Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.[OH-].[K+].C(OCC)(=O)C.CCCCCC>CC(O)C.[Ru](Cl)Cl.C1C=CC=CC=1.[Ru]>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2
Reactant: Nc1cccc2c1CC(=O)CC2
Agent: Cl[Ru]Cl
Agent: [Ru]
Agent: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: Nc1cccc2c1C[C@H](O)CC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Benzene ruthenium(II)chloride dimmer (0.2 g, 0.0004 mol, 0.02 eq), (1S,2R)-(−)-cis-1-Amino-2-indanol (0.24 g, 0.0016 mol, 0.08 eq) were taken in nitrogen bubbled IPA (50 ml). This solution was heated at 80° C. for 20 min and cooled back to RT. 8-amino-3,4-dihydronaphthalen-2(1H)-one (3.3 g, 0.02 mol) was taken in nitrogen bubbled IPA (98 ml), a solution of KOH (0.23 g, 0.004 mol, 0.2 eq) in IPA (50 ml) and the earlier prepared ruthenium solution were added drop wise simultaneously at RT. The overall reaction mixture was heated to 45° C. and stirred for 30 min at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.2). On completion of the reaction, cooled the reaction contents to rt, filtered on a silica gel bed and the bed was washed with ethyl acetate (4×30 ml). Filtrate was concentrated under reduced pressure, residue was taken in DCM (75 ml) and treated with charcoal. Filtered the contents over a silica gel bed and the bed washed with DCM (4×30 ml). DCM was distilled off completely and the crude obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane) to yield the titled product as a brown colored solid (2.1 g, 63% yield, mp 58-87° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[F:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:13])[C:10]([N:39]1[CH2:40][CH2:41][C@H:37]([F:36])[CH2:38]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: F[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
(R)-2-tert-Butoxycarbonylamino-propionic acid (1.0 g, 5.3 mmol), 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide (2.33 g, 12.2 mmol) and hydroxybenzotriazole (1.64 g, 12.2 mmol) were dissolved in DMF (50 ml). (S)-3-Fluoropyrrolidine hydrochloride (1.66 g, 13.2 mmol) and N,N-diisopropylethylamine (2.95 ml, 16.9 mmol) were added and the mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the solution was washed with 10% citric acid solution three times. The organic layer was washed with sodium bicarbonate solution which was then back-extracted with ethyl acetate four times. The combined organic layers were then washed further with lithium chloride solution, sodium chloride solution, and dried over magnesium sulfate. Concentration of the solution gave 1.3 g (94%) of [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:26]1[CH2:28][CH:27]1[C:29](OC)=[O:30])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[C:7]([N:26]1[CH2:28][CH:27]1[CH2:29][OH:30])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCC1CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of lithium aluminum hydride in diethyl ether (1 M, 15 mL, 15 mmol) under an atmosphere of nitrogen, a solution of methyl 1-trityl-2-aziridinecarboxylate (5.04 g, 14.7 mmol) in anhydrous ether (60 mL) was added over a period of 0.5 h. The resultant mixture was allowed to slowly warm up and stirred at room temperature for 1 hour. The resultant mixture was cooled back to 0° C. and treated successively with water (0.57 mL) over a period of 10 minutes, followed by addition of 15% aq NaOH (0.57 mL), and water (1.7 mL). The resultant suspension was filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was treated with a mixture of ether (40 mL) and hexane (200 mL) with cooling. The precipitate was collected by filtration to provide (1-tritylaziridin-2-yl)methanol as white solid. Without further purification, the alcohol (1.0 g, 3.17 mmol) was added portionwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.24 g, 6.0 mmol). To the resultant mixture, terta-n-butylammonium iodide (50 mg, 0.14 mmol) and benzyl bromide (0.65 g, 3.8 mmol) were added. The reaction mixture was stirred at room temperature overnight and treated with water (20 mL). The organic extract was diluted with ether, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 5% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:13]/[OH:14])/[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8].[CH:15]([O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35]O)[O:33][CH:34]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:13]/[O:14][CH2:35][C:32]1[O:33][CH:34]=[C:29]([O:28][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:30](=[O:37])[CH:31]=1)/[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCOC(=O)/C(=N\O)c1cccs1
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)/C(=N\OCc1cc(=O)c(OC(c2ccccc2)c2ccccc2)co1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 207.6 %

Procedure:
To an ice cooled solution of allyl (E)-2-(2-thienyl)-2-(hydroxyimino)acetate (1.0 gm, 4.734 mmol), 5-benzhydryloxy-2-(hydroxymethyl) pyran-4-one (1.46 gm, 4.734 mmol) and triphenylphosphine (1.24 gm, 4.734 mmol) in dry THF (30 ml) under nitrogen was added dropwise diethyl azodicarboxylate (820 μl, 5.208 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to afford the crude as yellow gum (4.93 gm). The product was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as eluant to provide the title compound as a gummy foam in 47% yield (1.11 gm).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)O
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (91 mg, 0.96 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-cyanophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 34; 160 mg, 0.48 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg, 0.58 mmol) and 1-Hydroxybenzotriazole (78 mg, 0.58 mmol) in DMF (15 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), and extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 180 mg.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:10]([O-])(=O)[CH:11]=C>>[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]=[CH2:11]
Reactant: C=CC(=O)[O-]
Agent: C=CC(=O)OC(C)(C)C
Product: C=C

Procedure:
The composition of the copolymers was determined by 13C-NMR in CDCl3. The acrylate ester content was calculated by averaging the integral values for the acrylate carbonyl and quaternary carbon of t-butyl group. Ethylene content is then obtained by correcting the total aliphatic integral for the t-butyl acrylate integration. Furthermore, acrylate-centered traits were quantified by integration of three clusters of methine resonances: EAE: 46.5, EAA/AAE: 44.2, AAA: 42.2 ppm. The copolymer was found to have 76 mol % t-butyl acrylate with EAE:EAA/AAE:AAA=8:38:53.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26].C(N1[C:36]([C:37](=[O:46])C2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)C#CC.C1(C#CCN2C(C(=O)C3C=C(C)C=C(C)C=3)=C(C(C)C)C(=O)NC2=O)C=CC=CC=1>>[C:37]([O:1][CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:10]([CH:22]([CH3:23])[CH3:24])[C:9](=[O:25])[NH:8][C:7]1=[O:26])(=[O:46])[CH3:36]
Reactant: CC#CCn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Reactant: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC=CCO)c1
Agent: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC#Cc2ccccc2)c1
Product: CC(=O)OCC=CCn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
1-(4-hydroxy-2-butenyl)-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione; 1-(2-butynyl)-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione;
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C@@H:27]12[N:34]([CH3:35])[C@@H:31]([CH2:32][CH2:33]1)[CH2:30][C:29](=[O:36])[CH2:28]2>O1CCCC1>[OH:36][C:29]1([C:19]2[N:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])[C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:28][CH:27]2[N:34]([CH3:35])[CH:31]([CH2:32][CH2:33]2)[CH2:30]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: CN1[C@@H]2CC[C@H]1CC(=O)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C2CCC1CC(O)(c1cc3ccccc3n1S(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1 equivalent of lithium diisopropylamide (15.5 mMol in tetrahydrofuran) is added via cannula to a solution of 1 equivalent of 1-phenylsulfonyl-1H-indole in tetrahydrofuran at -78° C. The reaction mixture is stirred at this temperature for 1.5 hours, warmed to room temperature for 1 hour and then cooled again to -78° C. To this solution is then added a solution of 1.02 equivalents of 3-tropanone in tetrahydrofuran and the resulting mixture is allowed to warm to room temperature over 18 hours. The reaction mixture is then partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The phases are separated and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography. Fractions shown to contain product are combined and concentrated under reduced pressure to provide 3-hydroxy-3-(1-phenylsulfonylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1]octane.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Cl:20][C:4]1[C:5]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2cccnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ncnc2cccnc12
Temperature: 25 °C

Procedure:
To a stirred solution of pyrido[3,2-d]pyrimidin-4-ol (A-2) (16 g, 109 mmol, 1.0 eq) and DMF (0.4 mL) in DCM (200 mL) at RT, oxalyl chloride (23.2 mL, 272 mmol, 2.5 eq) is added dropwise (over 5 min) and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is diluted with water (200 mL), neutralized with saturated aqueous NaHCO3 solution below 10° C. to adjust the pH to 8-9 and then extracted with ethyl acetate (4×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (16-50% ethyl acetate-petro ether) to afford the product, 4-chloropyrido[3,2-d]pyrimidine (A-3).
