Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH2:11].[N:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6](=[O:22])[C@H:7]([CH3:21])[NH:8][C:9](=[O:20])[C@H:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[S:19])[CH3:18])[NH:11][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N:25]=[N+:26]=[N-:27])=[CH:36][CH:35]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCNC(C)=S
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(C)=S)NC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (50 mg, 0.14 mmol) in 0.8 mL of THF was added a solution of 4-azidobenzoic acid (35 mg, 0.21 mmol) in 0.8 mL of THF. PyBOP (109 mg, 0.21 mmol) and DIPEA (59 mg, 0.42 mmol) were introduced into the reaction mixture. The reaction was stirred at room temperature for 6 h, and then solvent was removed under reduced pressure. Silica gel column chromatography (ethyl acetate: hexanes 10:1) afforded Nα-4-azidobenzoyl-Nε-thioacetyl-lysinyl-alaninyl-alanine methyl ester (58 mg, 0.115 mmol, 82%) as a pale yellow solid. 1H NMR (CD2Cl2, 500 MHz) δ (ppm): 1.39 (s, 3H), 1.40 (s, 3H), 1.47 (m, 2H), 1.67 (m, 2H), 1.88 (m, 2H), 2.87 (s, 3H), 3.57 (m, 2H), 3.68 (s, 3H), 4.41 (m, 1H), 4.46 (m, 1H), 4.64 (m, 1H), 7.05 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 8.32 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.CCO>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:11]([O:9][C:8](=[O:10])[C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[N:5][CH:6]=1)[CH3:12]
Reactant: O=C(O)c1cnccc1Cl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a solution of 4-chloro-nicotinic acid (2.5 g, 15.9 mmol) in DMF (26 mL)), were added Dicyclo-hexylcarbodiimide (DCC) (7.75 g, 37.5 mmol), 4-dimethylaminopyridine (DMAP) (0.286 g, 2.1 mmol) and EtOH (2.6 mL, 46.8 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was then distilled (0.1 mmHg) to afford 1.5 g (51%) of 4-chloro-nicotinic acid ethyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1.Cl.[Cl:30]CC[CH2:33][N:34](C)[CH3:35]>>[ClH:1].[ClH:30].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][N:34]([CH3:35])[CH3:33])[CH:10]=1
Reactant: CN(C)CCCCl
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Sc2ccccc2Cl)c1
Agent: Cl
Product: Cc1csc(Nc2ncc(SCCCN(C)C)cc2Sc2ccccc2Cl)n1

Procedure:
Prepared according to the method of Example 16 using methyl 3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 10.12 (bs, 1H), 8.41 (s, 1H), 7.61 (d, 1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.52 (s, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.70 (d, 6H), 2.18 (s, 3H), 1.84 (m, 2H); Mass spectrum (esi) m/z=451.0 (M+H-2HCl).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([NH:20][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH3:19])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2ccc(C(C)N)cc2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)N(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To 26.5 mg (0.10 mmol) 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)ethanamine (I63) and 27.7 μL (0.20 mmol) TEA in 1.5 mL DCM are added 11.0 μl (0.12 mmol) dimethylcarbamyl chloride at 0° C. The reaction mixture is stirred at r.t. over night and directly purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: C[C:2]1[NH:3][C:4]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[OH-].[Na+]>CO>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([C:4]1[NH:3][CH:2]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1)=[O:18]
Reactant: Cc1ccccc1C(=O)c1cc(C(=O)O)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(=O)c1cc(C(=O)O)c[nH]1
Yield: 117.9 %

Procedure:
