Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:10][C:11]2[O:12][CH2:13][C:14]([F:28])([F:27])[C@:15]3([N:26]=2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=2)[S:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=1.[C:43](=[NH:56])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:10][C:11]2[O:12][CH2:13][C:14]([F:28])([F:27])[C@:15]3([N:26]=2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:56]=[C:43]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH:23]=2)[S:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@@]3(CCSc4ccc(Br)cc43)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(NC2=N[C@@]3(CCSc4ccc(N=C(c5ccccc5)c5ccccc5)cc43)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 67.4 %

Procedure:
In a dry tube under an atmosphere of argon to a solution of (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-6′-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2-amine (789 mg, 1.21 mmol) in toluene (10 ml) were added consecutively benzophenone imine (439 mg, 2.42 mmol), sodium tert-butoxide (349 mg, 3.63 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl {CAS[564483-19-8]} (51.4 mg, 121 μmol), and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct {CAS[52522-40-4]} (37.6 mg, 36.3 μmol). The tube was sealed and the reaction mixture stirred at 110° C. for 15 hours. For the workup, the solvent was evaporated at reduced pressure and the residue purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=0:100 to 70:30 as the eluent. The (R)—N2-(bis(4-methoxyphenyl)(phenyl)methyl)-N6′-(diphenylmethylene)-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2,6′-diamine (613 mg, 67% yield) was obtained as a yellow solid. MS (ISP): m/z=752.5 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH3:4].Cl.O1CCOCC1>C(OCC)(=O)C.CO.CCOCC>[N:5]1([CH:3]([CH3:4])[CH2:2][OH:1])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CC(CO)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CO)N1CCNCC1
Reaction time: 18 h
Yield: 113.8 %

Procedure:
A suspension of tert-butyl 4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate (0.782 g, 3.2 mmol) in a mixture of ethyl acetate (10 ml) and methanol (10.00 mL), was treated drop-wise with 4.0M HCl in dioxane (12.00 ml, 48.00 mmol) at room temperature. The reaction mixture was stirred for 18 h. The reaction mixture was diluted with ether and the white solid filtered off, washed with ether and air dried to give 2-(piperazin-1-yl)propan-1-ol (0.525 g, 76%), as its dihydrochloride salt.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=S)[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Yield: 7.2 %

Procedure:
A solution of 69.90 g of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone in 4 liters of ethanol was hydrogenated at 500 pounds per square inch (psi) in the presence of 200 g of 5% palladium on carbon overnight at 100° C. The reaction mixture was filtered and evaporated to dryness. In sections, the material was dissolved in 1 volume of hot ethyl acetate, diluted with 2 volumes of hexane, filtered, and loaded onto a silica gel chromatography column. Elution with 35% ethyl acetate in hexane provided various fractions which were combined according to the purities of the respective compounds. A total of 4.6 g of Compound B were isolated by chromatography. Fractions which were predominantly Compound B were crystallized from ethyl acetate/hexane providing a total yield of Compound B of 13.79 g. Rechromatography of fractions containing impure Compound C on silica eluting with 25% ethyl acetate in hexane provided 9.82 g of Compound C.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]([F:15])([F:14])[C:11]([O-])=[O:12]>>[F:9][C:10]([F:15])([F:14])[C:11](=[O:12])[CH2:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(=O)c1ccco1
Product: O=C(CC(=O)C(F)(F)F)c1ccco1

