Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=O)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[S:33])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=S)cc2C)cc1
Temperature: 75 °C
Yield: 121.4 %

Procedure:
Methyl 2'-methyl-4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylate (D4, 200 mg, 0.647 mmol) was dissolved in toluene (25 ml) and Lawesson's reagent (130 mg, 0.324 mmol) was added. The solution was heated at 75° C. under argon for 1.5 hrs, then concentrated in vacuo. The resultant pale yellow solid was filtered through a neutral alumina column eluting with ether to remove excess Lawesson's reagent, then purified by column chromatography on silica gel eluting with ether to afford the title compound as a yellow solid (128 mg, 61%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C@@H:12]([CH3:14])[C@@H:11]3[O:15][C:16](=[O:18])[NH:17][C@@H:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]2[NH:17][C:16](=[O:18])[O:15][C@@H:11]12
Reactant: COc1ccc(CN2C[C@@H](C)[C@@H]3OC(=O)N[C@@H]3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNC[C@H]2NC(=O)O[C@@H]12
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3aR,7R,7aS)-5-(4-methoxybenzyl)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 20% palladium hydroxide on carbon (0.3 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 2 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7R,7aS)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (99%). LCMS (m/z): 157.1 (MH+) at 0.16 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=1)[CH3:2].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)(O)[O-].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[C:8]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[C:20]=2[Cl:21])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(I)c1
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(-c2cccc(Cl)c2Cl)c1

Procedure:
A mixture of 3-iodobenzeneacetic acid ethyl ester (0.87 g, 3 mmol, prepared by the method described in J. Chem. Soc. 1963, 5437), 2,3-dichlorophenylboronic acid (0.85 g, 4.5 mmol), bis(triphenylphosphine)palladium dichloride (0.10 g, 0.15 mmol) and 2N aqueous sodium bicarbonate solution (3 mL) in p-dioxane (6 mL) was heated at 160° C. in a microwave reactor for 5 min. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate in hexanes to provide the title product (0.48 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][CH:14]=[CH:13][CH:12]=2)=O.[ClH:19].C([O:27][NH2:28])C1C=CC=CC=1>C(O)(C)C>[Cl:19][CH2:2][CH2:3][CH2:4][C:5]1[N:28]([OH:27])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Cl
Reactant: NOCc1ccccc1
Reactant: O=C(CCCBr)Nc1cnc2ccccc2c1Cl
Solvent: CC(C)O
Product: On1c(CCCCl)nc2cnc3ccccc3c21
Temperature: 82 °C
Yield: 112 %

Procedure:
A mixture of 4-bromo-N-(4-chloroquinolin-3-yl)butanamide (2.090 g, 6.379 mmol) and O-benzylhydroxylamine hydrochloride (1.527 g, 9.569 mmol) in 20 mL of isopropanol was heated to 82° C. under an atmosphere of N2. After 18 hours the solution was cooled, solids were filtered off and rinsed with ether. The brown solid was dried to give 1.87 g of 2-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-1-ol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[N:5]([CH2:8][CH3:9])[C:6]=1Br.[Li]CCCC.CCCCCC.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1>C1COCC1.O>[CH2:8]([N:5]1[C:6]([Si:32]([CH3:34])([CH3:33])[CH3:31])=[C:2]([F:46])[N:3]=[C:4]1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CCn1c(-c2cccc3ccccc23)nc(Br)c1Br
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(-c2cccc3ccccc23)nc(F)c1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-dibromo-1-ethyl-2-naphthalen-1-yl-1H-imidazole (6.55 g, 17.2 mmol) in anhydrous THF (150 ml) at −78° C. under nitrogen is added a solution of n-BuLi in hexane (1.6 M, 11.8 ml, 19 mmol, 1.1 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 hr, and TMSCl (2.05 g, 19 mmol, 1.1 eq.) is added. The resulting solution is stirred at −78° C. After 1 hr, n-BuLi in hexane (1.6 M, 11.8 ml, 19 mmol, 1.1 eq.) is added dropwise. The resulting mixture is stirred at −78° C. for 1 hr, and N-fluorobenzenesulfonimide (5.99 g, 19 mmol, 1.1 eq.) is added. The resulting solution is stirred at −78° C. for 2 hr, warmed to rt slowly, and then stirred at rt overnight. Water (50 ml) is added to quench the reaction, and THF is evaporated. The residue is extracted with EtOAc (75 ml×2) and the combined organic layers are washed with water and brine, dried and concentrated to give crude 1-ethyl-4-fluoro-2-naphthalen-1-yl-5-trimethylsilanyl-1H-imidazole as a yellow oil. LCMS 313 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:30][CH3:31])=[C:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](SC)[CH:17]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].O[O:33][S:34]([O-:36])=O.[K+].[CH3:38]O>O>[CH2:1]([O:4][C:5]1[C:6]([CH2:30][CH3:31])=[C:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([S:34]([CH3:38])(=[O:36])=[O:33])[CH:21]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: CO
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2cccc(SC)c2)c(CC(=O)OC)c1CC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: C=CCOc1cc(OCC=C)c(C(=O)c2cccc(S(C)(=O)=O)c2)c(CC(=O)OC)c1CC
Yield: 93 %