Methyl 5-(2-methylbenzoyl)pyrrole-3-carboxylic acid (3.6 g.) was combined with 40 ml. of methanol and 40 ml. of 1N sodium hydroxide, refluxed for 2.5 hours, the methanol evaporated, the aqueous residue diluted with approximately one volume of water and extracted with ether. The aqueous phase was cooled and acidified with conc. hydrochloric acid to yield crude product (4.0 g.), recovered by filtration. Recrystallization from methanol afforded purified 5-(2-methylbenzoyl)pyrrole-3-carboxylic acid (2.2 g., m.p. 280°-282° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[CH:35]=[CH:34]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][N:33]2[CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc2ccn(CC3CNC3)c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4 g, 0.93 mmol), 1-azetidin-3-ylmethyl-6-fluoro-1H-indole (0.19 g, 0.93 mmol) and triethylamine (0.19 ml, 1.4 mmol) in dimethylsulfoxide (20 ml) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The hydrogen chloride salt was prepared in ethyl acetate and collected as a yellow solid: mp: 138° C. (dec).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH2:13]([OH:16])[C:14]#[CH:15]>O1CCCC1>[CH2:13]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]#[CH:15]
Reactant: C#CCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)CC(=O)OCC
Yield: 95.3 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (294 g) in tetrahydrofuran (200 ml) was added over 3hours to a stirred, ice-cooled suspension of sodium hydride (150 g of a 80% dispersion in mineral oil) in tetrahydrofuran (500 ml) at such a rate than the reaction temperature remained ≤20°. A solution of prop-2-ynol (100 g) in tetrahydrofuran (200 ml) was then added over 2 hours to the above mixture with stirring and ice-cooling at such a rate that the reaction temperature never exceeded +25°. The mixture was then stirred at room temperature for 16 hours, poured into 2 M HC1 (900 ml) and the layers separated. The organic layer was evaporated and the resulting red oil was separated in a separating funnel from the mineral oil. The red oil was taken up in dichloromethane and the resulting solution was washed several times with water, dried over Na2SO4 and evaporated to give the title compound (313 g) as a dark oil which was used directly in Preparation 8.
Reaction SMILES: C([O:8][C:9](=[O:34])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.O[CH:36]1[CH2:41][C:40](=[O:42])[NH:39][C:37]1=[O:38].Cl.CN(CCCN=C=NCC)C>CO.CCOCC.[Pd]>[O:42]=[C:40]1[CH2:41][CH2:36][C:37](=[O:38])[N:39]1[O:34][C:9](=[O:8])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C1CC(O)C(=O)N1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
2-[(4-Benzyl benzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester (650 mg, 1.36 mmole) was hydrogenated at 45 psi at room temperature in methanol (50 ml) over 5% palladium on barium sulfate (650 mg) for 1 hour. The catalyst was filtered off and washed with methanol. The filtrate was concentrated and traces of methanol removed by twice diluting the sample with methylene chloride and reconcentrating. The intermediate 2-[(4-benzyl benzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid was dissolved in dry dimethylformamide (14 ml) and hydroxysuccinimide (235 mg, 2.04 mmole) and dimethylaminopropylethylcarbodiimide hydrochloride (391 mg, 2.04 mmol) added. After stirring at room temperature for 20 hours the solution was diluted with ether (50 ml) and washed with 1N hydrochloric acid (50 ml, 2×25 ml) and saturated sodium bicarbonate solution (25 ml) and dried with magnesium sulfate. After filtration and concentration 566 mg (86%) of 2-[(4-Benzylbenzyl) methoxyphosphinoylmethyl]-4-methyl-pentanoic acid 2,5-dioxo-pyrrolidin-1-yl ester was obtained as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[OH:24])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1cc(CCN2CCCC2)cs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(F)cc1)c1sccc1CCN1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
A solution of 1-(2-(thiophen-3-yl)ethyl)pyrrolidine (1.0 g, 5.5 mmol) in THF (11.0 mL) was cooled to −78° C. in a dry-ice acetone bath before dropwise addition of n-butyllithium solution (2.5 M in hexanes, 2.4 mL, 6.0 mmol). The reaction mixture was stirred at −78° C. for 1 h and then neat p-fluorobenzaldehyde (0.65 mL, 6.1 mmol) was added dropwise via syringe. The mixture was allowed to warm to room temperature over 16 h and subsequently diluted with saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4. The residue remaining after solvent removal in vacuo was purified by flash chromatography to afford the desired alkylation product as a white solid (353 mg, 1.16 mmol, 21% yield). MS (M+H)+ 306.