Procedure:
The diketone 19 was synthesized from acetylfuran and trifluoracetate to obtain the 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione 19 product as follows. 2-Acetylfuran 18 (11.0 g, 210 mmol) was dissolved in benzene (210 mL). At room temperature was added KOtBu (23.6 g, 210 mol). The resulting red solution was cooled to 5° C. Ethyl trifluoracetate 6 (25 mL, 29.8 g, 210 mmol) was added dropwise in approximately 20 minutes keeping the temperature below 15° C. Then the mixture was stirred for 16 hours at room temperature. The mixture was poured in ice-water (300 mL) containing concentrated sulfuric acid (5 g). The aqueous mixture was extracted with tBME (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4) and concentrated to give a dark brown oil (20.8 g). The crude product was purified by kugelrohr distillation to give compound 19 (17.0 g, 39%) as a yellowish oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:17]O)[CH2:6][N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:4]1.C(Br)(Br)(Br)[Br:20].CCOCC>C(Cl)Cl>[Br:1][CH2:2][C:3]1([CH2:17][Br:20])[CH2:6][N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)N2CC(CO)(CBr)C2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)(CBr)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
(3-(Bromomethyl)-1-(p-toluenesulfonyl)azetidin-3-yl)methanol (10.2 g, 30.6 mmol) was dissolved in DCM (100 mL) and CBr4 (16.9 g, 51 mmol) was added. The solution was cooled to 0° C. and then PPh3 (13.4 g, 51 mmol) was added in one portion. The resulting mixture was stirred at 0° C. for 2 h, then warmed to rt and stirred for 4 h. Et2O (100 mL) was added and the yellow precipitate was filtered. The filtrate was concentrated under reduced pressure and purification by flash chromatography (Biotage Isolera, 100 g KP-SIL, 0-30% EtOAc in hexanes) gave the title compound as colourless crystals (8.05 g, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 3.60 (s, 4H), 3.54 (s, 4H), 2.48 (s, 3H); MS ESI 398.1 [M+H]+, calcd for [C12H15Br2NO2S+H]+397.9.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([C:19]4([O:25][CH3:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:10]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:38][C:39]([NH2:41])=[O:40].[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([C:19]4([O:25][CH3:26])[CH2:24][CH2:23][CH2:22][N:21]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:20]4)[N:15]3[CH3:18])=[C:11]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:10]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: NC(=O)CBr
Reactant: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC1(c2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)CCCN(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine from Example 713 (1.0 g, 2.10 mmol), 2-bromoacetamide (290 mg, 2.10 mmol), sodium iodide (32 mg, 0.21 mmol) and K2CO3 (610 mg, 4.41 mmol) in MeCN (20 mL) was stirred at r.t. for 66 h. The reaction mixture was diluted with EtOAc, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with Et2O affording 716 (675 mg, 59%). LCMS (method I): RT 2.66 min, [M+H]+ 548.2. 1H NMR (DMSO, 400 MHz): δ 7.93-7.92 (1 H, m), 7.66-7.62 (1 H, m), 7.26-7.22 (2 H, m), 7.14 (1 H, s), 7.07 (1 H, s), 4.26 (4 H, brd s), 3.98-3.88 (4 H, m), 3.80-3.75 (4 H, m), 3.10-3.00 (4 H, m), 3.00-2.90 (3 H, m), 2.70-2.60 (1 H, m), 2.45-2.35 (1 H, m), 2.15-1.95 (2 H, m), 1.95-1.77 (1 H, m), 1.78-1.68 (1 H, m), 1.37-1.37 (6 H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10](=[O:24])[CH:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH3:12])=[CH:4][CH:3]=1.[I-].[NH2:26][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10](=[O:24])[CH:11]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])[CH3:12])=[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]3[N:26]=2)=[CH:4][CH:3]=1
Reactant: N[n+]1ccccc1
Reactant: CC(C(=O)C#Cc1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C(=O)c1c(-c2ccc(F)cc2)nn2ccccc12)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.1 g (3.4 mmol) of 2-(5-(4-fluorophenyl)-3-oxopent-4-yn-2-yl)isoindoline-1,3-dione and 785 mg (3.4 mmol) of N-aminopyridinium iodide in 10 ml of acetonitrile was added dropwise 1.04 g of DBU in 5 ml of acetonitrile at 0° C. for 20 minutes under a nitrogen atmosphere. The reaction was stirred at RT overnight, and it was worked up with ethyl acetate and ammonium chloride to produce 2-(1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl)isoindoline-1,3-dione as a crude solid. The phthalimide intermediate was reacted with 500 μl of hydrazine hydrate at RT in ethanol overnight. After workup with ethyl acetate and ammonium chloride, 1 g of crude product was obtained. The crude product was purified by C18-reverse-phase preparative HPLC. Addition of dilute HCl to the fractions containing purified product followed by lyophilization furnished 110 mg of 2-amino-1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride. Compound 1052.
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.[O:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:20][C:21]1[CH:46]=[CH:45][C:24]([C:25]([NH:27][C:28]2[S:29][C:30]3[C:36](N4CCOCC4)=[CH:35][CH:34]=[C:33]([O:43][CH3:44])[C:31]=3[N:32]=2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][C:28]2[S:29][C:30]3[C:36]([N:16]4[CH2:17][CH2:18][CH2:19][O:13][CH2:14][CH2:15]4)=[CH:35][CH:34]=[C:33]([O:43][CH3:44])[C:31]=3[N:32]=2)=[O:26])=[CH:45][CH:46]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reactant: C1CNCCOC1
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(N2CCCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and [1.4]Oxazepane as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=402 (M+H+).
Reaction SMILES: [ClH:1].C(OC(NCCC=O)=O)(C)(C)C.C(=O)C1OC=CC=1.C(OC([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C@@H:33]1[CH2:37][CH2:36][N:35]([S:38]([C:41]2[C:42]3[C:43]([Cl:51])=[CH:44][N:45]=[CH:46][C:47]=3[CH:48]=[CH:49][CH:50]=2)(=[O:40])=[O:39])[CH2:34]1)=O)(C)(C)C>>[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C@@H:33]1[CH2:37][CH2:36][N:35]([S:38]([C:41]2[C:42]3[C:43]([Cl:51])=[CH:44][N:45]=[CH:46][C:47]=3[CH:48]=[CH:49][CH:50]=2)(=[O:40])=[O:39])[CH2:34]1.[ClH:1]
Reactant: CC(C)(C)OC(=O)NCCCN[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CC(C)(C)OC(=O)NCCC=O
Agent: Cl
Solvent: O=Cc1ccco1
Product: NCCCN[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
Hydrochloride of the compound obtained in Example 19-2 and 3-(tert-butoxycarbonylamino)propionaldehyde can be used in the method of Example 4-1, Step A instead of hydrochloride of the compound prepared in Example 1-1 and furfural, respectively, to prepare (R)-3-[3-(tert-butoxycarbonylamino)propyl]amino-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine, and then the resultant can be used in the method of Example 1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=O)=O.[CH3:19][C:20]1[C:25](O)=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>ClCCCl.CN(C=O)C>[CH3:19][C:20]1[C:25]([O:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ncccc1OC1CCNCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.1 g), 2-methylpyridin-3-ol (500 mg), potassium carbonate (1.7 g), and DMF (10 ml) were mixed, followed by stirring at 100° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (10 ml), and TFA (4.5 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a 1M aqueous NaOH solution were the added thereto, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain 2-methyl-3-(piperidin-4-yloxy)pyridine (355 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[O:15]([C:22](OC1C=CC=CC=1)(OC1C=CC=CC=1)[CH2:23][N+:24]([O-:26])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][N+:24]([O-:26])=[O:25])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: O=[N+]([O-])CC(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)o1
Temperature: 40 °C
Yield: 1.9 %