Procedure:
Methyl 3,5-diallyloxy-2-ethyl-6-(3-methylsulfanyl-benzoyl)phenylacetate (550 mg, 1.3 mmol) obtained in Example 94, Step 1 was dissolved in a mixed solvent of methanol (12 mL) and water (6 mL), and Oxone (trademark; 1.9 g, 3.1 mmol) was slowly added thereto with stirring under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain methyl 3,5-diallyloxy-2-ethyl-6-(3-methanesulfonyl-benzoyl)phenylacetate (550 mg, 93%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C@H:42]3[CH2:47][CH2:46][C@H:45]([N:48]4[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]4)[CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1CCN([C@H]2CC[C@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-2-methyl-4-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-2,3-dihydro-1H-isoindol-1-one. 1H NMR (CDCl3, 400 MHz): δ=1.25-1.30 (m, 6 H), 1.40-1.55 (m, 2 H), 1.62 (q, J=12.80 Hz, 2 H), 1.97 (d, J=12.63 Hz, 2 H), 2.13 (d, J=11.87 Hz, 2 H), 2.37 (s, 3 H), 2.50 (d, J=12.13 Hz, 2 H), 2.61 (br. s., 2 H), 2.77 (br. s., 3 H), 3.14-3.20 (m, 2 H), 3.22 (s, 3 H), 3.93 (s, 3 H), 4.00-4.10 (m, 4 H), 4.38 (s, 2 H), 6.89 (dt, J=8.15, 2.24 Hz, 1 H), 6.94 (t, J=2.02 Hz, 1 H), 7.34 (d, J=8.59 Hz, 1 H), 7.63 (s, 1 H), 8.29 (d, J=8.59 Hz, 1 H), 8.39 (s, 1 H), 8.63 (d, J=8.59 Hz, 1 H), 10.50 (s, 1 H). MS (ES+): m/z 760.32 [MH+]; HPLC: tR=1.20 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[NH:18]([C:19]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=S)Nc1ccccc1
Temperature: 75 °C

Procedure:
To a solution of t-butyl 2-aminoethylcarbamate (1.76 ml) in ethanol (22 ml) was added dropwise phenyl isothiocyanate (1.5 g), and the mixture was heated at 75° C. for one hour. The reaction mixture was concentrated under reduced pressure and crystallized from n-hexane to give the title compound (3.25 g).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[CH2:17][O:18][CH3:19])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:19][O:18][CH2:17][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8]1
Reactant: COC[C@@H]1Cc2ccccc2N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H]1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-2-methoxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.863 g, 4.67 mmol, 1 eq) in CH2Cl2 (50 mL) was cooled to 0° C. and TFA (12 mL) was added. The reaction was stirred at room temperature for 1 hr and then poured carefully into 1 N NaOH. The pH was adjusted to basic with 2.5 N NaOH and it was extracted with CH2Cl2. The combined organics dried over sodium sulfate and concentrated to afford the title compound as a yellow oil, which was used crude in the following reaction. NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:10]2[C:9]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:8]=3[S:7][C:6]3[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH2:11]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1ccc(Cl)cc1S2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
38.8 G. of 3,10-dichloro-10,11-dihydro-8-fluoro-dibenzo[b,f]thiepin into 100 ml. of chlorofrom are heated with 82 g. of 1-carbethoxypiperazine for 24 hours under reflux conditions. The reaction mixture is poured on ice water and equilibrated with chloroform. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, Raw 1-carbethoxy-4-(3-chloro-10,11-dihydro-8-fluoro-dibenzo[b,f]thiepin10-yl)-piperazine is obtained as a yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12](O)[CH2:11][CH:10]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[OH-].[Na+]>CCOCC.CN(C=O)C>[Cl:3][CH:12]1[C:13]2[C:9](=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11]1
Reactant: O=S(Cl)Cl
Reactant: OC1CC(c2ccc(F)cc2)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(C2CC(Cl)c3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionylchloride (44 ml) was added dropwise with water-cooling to a solution of 5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-ol in ether (2L) with a catalytic amount of DMF (0.5 ml). Then the mixture was stirred for 2 hours at room temperature, poured into ice and neutralized with 9N NaOH. The organic phase was separated, dried (MgSO4) and evaporated to give 140 g of crude 1,5-dichloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37](O)=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)=[O:38])[CH:25]=[C:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:29]=1[OH:30])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Yield: 62 %

