Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7](Br)[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Yield: 92.4 %

Procedure:
In a Pyrex (registered Trade Mark) vessel, a solution of 540 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 1), 322 mg of tri-n-butyl-tinhydride and 24 mg of 2,2'-azobisisobutyronitrile in 6 ml of benzene was irradiated with light from a high pressure mercury lamp at room temperature for 30 minutes. To the reaction mixture was added an aqueous sodium carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with water and aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (4:1) as eluent to give 435 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:22][C:20]=3[CH:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+].[CH2:39]1COCC1>>[CH2:15]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH2:29][C:30]([OH:32])=[O:31])[CH3:39])=[O:27])=[CH:22][C:20]=2[CH:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:1])([CH3:35])[CH3:36])=[C:7]([CH3:33])[CH:8]=1)[CH2:13][CH3:14])[CH3:16]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2o1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)CC(=O)O)ccc2o1
Yield: 74 %

Procedure:
[(2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carbonyl)-methyl-amino]-acetic acid (Example 9) (47 mg, 0.093 mmol) in THF (2.0 mL) are reacted with NaBH4 (7 mg, 0.18 mmol) analogous to Example 8 to yield title compound (35 mg, 74%). MS (ES) m/e: 508.3 (M−1), 510.3 (M+1)
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][CH3:7])C.Cl.C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[N:23]=[C:22]([C:37]([NH:39][NH2:40])=[O:38])[CH:21]=1>C(OCC)(=O)C.O>[CH:4](=[N:40][NH:39][C:37](=[O:38])[C:22]1[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[N:23]=1)[C:5]#[C:6][CH3:7]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: CC#CC(OCC)OCC
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC#CC=NNC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
2-butyne-1-al diethyl acetal (0.27 g, 0.000993×2 mol) was mixed with a 2N aqueous hydrochloric acid solution (about 3 ml) and 5 ml of benzene, and then the resultant mixture was stirred at about 70° C. for about 2 hours. After cooling to room temperature, the obtained mixture was mixed with 4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.325 g, 0.000993 mol), and the resultant mixture was stirred at room temperature for 45 minutes. The obtained reaction solution was distributed in ethyl acetate-water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: Cl.C([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#N.Cl>O>[NH:10]1[C:7]2[C:8](=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH:5]=[C:6]1[C:7]#[N:10]
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: O
Product: N#Cc1cc2ccccc2[nH]1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
4-Cyanophenylhydrazine hydrochloride (26.24 kg) and the Amine Ketal hydrochloride (1 mol equiv. 38.57 kg) were charged to the reaction vessel (RV3; nominal capacity 250 L; working capacity ca300 L) followed by water (92 L) and conc. hydrochloric acid (65.6 L). The reaction mixture was stirred and heated to 80-90° for up to ca 5 h and monitored by proton NMR (see note below). When the reaction was deemed to be complete, the reaction mixture was cooled to 0-5° C. and aged for 1 hour at this temperature. The racemic Indole Nitrile Hydrochloride was filtered using a 27″ nutsche filter and washed thoroughly with water (3×26 L or until the washing is >pH5). The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3, followed by water (164.5 L) and THF (66 L). The pH was adjusted to pH 13 with 6M NaOH (ca 30 L) and the reaction mixture stirred for 30 min. A sample was removed, the solid filtered off and checked by proton NMR (see note be low) to ensure the free base had been generated. The THF was then distilled off in vacuo at <40° C., the aqueous reaction mixture cooled to 0-5° C. and aged for a further 1 h. The solid was isolated by filtration using a 27″ nutsche filter, washed by displacement with water (2×33 L or until the washings are <pH9) and dried in vacuo at 55-60° C. to constant weight to give the racemic Indole Nitrile as an off-white solid (25.13 kg corrected for water content, 72.2% th, 65%w/w vs the Hydrazine hydrochloride input).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11](=[O:28])[CH:10]=1
Reactant: CCOC(=O)C(C)(CCn1ccc(OCc2ccccc2)cc1=O)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)C(C)(CCn1ccc(O)cc1=O)S(C)(=O)=O
Temperature: 85 °C

