (70 mL) and 3 N aq. NaOH (19 mL), (R)-epichlorohydrine is added. The mixture is stirred at rt for 41 h. The mixture is diluted with EA and washed with 1 M aq. NaOH. The washing is extracted back with EA. The organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge C18, 50×50 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of concentrated aq. ammonia) to give diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (990 mg) as a pale yellow resin; LC-MS: tR=0.65 min; [M+1]+=442.09. b) A solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (450 mg, 1.02 mmol) in 7 N NH3 in methanol is stirred in a sealed vessel at 65° C. for 16 h. The solvent is evaporated and the crude product is purified by prep. HPLC. The product containing fractions are filtered over Amberlyst A21. The filtrate is concentrated and dried to give the title compound (381 mg) as a yellow resin; LC-MS: tR=0.44 min; [M+1]+=459.10; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.73 (q, J=7.5 Hz, 2H), 2.88 (dd, J=12.8, 9.0 Hz, 1H), 3.10 (dd, J=12.5, 3.0 Hz, 1H), 3.73 (s, 2H), 3.81 (d, J=5.3 Hz, 2H), 4.04-4.12 (m, 1H), 7.75 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O1CCC[CH2:11]1.[OH-].[K+].CI>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: C1CCOC1
Reactant: Oc1ccc(Br)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(F)c1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
Into a 250-mL round-bottom flask, was placed 4-bromo-3-fluorophenol (5.0 g, 26.18 mmol, 1.00 equiv), tetrahydrofuran (50 mL). This was followed by the addition of potassium hydroxide (2.94 g, 52.40 mmol, 2.00 equiv) in portions. To this was added CH3I (5.6 g, 39.45 mmol, 1.51 equiv) dropwise. The resulting solution was stirred for 4 h at 30° C. TLC (Petroleum ether: EtOAc=1:4) controlled the reaction process. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 5.2 g (97%) of 1-bromo-2-fluoro-4-methoxybenzene as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42]
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (180 mg, 527 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (302 mg, 790 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1 mg, 105 μmol), cesium carbonate (686 mg, 2107 μmol) in DMF (2 mL) and water (0.4 mL) was first sparged with argon for 5 min then heated to 100° C. with stirring. 2:20 pm After 10 min, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with isocratic 4% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C29H29ClN6O4: 560.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].C[Si](C)(C)[O:33][CH:34]=[C:35]([CH3:37])[CH3:36].[BH4-].[Na+]>CN(C=O)C.F[Zn]F>[OH:33][CH2:34][C:35]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30])([CH3:37])[CH3:36]
Reactant: CC(C)=CO[Si](C)(C)C
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Agent: F[Zn]F
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1C(C)(C)CO
Reaction time: 0.17 h

Procedure:
To a microwave vial was added difluorozinc (16 mg, 0.15 mmol) and Pd(tBu3P)2 (7.6 mg, 0.015 mmol). The vial was capped and purged with nitrogen for 10 minutes. DMF (1 mL) was added and the reaction mixture was allowed to stir for 10 minutes. (4-Bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (140 mg, 0.30 mmol) dissolved in DMF (0.5 mL) was added followed by trimethyl(2-methylprop-1-enoxy)silane (83 μL, 0.45 mmol). The reaction vessel was placed in an oil bath held at 80° C. for 16 hours. The reaction mixture was filtered, quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in MeOH (2 mL). NaBH4 (34 mg, 0.90 mmol) was added and the reaction mixture immediately turned from yellow to brown. The mixture was filtered and purified by HPLC (1-99%) MeOH:H2O to provide [4-(2-hydroxy-1,1-dimethyl-ethyl)-3-methoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z talc. 461.5, found 462.2 (M+1)+. Retention time: 2.73 minutes (4 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow foam (36%). MS (ESI): m/z=551.06 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:24]([O:26][C:27](=[O:34])/[CH:28]=[CH:29]/[CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][C:27]([C@H:28]1[C@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:34])[CH3:25]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CC(C)C
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (2.84 g, 12 mmol), followed by TFA (1.0 M solution in CH2Cl2, 1.0 mL, 1 mmol) were added to a solution of (E)-5-methyl-hex-2-enoic acid ethyl ester (1.56 g, 10.0 mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogen atmosphere. After 15 minutes, the bath was removed and stirring was continued overnight. Saturated sodium bicarbonate was added, and the organic portion was separated, washed with brine, and dried. The product was purified by chromatography on silica gel, and compound was eluted with 20% ethyl acetate in hexane to give (trans)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 3 as an oil (1.28 g, 44%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[O:20])[CH:13]=2)[CH:8]=[N:7]1.[CH2:32]1COCC1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@H:19]3[CH2:32][O:20]3)[CH:13]=2)[CH:8]=[N:7]1
Reactant: C1CCOC1
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)cc21
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H]3CO3)C(C)C)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
A flame dried 100-mL, round-bottom flask was charged with sodium hydride (1.45 g, 60.0 mmol) and trimethyloxosulfonium iodide (8.0 g, 36 mmol). The flask was evacuated and refilled with N2, and dry DMSO (50 mL) was added. The mixture was stirred at rt for 2 h to give a solution of the sulfur ylid. A second 100-mL, round-bottom flask was charged with tert-butyl (2S,4S)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methyl-1-oxohexan-2-ylcarbamate (830 mg, 1.92 mmol) and THF (10 mL). The flask was evacuated and refilled with N2, and the sulfur ylid solution (6.0 mL) was added through a cannula. The resulting mixture was stirred for 2-3 h at rt. The reaction mixture was quenched with brine and extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography to afford tert-butyl (1S,3S)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methyl-1-((S)-oxiran-2-yl)pentylcarbamate (410 mg, 48%). 1H NMR (400 MHz, CDCl3): 0.81-0.92 (m, 5H), 1.26 (m, 2H), 1.47 (s, 6H), 1.65 (m, 6H), 2.17 (m, 2H), 2.68 (m, 1H), 2.95 (m, 1H), 3.30 (s, 3H), 4.11 (m, 1H), 4.47 (m, 2H), 6.99 (m, 1H), 7.21 (m, 1H), 7.60 (m, 1H), 7.95 (m, 1H); MS: 446 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([N:7]=[C:8]1[N:12]([CH2:13][CH2:14][C:15](=[S:17](=[O:19])=[O:18])C)[C:11]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:23][C:10]=2[S:9]1)=[O:6].Cl[C:33]1C=CC=C(C(OO)=O)C=1.N=C1N(CCCSC)C2C=CC(OC(F)(F)F)=CC=2S1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([N:7]=[C:8]1[N:12]([CH2:13][CH2:14][CH2:15][S:17]([CH3:33])(=[O:19])=[O:18])[C:11]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:23][C:10]=2[S:9]1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(CCn1c(=NC(=O)c2cccc(Cl)c2)sc2cc(OC(F)(F)F)ccc21)=S(=O)=O
Agent: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Solvent: ClCCl
Product: CS(=O)(=O)CCCn1c(=NC(=O)c2cccc(Cl)c2)sc2cc(OC(F)(F)F)ccc21
Reaction time: 18 h