Procedure:
This is prepared analogously to Example 12 from ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate, 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid, phosphorus trichloride and pyridine. Yield 62% of theory; m.p. 105°-107° C. (recrystallised from ethyl acetate/ligroin).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]2[CH2:2][OH:1])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Reactant: OC[C@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCCN1CCc1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 4-chlorophenethyl tosylate (931 mg, 3.00 mmol), sodium carbonate (320 mg, 3.00 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 10 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-1-(4-chlorophenethyl)-2-hydroxymethylpiperidine in the form of a light yellow oil (354 mg, 56%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C.CCOC(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cnc(OC2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
As shown in step 7-i of Scheme 7, to a solution of 1,4-dioxaspiro[4.5]decan-8-ol (compound 1021, 1.0 g, 6.32 mmol) in DMF (10 mL) was added NaH (370 mg, 9.25 mmol). The reaction mixture was stirred for 20 minutes before the addition of 2-chloropyrimidine (869 mg, 7.59 mmol). The mixture was stirred for 30 minute at RT and then heated to 100° C. for 9 hours. After cooling, the mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0-40% EtOAc/hexanes) to produce 2-(1,4-dioxaspiro[4.5]decan-8-yloxy)pyrimidine (compound 1022) as a colorless oil: 1H NMR (300 MHz, Chloroform-d) δ 8.52 (d, J=4.8 Hz, 2H), 6.92 (t, J=4.8 Hz, 1H), 5.15 (ddd, J=10.7, 6.5, 4.2 Hz, 1H), 4.05-3.87 (m, 4H), 2.14-1.85 (m, 6H), 1.79-1.65 (m, 2H); ESMS (M+H+)=237.12.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([OH:24])[C:19]([O:21]CC)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([OH:24])[C:19]([OH:21])=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 50 °C

Procedure:
Ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate (4550 mg raw material from previous step 22.1; max. 10.72 mmol) dissolved in 13 ml of ethanol was treated with 6.43 ml 2N aq. NaOH overnight at room temperature. To complete the reaction, the mixture was then heated to 50° C. for 2 h. Water was added followed by extraction with MTBE (3×). The aqueous layer was acidified to pH 3 using 2M HCl and extracted three times with dichloromethane. The combined dichloromethane layers were then successively washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as a pale brown powder (2450 mg, yield: 58%). ESI-MS [M+H]+=397.2.
Reaction SMILES: [K].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][Cl:21]>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:20][Cl:21])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCBr
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCCl)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the potassium salt of 3-benzyloxybenzoic acid (2.39 g, 8.91 mmol) was added the bromochloromethane (8.7 ml, 15 eq.) and DMF (10.7 mL). The mixture was then stirred at room temperature for 12-18 hours. The mixture was then filtered and the filtrate concentrated. Purification of the crude product via flash chromatography (EtOAc: Hexanes 1:10) yielded 1.2 g of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ=5.12 (s, 2H), 5.96 (s, 2H), 7.22-7.25 (m, 1H), 7.26-7.47 (m, 6H), 7.68-7.72 (m, 2H), MS(ESI) 276.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[N:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:23]2[N:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Nc1cccnn1
Product: O=C(Nc1cccnn1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) and 3-pyridazinamine (CAN 5469-70-5) as starting materials; MS (ESI) 367.2 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([O:24][C:25]([C:27]1[N:28]2[CH:31]([S:32][CH2:33][C:34]=1[CH:35](Cl)[CH:36]=O)[CH:30]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:29]2=[O:47])=[O:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[NH:7]([C:8]1[S:9][C:35]([C:34]2[CH2:33][S:32][CH:31]3[N:28]([C:29](=[O:47])[CH:30]3[NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:27]=2[C:25]([O:24][CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:26])=[CH:36][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Cl)C=O)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12

Procedure:
N-Phenylthiourea (3.34 g) is added to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(1-chloro-2-oxoethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (a mixture of the epimers of the chloroaldehyde) (10.3 g) in a mixture of tetrahydrofuran (100 cc) and ethanol (40 cc), and the reaction mixture is then heated at the reflux temperature for 135 minutes. It is diluted with ethyl acetate (250 cc) and a half-saturated sodium bicarbonate solution (500 cc). The organic layer is washed with a half-saturated sodium chloride solution (250 cc) and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue obtained is chromatographed on a column (height: 30 cm; diameter: 7 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.7 bar (70 kPa) with a 70:30 (by volume) mixture of cyclohexane and ethyl acetate. After 1.5 liters of eluate have been collected, 100 cc fractions are collected and fractions 20 and 21 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is triturated with isopropyl ether (30 cc). 3-(2-Anilino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.7 g) is obtained in the form of a yellow solid.