Procedure:
Ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (2.4 g, 5.9 mmol) which may be prepared by the same method disclosed in Example 51, step A, was dissolved in ethanol (100 ml) and cooled with a dry ice/acetone bath. To the cooled solution was added Pearlman's catalyst (2.0 g) and cyclohexene (9.0 ml, 88.4 mmol) then heated to 85° C. for 3 hours. The reaction mixture was cooled to RT and filtered through celite (approx 2 inches) to remove catalyst. The celite was washed with an additional 100 ml of ethanol. The filtrate was then concentrated under reduced pressure and the residue was dried under vacuum to afford a light gray solid. (1.75 g, 94%). MS (LC/MS) m/z 318.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.02 Hz, 3H) 1.56 (s, 3H) 2.02-2.26 (m, 1H) 2.33-2.48 (m, 1H) 3.14 (s, 3H) 3.67-3.84 (m, 1H) 3.84-4.02 (m, 1H) 4.13 (dd, J=7.02, 4.49 Hz, 2H) 5.55 (d, J=2.54 Hz, 1H) 5.85 (dd, J=7.42, 2.54 Hz, 1H) 7.48 (d, J=7.42 Hz, 1H)
Reaction SMILES: [N:1]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:25]([NH:27][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](N)[CH:36]=2)[CH2:31][CH2:30][C@H:29]1[O:39][C:40](=[O:42])[CH3:41])=[O:26]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:25]([NH:27][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:8][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:36]=2)[CH2:31][CH2:30][C@H:29]1[O:39][C:40](=[O:42])[CH3:41])=[O:26]
Reactant: NC(=O)N1CCCC1
Reactant: CC(=O)O[C@@H]1CCc2ccc(N)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCc2ccc(NC(=O)N3CCCC3)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of pyrrolidine carboxarnide (1.5 mL) in CH2Cl2 (25 mL) was treated with POCl3(0.23 mL). After 1.5 h, the solution was treated with triethylamine (1 mL) and 115 (0.5 g). After stirring over night, the solvent was evaporated, the residue was treated with ice-water, the mixture neutralized, and the mixture extracted with EtOAc. The extracts were washed with brine and the solvent was dried and evaporated to give a dark oil. The oil was purified by radial chromatography eluting with 5% EtOH-CHCl3 to give a tan solid that was recrystallized from EtOAc to give a white solid (0.18 g), m.p. 229° C., dec.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].Cl>C(OCC)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[CH:2][C:7]=1[Si:17]([CH3:19])([CH3:18])[CH3:16]
Reactant: COc1ccc(Br)cc1Br
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(Br)c([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dibromoanisole (13.3 g, 50 mmol) in diethyl ether (50 ml) at 0° C. was added over 20 min 1.5M butyllithium (33.4 ml) and the reaction was allowed to react 15 min at 0° C. Then trimethylsilylchloride (5.43 g, 50 mmol) in diethyl ether (20 ml) was added over 10 min and the resulting mixture was stirred 18 hours at room temperature. At 0° C. 3N HCl (50 ml) was added and the organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. 4-Bromo-3-trimethylsilylanisole was purified by chromatography on silica gel (eluted with cyclohexane) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCCC1>[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:27]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)c(F)c3F)c2)CC1
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) was allowed to stand for 10 min. 2,3,4,5-Tetrafluorobenzoyl chloride (31 μL, 0.229 mmol) was added to the reaction mixture. The reaction mixture was mixed for 24 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with 7M ammonia in methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. This purification was unsuccessful. The solvent was concentrated in vacuo. The residue was dissolved in water, basified with ammonium hydroxide, and extracted with methylene chloride. The organic extracts were washed with brine, glacial acetic acid (0.5 mL) was added to the organic extracts and the solution was mixed for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43.7 mg (97%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[N:18]=[N:19][C:20]([OH:23])=[CH:21][CH:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[C:17](=[O:16])[CH:22]=[CH:21][C:20]([OH:23])=[N:19]1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Oc1ccc(O)nn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2nc(O)ccc2=O)[C@@H]1O