Procedure:
21·4 g (0·1 mol) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine and 35·1 g (0·1 mol) of 1,1,1-triphenoxy-2-nitroethane are boiled for 3 hours in 250 ml of acetonitrile under a nitrogen atmosphere. The solvent is evaporated off under vacuum after cooling to 40° C. and the yellow oil left behind is chromatographed on 560 g of silica gel with dichloromethane/methanol (95:5). After concentration by evaporation under vacuum, the main fraction yields 28·7 g (76%) of the title compound in the form of a yellowish, viscous oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11](=N)N)[N:8]=1.[CH:14]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33]CCl)[CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Na+]>C(O)C>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[N:8]=1
Reactant: N=C(N)SCc1csc(N)n1
Reactant: ClCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(CSCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Yield: 71 %

Procedure:
S-(2-Aminothiazol-4-ylmethyl)isothiourea dihydrochloride (2.6 g) and 4-benzhydryl-1-(2-chloroethyl)piperazine (3.87 g) were suspended in ethanol (50 ml) in a stream of nitrogen, and thereto was added at a time water (30 ml) containing sodium hydroxide (2.8 g) at ambient temperature with stirring, and the stirring was continued at 50° C. for half an hour. The precipitated crystals were collected by filtration, washed with ethanol and then recrystallized from methanol to give pale yellow crystals (3.0 g) of 2-amino-4-[2-(4-benzhydrylpiperazin-1-yl)ethylthiomethyl]thiazole, mp 159°-161° C.
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:16]([CH3:26])[CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:15])=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>ClCCl>[Br:15][C:9]1[C:8]2[N:7]3[C@H:16]([CH3:26])[CH2:17][NH:18][C:19](=[O:20])[C:6]3=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc2cccc(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC(=O)c2cc3cccc(Br)c3n21
Temperature: 25 °C