Reaction SMILES: [C:1]([Li])(C)(C)C.CCCCC.Br[C:12]1[C:13]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:14][N:15]([CH3:26])[C:16]=1[C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21].CI>C1COCC1>[C:20]([SiH2:19][O:18][C:17]([CH3:25])([CH3:24])[C:16]1[N:15]([CH3:26])[N:14]=[C:13]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:12]=1[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCC
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1C(C)(C)O[SiH2]C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.5 M solution of tert-butyllithium in pentane (0.5 ml, 748 μmol) was added dropwise to a solution of 4-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (280 mg, 623 μmol; example 8 b]) in THF (2 ml) at −78° C. under an argon atmosphere. After 15 min methyl iodide (177 mg, 1.2 mmol) was added at −78° C. The reaction mixture was stirred for another 30 min at −78° C. and then for 2 h at RT. After quenching with saturated aqueous NaHCO3 solution the reaction mixture was partitioned between tert-butyl methyl ether and water. The ether phase was dried over sodium sulfate and concentrated in vacuo to give 240 mg (620 μmol, quant.) 5-(tert-butyl-dimethyl-silanyloxymethyl)-1,4-dimethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole as yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[I:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18].ICC>C1COCC1>[I:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH2:1][CH3:2])[C:17]([OH:19])=[O:18]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)Cc1ccccc1I
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C(=O)O)c1ccccc1I
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Lithium diisopropylamide solution (2.0 M in THF/heptane/ethylbenzene, 3.82 mL, 7.63 mmol) was added to dry THF (10 mL) under an atmosphere of nitrogen and cooled to 0° C. A solution of 2-(2-iodophenyl)acetic acid (500 mg, 1.91 mmol) in dry THF (15 mL) was then added dropwise. This solution was stirred for 40 minutes at 0° C. before the addition of iodoethane (0.92 mL, 11 mmol). The solution was returned to room temperature and stirred for 4 hours. The resulting mixture was quenched with the addition of H2O (10 mL) and then 2 M HCl (20 mL). The aqueous layer was extracted with EtOAc (3×30 mL), the organic layers were combined and washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound I1 as a pale yellow oil (479 mg, 87%); 1H NMR (400 MHz, d6-DMSO) δ 12.49 (s, 1H), 7.88 (dd, J=7.9, 1.2 Hz, 1H), 7.39 (td, J=7.6, 1.2 Hz, 1H), 7.32 (dd, J=7.8, 1.7 Hz, 1H), 7.01 (J m, 1H), 3.77 (t, J=7.5 Hz, 1H), 1.98-1.86 (m, 1H), 1.73-1.60 (m, 1H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[S:9][C:10]2[C:15](=[O:16])[NH:14][C:13](=[S:17])[NH:12][C:11]=2[N:18]=1.[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CS(C)=O>[NH2:7][C:8]1[S:9][C:10]2[C:15](=[O:16])[N:14]=[C:13]([S:17][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:20]=3[F:19])[NH:12][C:11]=2[N:18]=1
Reactant: Nc1nc2[nH]c(=S)[nH]c(=O)c2s1
Reactant: Fc1cccc(CBr)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc2[nH]c(SCc3cccc(F)c3F)nc(=O)c2s1
Reaction time: 72 h

Procedure:
Potassium t-butoxide solution (0.45 ml of 1M solution in tetrahydrofuran) was added to a stirred solution of 2-amino-5,6-dihydro-5-thioxo-thiazolo[4,5-d]pyrimidin-7(4H)-one (0.09 g) [Cited: Indian J. Chem., Sect. B (1989), 28B(11), 964-5.] and 2,3-difluorobenzyl bromide in dimethyl sulphoxide (2 ml). After stirring for 3 days, the reaction mixture was poured onto water to give and the subtitle compound, isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([O:28]C)=[O:27])[CH2:19]3)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([OH:28])=[O:27])[CH2:19]3)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCN(c2ccccc2C(=O)O)C1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Methyl 2-[3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]carbonylaminomethyl]piperidin-1-yl]benzoate (29.5 mg, 0.0609 mmol) was dissolved in methanol (3 mL). To this solution, a 1 mol/L aqueous potassium hydroxide solution (0.183 mL, 0.183 mmol) was added and the mixture was stirred for 2 hours while being refluxed. Subsequently, the reaction mixture was concentrated and water was added to the residue, followed by 2 mol/L hydrochloric acid to make the mixture acidic. The crystallized powdery product was collected by filtration and washed with water to give 23.2 mg (81%) of the desired product as a colorless powder.