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].CO>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])=[O:6]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-chloropropanesulfonyl chloride (commercially available, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in an ice-water bath was added t-butylamine (commercially available, for example, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was applied to a SCX-2 cartridge (50 g) (preconditioned with methanol) and the cartridge eluted with methanol (2 column volumes). The methanol fraction was concentrated in vacuo to give the title compound as a white waxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:17]=[N:16][C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[CH3:18])(=[O:3])[CH3:2].[Se](=O)=[O:20]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:17]=[N:16][C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[CH:18]=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cnc2[nH]c(=O)[nH]c(=O)c2c1C
Reactant: O=[Se]=O
Solvent: CC(=O)O
Product: CC(=O)OCc1cnc2[nH]c(=O)[nH]c(=O)c2c1C=O
Yield: 89.4 %

Procedure:
A mixture of 6-acetoxymethyl-5-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.14 g, 12.5 mmol) and selenium dioxide (2.09 g, 18.9 mmol) in glacial acetic acid (100 mL) is heated at reflux for 20 hours, and then the mixture is filtered through a Celite pad while hot. The filtrate is concentrated in vacuo, and the residue is crystallized from methanol to give 6-acetoxymethyl-5-formylpyrido[2,3-d]-pyrimidine-2,4(1H, 3H)-dione (2.94 g, 86.6%), mp 263°-264° C. (decomposition). 1H NMR (Me2SO-d6) d 2.02 (3H, s, Ac), 5.03 (2H, s, CH2), 8.75 (1H, s, H-7, 10.49 (1H, s, CHO).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[NH:22]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2)[C:23]([CH3:25])=[O:24]>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([NH:22][C:23](=[O:24])[CH3:25])[CH:27]=2)[NH:31][C:30]1=[O:35]
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: CC(=O)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 69.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-acetamino-1,3-dihydro-indol-2-one as starting materials to give N-{3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (55 mg, 69.7%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[C:32]([CH3:34])([CH3:33])[O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:37]>CCO>[ClH:37].[CH3:34][C:32]([OH:31])([CH3:33])[C@H:28]([C:25]1[N:24]=[C:23]([NH:22][C:10]2[C:9]([O:8][C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][N:11]=2)[S:27][N:26]=1)[OH:29]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
(S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (145 mg, 0.2774 mmol) was dissolved in EtOH (5 mL), and 6M HCl (0.3 mL) was added. The reaction was stirred at ambient temperature for 2 hours and then at 70° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried, filtered, concentrated and purified over silica gel (10% methanol in EtOAc) to afford (S)-2-methyl-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (111.7 mg, 0.215 mmol, 77.6% yield) as a pale yellow solid after HCl salt formation. Mass Spectrum (apci) m/z=465.2 (M+H—HCl).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][O:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][OH:22]>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[OH:22][CH2:21][CH2:20][N:19]1[CH2:10][CH2:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:9]
Reactant: NCCO
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1

Procedure:
3,3-Diphenyldihydrofuran-2(3H)-one (1.0 g, 4.20 mmol), 2-aminoethanol (2.56 g, 42.0 mmol) and zinc chloride (0.020 g, 0.147 mmol) were heated together at 100° C. for 18 hours. The reaction was cooled, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave the title compound. MS (DCI+) m/z 282.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][C:16](=O)[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][CH:16]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc3nc(N4CC(=O)C4)sc3c2)cn1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3nc(N4CC(N5CCCC5)C4)sc3c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-one (Reference Example 4, 17 mg, 0.06 mmol), pyrrolidine (0.015 mL, 0.18 mmol), and a catalytic amount of acetic acid (0.005 mL) in toluene (0.4 mL) was stirred at room temperature for 5 minutes, then sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 1 M aqueous K3PO4 (0.4 mL), and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (60:40 dichloromethane/acetonitrile to 56:40:4 dichloromethane/acetonitrile/methanol) to give 6-(1-methyl-1H-pyrazol-4-yl)-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.84-1.90 (m, 4H), 2.59-2.66 (m, 4H), 3.59-3.68 (m, 1H), 3.92 (s, 3H), 4.06-4.12 (m, 2H), 4.26-4.32 (m, 2H), 7.45 (dd, J=1, 8 Hz, 1H), 7.50 (dd, J=2, 8 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 7.85 (d, J=2 Hz, 1H), 7.92 (d, J=1 Hz, 1H); MS (ESI) m/z 340 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:2].[C:11](Cl)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].[Na+].[Cl-]>C(Cl)(Cl)Cl>[C:11]([O:10][CH2:9][C:3]1([CH2:1][CH3:2])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]
Reactant: CCC1(CO)COC(=O)N1
Reactant: C/C=C/C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C/C=C/C(=O)OCC1(CC)COC(=O)N1

Procedure:
3.1 grams (0.021 mole) 4-ethyl-4-hydroxymethyl-2-oxazolidinone, prepared identically to that discussed in example 1, 2.3 grams (0.022 mole) trans-crotonyl chloride, and 25 milliliters chloroform were mixed in a one-necked round-bottom flask. The procedure employed was identical to that discussed in example 1. 4.20 grams (98% of the yield theoretically expected) of pure product was obtained as a clear oil The product exhibited the following spectral data: 1H NMR (CDCl3) δ0.90(t, 3H J=1.8 Hz), 1.48-1.67 (m, 2H), 1.83(d, 3H J=3.6 Hz), 3.97-4.19(m, 4H), 5.79(d, 1H J=3.6 Hz), 6.90-6.99(m, 2H); 13C NMR (CDCl3) δ7.3, 18.1, 28.3, 60.2, 66.7, 70.9, 121.7, 146.3, 159.6, 166.0; IR (NaCl) 3229, 3020, 2960, 1780 cm-1 ; MS m/z 213. This monomer can be chlorinated or brominated by the same procedure as in example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[C:12](=[O:31])[NH:11][C:10]=3[CH:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.Cl[CH2:35][C:36]1[O:40][N:39]=[C:38]([CH2:41][O:42][CH3:43])[N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]4)[C:12](=[O:31])[N:11]([CH2:35][C:36]4[O:40][N:39]=[C:38]([CH2:41][O:42][CH3:43])[N:37]=4)[C:10]=3[CH:9]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COCc1noc(CCl)n1
Reactant: COc1cc(F)ccc1-c1cc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[6-(4-fluoro-2-methoxyphenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (1.0 g, compound B63) and 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole (342 mg) in dry DMF (20 ml) is added potassium carbonate (291 mg). The mixture is stirred for 2 h at 100° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo. The residue is purified by flash column chromatography [amino phase silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 (v/v)] to afford the title compound as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7]1([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[C:7]1([C:13]2[C:14]([OH:15])=[N:6][C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:19]=2[OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(O)c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 10 g 1,2,4-triazol-3-amine and 33.7 g diethyl phenylmalonate in N,N-dibutylbutan-1-amine is stirred at 185° C. over night. The solution is diluted with 10% w/w NaOH solution, the resulting mixture is stirred for 30 min and the organic phase is separated. The aqueous layer is extracted with diethylether, acidified with concentrated HCl until precipition of the product is complete and the precipitate collected by filtration to yield the product, which is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:26]3[CH2:27][CH2:28][CH:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCC(c4ccccc4)CC3)CC2)cc1

Procedure:
3.0 g of 1-(4-nitrophenyl) -4-piperidone and 2.2 g of 4-phenylpiperidine were reacted as in Example 1. The product contained 1/6 mol of water of crystallization.