Procedure:
A solution of 6.10 g (14.3 mmol) (R)-7-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester in 65 ml dichloromethane was cooled down to 0° C. and treated dropwise with 32 ml (28.7 mmol) trifluoroacetic acid. The cooling bath was removed and after 45 min. stirring at room temperature all volatile components were removed at a rotary evaporator and the remaining oil was dissolved in 35 ml methanol. To this solution, 7.93 g (57.4 mmol) potassium carbonate was added and the reaction was stirred for 16 h. The suspension was poured onto water and ethyl acetate; the organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane, tert-butyl methyl ether was added and the solution was concentrated at a rotary evaporator until a white precipitate began to form. The suspension was filtered, the solid material was washed with tert-butyl methyl ether and dried under high vacuum to give the desired compound as white crystalline solid. ISP-MS: m/e=2381.1 ([M+H+1]).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: OB(O)c1cccc(F)c1
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (step 1, 300 mg, 1.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (132 mg, 0.11 mmol) in 1,2-dimethoxyethane (6 mL) was stirred at 50° C. under nitrogen for 30 min. Then 3-fluorophenylboronic acid (191 mg, 1.37 mmol) and 2 M sodium carbonate solution (2.28 mL, 4.55 mmol) was added, and the resulting mixture was heated at 90° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated sodium hydrogen carbonate aqueous (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by TLC [hexane/ethyl acetate (8:1)] to give 107 mg (34%) of the title compound as colorless oil: 1H-NMR (CDCl3) δ 7.91 (1H, d, J=2.4 Hz), 7.41 (1H, dd, J=8.4, 2.4 Hz), 7.26–7.14 (2H, m), 6.91–6.79 (3H, m), 4.34 (2H, s), 3.84 (3H, s).
Reaction SMILES: [N+](=[C:3]([C:10](=O)[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([OH:19])[CH3:18])[C:15](=[O:20])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(C(C)C)CC)(C)C.C([S:51][C@@H:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])[C@H:54]([CH2:63][O:64][CH2:65][CH:66]([F:68])[CH3:67])[CH2:53]1)(=O)C.C[O-].[Na+]>C(OCC)(=O)C.C(#N)C.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC.O.CN(C)C(=O)C>[CH2:60]([O:59][C:57]([N:55]1[CH2:56][C@@H:52]([S:51][C:10]2[C@H:11]([CH3:12])[C@H:13]3[N:14]([C:15](=[O:20])[C@@H:16]3[C@H:17]([OH:19])[CH3:18])[C:3]=2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH2:53][C@H:54]1[CH2:63][O:64][CH2:65][CH:66]([F:68])[CH3:67])=[O:58])[CH:61]=[CH2:62]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCC(C)F
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Agent: C[O-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCC(C)F)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 0 °C
Reaction time: 10 h
Yield: 27.1 %

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (621 mg) in ethyl acetate (10 ml) was added rhodium(II) octanoate (10 mg) under nitrogen atmosphere, which was heated under reflux for 30 minutes. The solvent was evaporated and the remaining ethyl acetate was removed as the acetonitrile (10 ml) azeotrope to give a residue, which was dissolved in acetonitrile (10 ml) and cooled to 0° C. under nitrogen atmosphere. To the solution were added diphenyl chlorophosphate (480 μl), N,N-diisopropyl-N-ethylamine (421 μl) and N,N-dimethylacetamide (5 ml), and the solution was stirred for 10 hours at 0° C. To the solution was added at 0° C. a reaction mixture of (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-fluoropropyl)oxymethylpyrrolidine (790 mg) and 28% sodium methoxide (485 μl) in acetonitrile (5 ml) which reaction had been carried out at -20° C. for 15 minutes. The reaction mixture was allowed to warm at ambient temperature and stirred for 5 hours, which was poured into a mixture of ethyl acetate (50 ml) and water (20 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo to give a residue, which was chromatographed on silica gel (100 ml) eluting with a mixture of hexane and ethyl acetate (1:1-1:2 V/V) to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoropropyl)oxymethylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (300 mg).