Procedure:
A mixture containing I g of 6-cyano-2,2-dimethyl-3,4-epoxychromane, 1.1 g of 3,6-dihydroxypyridazine and 0.20 ml of a methanolic solution containing 357. of benzyltrimethylammonium hydroxide, in 5 ml of dioxane and 5 ml of dimethylformamide, is refluxed for 50 hours. It is concentrated under vacuum and the residue is then triturated in 15 ml of water. The precipitate formed is filtered off and washed with water and then isopropyl ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1.Cl[CH2:17][C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[N:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]4[O:22][C:21]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])=[N:20][N:19]=4)[C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1cccc(-c2nnc(CCl)o2)c1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1cccc(-c2nnc(CN3CCCn4c(-c5ccncc5)nnc43)o2)c1
Yield: 16.3 %

Procedure:
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (172 mg, 0.85 mmol) and 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzonitrile (94 mg, 0.43 mmol) were dissolved in butanone (5 ml) and K2CO3 (118 mg, 0.85 mmol) and KI (35 mg, 0.21 mmol) were added. The reaction mixture was refluxed for 1 h and the solvent was evaporated. The residue was dissolved in K2CO3 (aq., 1M, 25 ml) and was extracted with DCM. The combined organic layers were dried (Na2SO4) and purified with prep. HPLC to give the title compound (27 mg, 16%). 1H NMR: 8.75 (d, 2H), 8.30 (m, 2H), 7.79 (d, 1H), 7.63 (m, 1H), 7.53 (dd, 2H), 5.57 (d, 2H), 4.06 (t, 2H), 3.58 (t, 2H), 1.99 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Product: Cc1cc(OC(=O)N(C)C)nc(C(Cl)(Cl)Cl)n1

Procedure:
The pyrimidinyl carbamate compounds of the present invention may be prepared by reacting trichloroacetamidine with the corresponding acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carbamoyl chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with methylacetoacetate to form 4-hydroxy-6-methyl-2-trichloromethylpyrimidine. In equation (B), the 4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with dimethylcarbamoyl chloride to form 6-methyl-2-trichloromethyl-4-pyrimidinyl dimethylcarbamate. ##STR3##
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(Cl)Cl.CO>[OH:1][CH2:2][C@@H:3]1[N:8]([CH3:18])[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CN1CCN(C(=O)OC(C)(C)C)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (115 mg, 0.53 mmol) in acetonitrile (1.4 mL) and water (0.3 mL) was added Formalin (0.11 mL, 1.6 mmol) followed by sodium triacetoxyborohydride (225 mg, 1.1 mmol). The reaction mixture was stirred for 20 minutes at ambient temperature. The reaction mixture was then basified via the addition of saturated aqueous sodium carbonate solution (1 mL), diluted with methylene chloride (50 mL) and methanol (5 mL), and washed with saturated aqueous sodium bicarbonate solution (2×15 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to afford a white crystalline solid, which was used in the next step without any further purification (120 mg, 98%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:33])[C@@H:11]([NH:20][C:21](=[O:32])[C@H:22]([NH2:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][CH:8]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:43]=[C:44](Cl)OC(Cl)(Cl)Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:33])[C@@H:11]([N:20]2[C:21](=[O:32])[C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[NH:31][C:44]2=[O:43])[C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[S:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc([C@@H](N)C(=O)N[C@H](C(=O)Nc2nc(C(C)=O)cs2)[C@@H](C)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@H]2NC(=O)N([C@H](C(=O)Nc3nc(C(C)=O)cs3)[C@@H](C)c3ccccc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 119.8 %

Procedure:
(2S,3S)-N-(4-Acetyl-thiazol-2-yl)-2-[(R)-2-amino-2-(4-methoxy-phenyl)-acetylamino]-3-phenyl-butyramide (2.7 g, 90% purity, 5.2 mmol) and diisopropylethylamine (4.2 mL, 23.6 mmol) in tetrahydrofuran (50 mL) were added to a solution of diphosgene (0.48 mL, 4 mmol) in a mixture of toluene (50 mL) and tetrahydrofuran (50 mL) over 10 minutes at 0° C. The mixture was stirred at 0° C. for 20 minutes and diluted with ethyl acetate. The mixture was washed with water, brine and dried (sodium sulfate). Evaporation of the solvents and chromatography of the residue over silica gel with 0.4-1% v/v methanol in dichloromethane gave (2S,3S)-N-(4-acetyl-thiazol-2-yl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyramide (2.36 g, 92%) as a white solid.
Reaction SMILES: N1C=CC=CC=1.OCC[C:10]1([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:14][C:13](=[O:15])[CH:12]([CH3:16])[S:11]1.[C:23]([O:26][C:27](=O)[CH3:28])(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][CH2:28][N:14]1[C:13](=[O:15])[CH:12]([CH3:16])[S:11][CH:10]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:25])[CH3:24]
Reactant: CC1SC(CCO)(c2cccnc2)NC1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCN1C(=O)C(C)SC1c1cccnc1
Reaction time: 2 h
Yield: 77 %