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15][CH:16]2[CH2:21]CCC[O:17]2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.O1CCOCC1.CC#N.C(Cl)Cl.C(Cl)(=O)C.CCN(C(C)C)C(C)C>>[C:16]([O:15][CH2:14][C@:10]([CH3:22])([CH2:9][C@H:8]([NH:23][C:24]([C:26]1[NH:27][N:28]=[N:29][CH:30]=1)=[O:25])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:2][CH:3]=1)[C:11]([OH:13])=[O:12])(=[O:17])[CH3:21]
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)OC[C@](C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reaction time: 0.17 h
Yield: 4.4 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (126 mg, 255 μmol) was combined with 4 M HCl in dioxane (191 mL, 765 μmol) in MeCN (0.7 mL, 10 mmol). The mixture was then concentrated under reduced pressure and the residue was purified by reverse phase chromatography. DCM (1 mL, 20 mmol) and acetyl chloride (24 mg, 306 μmol) were added, followed by DIPEA (133 mL, 765 μmol). The resulting mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (5 mg). MS m/z [M+H]+ calc'd for C24H26N4O5, 451.19. found 451.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([S:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Sc3ccc(Cl)cc3)c(=O)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of [8-chloro-3-(4-chlorophenylsulfanyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.26 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.25 g) and acetic acid chlorodifluoromethyl ester (0.13 mL) was stirred at 80° C. for 17 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (7:3 by volume) to afford title compound, 0.044 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25]([CH3:27])=C)[C:21]([O:28][CH2:29][O:30][CH3:31])=[C:20]([C:32]([O:34][CH2:35][O:36][CH2:37]OC)=[O:33])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[O:40]=[O+][O-].CSC>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25](=[O:40])[CH3:27])[C:21]([O:28][CH2:29][O:30][CH3:31])=[C:20]([C:32]([O:34][CH2:35][O:36][CH3:37])=[O:33])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=C(C)Cc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OCOCOC)c1OCOC
Solvent: CO
Solvent: CSC
Product: CCOc1ccc(-c2nc(-c3cc(CC(C)=O)c(OCOC)c(C(=O)OCOC)c3)cs2)cc1OCC
Reaction time: 1 h

Procedure:
In 20 ml of methanol was dissolved 1 g of 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxymethoxycarbonyl-4-methoxymethoxy-5-(2-methyl-2-propenyl)phenyl]thiazole. Into the solution being stirred under ice-cooling was blown ozone. After 1 hour, 0.5 ml of methyl sulfide was added. The mixture was stirred at the same temperature for 30 minutes. The solvent was removed from the reaction mixture by distillation. To the residue were added 50 ml of dichloromethane and 25 ml of water. The organic layer was separated, washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane/n-hexane =2/3 by v/v) to obtain 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl)thiazole as a colorless oily substance.
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH:3]=[CH:2]1.O[CH2:17][CH:18]1[CH2:27][CH2:26][N:25]2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19]1>>[S:1]1[C:5]2=[C:6]([C:13]([O:15][CH2:17][CH:18]3[CH2:27][CH2:26][N:25]4[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:19]3)=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)c1c2ccccc2n2ccsc12
Reactant: OCC1CCN2CCCCC2C1
Product: O=C(OCC1CCN2CCCCC2C1)c1c2ccccc2n2ccsc12

Procedure:
Thiazolo[3,2-a]indole-9-carboxylic acid (D16) was converted to its acid chloride and reacted with eq-2-hydroxymethylquinolizidine using a procedure analogous to that described in Example 10 to afford the title compound as a white solid mp 129°-131° C. (ether).