Procedure:
2-(3-Chlorobenzoylimino)-3-(3-methyl-sulphonylpropyl)-6-trifluoromethoxybenzothiazoline may be prepared in the following way: 75% m-chloro-perbenzoic acid (5.2 g) is added in the course of about 10 minutes, to 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (3.9 g) in solution in dichloromethane (100 cc) stirred at a temperature close to 20° C. The reaction mixture is brought to the boil for 18 hours. After cooling to a temperature close to 20° C., the precipitate is filtered off and washed with dichloromethane (50 cc) and the filtrate is concentrated to dryness under reduced pressure after washing with 1N sodium hydroxide solution. The oil obtained is crystallised from ethyl acetate. 2-(3-Chlorobenzoylimino)-3-(3-methylsulphonylpropyl)-6-trifluoromethoxybenzothiazoline (0.6 g) melting at 188° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:15][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(C)c1ccc(Cl)nn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 2-(6-chloropyridazin-3-yl)propanoate (2.8 g, 13.04 mmol) in THF (28 mL) was added lithium hexamethyldisilazide (1.0 molar in THF, 15.65 mL, 15.65 mmol) at −70° C. in dropwise fashion. The reaction was stirred at −70 for 30 min and then iodomethane (0.816 mL, 13.04 mmol) was added. The reaction was stirred for 2 hrs as allowed to warm to room temperature. The reaction was concentrated to dryness via rotary evaporation and the resulting material was purified by MPLC (98:2, DCM:MeOH) to provide the title compound, ethyl 2-(6-chloropyridazin-3-yl)-2-methylpropanoate (54B, 2.82 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.07 Hz, 3 H) 1.58 (s, 6 H) 4.08 (q, J=7.07 Hz, 2 H) 7.83-7.97 (m, 2 H).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].I[CH3:27]>O1CCCC1.C(OCC)C>[CH3:27][O:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CI
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCC(OC)c1coc([Si](C)(C)C)c1

Procedure:
A mixture of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (318.5 mg, 0.9 mmol), sodium hydride (60% dispersion in oil; 150 mg, 3.8 mmol) and iodomethane (0.29 ml, 4.7 mmol) in tetrahydrofuran (7 ml) was refluxed for 16 hours. On cooling, the mixture was diluted with ethyl ether (20 ml), quenched with methanol (2 ml) and washed with water. Evaporation of the dried (magnesium sulfate) organic phase gave a deep yellow oil, identified as 4-(1-methoxytridecyl)-2-trimethylsilyfuran.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:7]=1[F:13])=[O:4].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(OCC)C.[Cu](I)I>[NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:8][C:7]=1[F:13])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#C[Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
A solution of (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (1.00 g, 2.51 mmol) in triethylamine (1.5 mL, 10.8 mmol) was thoroughly degassed with argon, bis-dichlorotriphenylphosphine palladium(II) (20.3 mg, 0.05 mmol) added followed by copper iodide (9.8 mg, 0.05 mmol) and trimethylsilylacetylene (277 mg, 2.77 mmol) and the mixture stirred under argon at ambient temperature for 3 hours. Additional triethylamine (1.5 mL, 10.8 mmol) was added to form a stirrable reaction mixture and stirring continued for an additional 20 hours. The reaction mixture was diluted with diethyl ether and a small amount of Celite added prior to filtration through Celite. The Celite was eluted with diethyl ether (4×20 mL) and the combined organic filtrates concentrated in vacuo. The resulting green oil was dissolved in a small amount of diethyl ether and diluted with hexanes (10 mL) to induce crystallization. The product was isolated by filtration, washed with hexanes and dried in vacuo to afford (2S,3S)-2-amino-N-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-3-phenyl-butyramide as a grey solid (610 mg, 66%). A second crop of product was obtained by reprocessing of the mother liquors from the initial crystallization (168 mg, 18%).