Procedure:
Pyridine (0.5 ml) was added to a solution of -(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4one (0.5 g, 2.1 mmol) in acetic anhydride (2 ml) under cooling with ice. This cooling with ice was further continued for 2 hours. The product mixture was concentrated by evaporation under reduced pressure, and subjected to medium-pressure chromatography (hexaneacetone), giving 3-(2-acetoxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.45 g, 77% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.C(N(CC)C(C)C)(C)C.[NH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C)C(=O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:6]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:7]=1)=[O:21]
Reactant: NC1CCOCC1
Reactant: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCBr
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCNC1CCOCC1
Temperature: 120 °C
Yield: 71.2 %

Procedure:
To a solution of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide (0.050 g, 0.12 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and 4-aminotetrahydropyran (0.032 mL, 0.32 mmol) in a heavy-walled sealed tube. The solution was heated under microwave irradiation at 120° C. for 1 h. The solution was concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown solid (0.039 g, 59%). LCMS m/z (%)=457 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.81 (dd, J=2.6, 9.0 Hz, 1H), 7.79-7.72 (, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.48-7.40 (m, 1H), 7.28-7.20 (m, 2H), 6.34 (d, J=1.8 Hz, 1H), 4.28-4.23 (m, 2H), 3.84 (dd, J=4.0, 11.4 Hz, 2H), 3.69 (s, 3H), 3.40-3.32 (m, 2H), 3.32-3.14 (m, 2H), 3.14-3.03 (m, 1H), 1.85 (m, 2H), 1.48-1.36 (m, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1.[CH2:11]([O:14][C:15]([N:17]1[C@H:21]([CH:22]=[O:23])[CH2:20][C@@H:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:18]1)=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([O:14][C:15]([N:17]1[C@H:21]([CH:22]([OH:23])[C:8]2[S:7][C:6]3=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:10]3[CH:9]=2)[CH2:20][C@@H:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH2:18]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: CSc1ncc2sccn12
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2c(SC)ncc2s1
Yield: 52.1 %

Procedure:
The procedure of Synthesis Example 10-a) is repeated, except that 1.60 g of 5-methylthioimidazo[5,1-b]thiazole and 2.97 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine are used and the purification is successively performed by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) and on silica gel (hexane:ethyl acetate=1:2) to give 2.37 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(5-methylthioimidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) as a yellow amorphous material.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1nc2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3ccc(Br)cc3o2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A mixture of 4-[N-methyl-N-(6-bromo-2-benzoxazolyl)amino]phenol (0.6, 0.002 mole), ethyl 2-bromopropionate (0.4 g, 0.002 mole), anhydrous potassium carbonate (0.3 g, 0.002 mole) and methyl ethyl ketone (6 ml) was heated under reflux, with stirring, for a period of 3 hours. Thin layer chromatography indicated that the reaction had not gone to completion and therefore further anhydrous potassium carbonate (0.15 g) and methyl ethyl ketone was added and the mixture was heated under reflux for a further period of 3 hours. The solvent was removed by distillation under reduced pressure, water (50 ml) was added to the residue and the aqueous mixture was extracted with diethyl ether (3×30 ml). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated to give a dark red oil. The oil was heated at a temperature of 100° C. at a pressure of 0.1 mm Hg for a period of 2 hours to remove residual ethyl 2-bromopropionate and the residue was recrystallised from hexane/cyclohexane to give the title compound as a white solid (0.45 g), mp 91°-92° C.