Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH2:22])=[N:18][CH:19]=1.C(N(C(C)C)CC)(C)C.[O:32]=[C:33]1[CH2:38][S:37][C:36]2[CH:39]=[CH:40][C:41]([C:43](O)=[O:44])=[N:42][C:35]=2[NH:34]1.O.OC1C2N=NNC=2C=CC=1.C(Cl)CCl>CN(C=O)C>[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:43]([C:41]2[CH:40]=[CH:39][C:36]3[S:37][CH2:38][C:33](=[O:32])[NH:34][C:35]=3[N:42]=2)=[O:44])=[N:18][CH:19]=1
Reactant: COc1ccc2nccc(-c3ccc(CCN)nc3)c2n1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc2nccc(-c3ccc(CCNC(=O)c4ccc5c(n4)NC(=O)CS5)nc3)c2n1
Reaction time: 18 h
Yield: 78.4 %

Procedure:
To a stirred solution of (2-{5-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-pyridinyl}ethyl)amine hydrochloride salt (1.08 mmole) in DMF (25 mL) at RT was added diisopropylethylamine (0.75 mL, 4.32 mmole), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (0.23 g, 1.08 mmole), hydroxybenzotriazole hydrate (0.16 g, 1.19 mmole) and EDC (0.23 g, 1.19 mmole). After 18 h, the reaction contents were concentrated and dried under high vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.40 g, 79%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.55 (m, 1H), 9.19 (m, 1H), 9.09 (d, J=8.3 Hz, 1H), 8.53 (d, J=9.2 Hz, 1H), 8.42 (m, 1H), 8.23 (d, J=7.7 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.61 (m, 2H), 4.5 (s, 3H), 4.02 (m, 2H), 3.62 (m, 2H), 3.54 (m, 2H). LC-MS (ES) m/e 473 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(N3CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and morpholine. White solid. MS (m/e): 373.0 ([M+H]+, 100%).
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:18](Cl)=[C:17]([C:20]#[N:21])[C:16]([C:22]([F:25])([F:24])[F:23])=[N:15]2)=[CH:12][CH:13]=1)(=[O:7])=[O:6].[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30].[F-].[Cs+].Cl>CS(C)=O.C(#N)C.O>[C:20]([C:17]1[C:16]([C:22]([F:24])([F:23])[F:25])=[N:15][N:14]([C:11]2[N:10]=[CH:9][C:8]([S:5]([NH2:4])(=[O:6])=[O:7])=[CH:13][CH:12]=2)[C:18]=1[O:30][CH2:29][C:28]([CH3:32])([CH3:31])[CH3:27])#[N:21]
Reactant: CC(C)(C)CO
Reactant: CN(C)C=NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)COc1c(C#N)c(C(F)(F)F)nn1-c1ccc(S(N)(=O)=O)cn1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
6-[5-chloro-4-cyano-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid dimethyl-aminomethyleneamide (81.3 mg, 0.2 mmol) and 2,2-dimethyl-1-propanol (35.3 mg, 0.4 mmol) were dissolved in dry DMSO (0.5 ml) and cesium fluoride (60.7 mg, 0.4 mmol) was added to the solution. The resulting mixture was stirred at 20° C. for a period of 24 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (2 ml) and the resulting mixture was extracted with ethyl acetate (2 ml). The ethyl acetate mixture was filtered into a vial and evaporated to dryness under nitrogen atmosphere to leave a residue. Acetonitrile (2 ml) was added, and the mixture shaken to dissolve the residue. 2N HCl (1.5 ml) was added into the acetonitrile mixture, and the reaction mixture warmed to 70° C. for a period of 18 hours. After cooling down, the acetonitrile was evaporated under reduced pressure, and ethyl acetate (5 ml) was added to the evaporated mixture with stirring. The ethyl acetate layer was then separated, washed with saturated sodium chloride (5 ml), dried over magnesium sulfate and concentrated. HPLC purification of the residue obtained above gives the title compound. (37.6 mg, 46%). MS: 404.5, r.t.: 2.7.
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Cl:8])[N:7]=1.[CH2:27]([Sn](CC)(CC)CC)[CH3:28]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([CH2:27][CH3:28])[C:3](=[O:26])[N:4]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC[Sn](CC)(CC)CC
Reactant: O=C(Cn1c(-c2ccccc2)c(Cl)nc(Cl)c1=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1nc(Cl)c(-c2ccccc2)n(CC(=O)OCc2ccccc2)c1=O

Procedure:
A solution of benzyl (3,5-dichloro-2-oxo-6-phenylpyrazin-1(2H)-yl)acetate [Parlow et al. (2003) J. Med. Chem. 46, 4050-4062] (1.05 g, 2.70 mmol), tetraethyltin (0.641 mL, 3.24 mmol), and tetrakis(triphenylphosphine)palladium (31.0 mg, 0.027 mmol) in toluene (15 mL) was heated at reflux for 5.5 h. The solution was concentrated in vacuo and the crude product purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 90:10 to give the title compound. MS: m/z=383 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](Cl)=[O:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:51])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccc(Oc4ccccc4)c3)CN2C1=O
Yield: 15.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-phenoxybenzoyl chloride (122 μL, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 21 mg (16%) of 18-(3-phenoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.0% pure (HPLC), MS m/z 765 (M−H)−, HRMS: calcd. 767.2962 and found 767.2971 (M+H)+, mp 123-125° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2].[CH:61](OC)=[O:62]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:61]=[O:62])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: COC=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC=O)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (30 mg) is mixed with methyl formate (0.5 ml) and is stirred at 0° C. for 1 hr. The reaction mixture is allowed to warm to room temperature and then is stirred overnight. The excess methylformate is removed with nitrogen flow and the crude mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].C([O:12][CH:13](OCC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)C.C(OC(OCC)C1C=CC=C([N+]([O-])=O)C=1)C.[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(O)C.O.C(N(CC)CC)C>[CH:13]([C:14]1[CH:15]=[C:16]([NH:20][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])[CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: CCOC(OCC)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccn1
Agent: CCOC(OCC)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cccc(NC(=O)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of pyridine-2-carboxylic acid chlorid (6.5 g) in methylene chloride (75 ml) was added a mixture of triethylamine (6.3 g) and 3-aminobenzaldehyde diethylacetal (9.75 g); (3-aminobenzaldehyde diethylacetal was prepared by reducing (H2, Pd/C, MeHH) 3-nitrobenzaldehyde diethyl acetal, which in turn was made by acetalization of 3-nitrobenzaldehyde with triethylorthoformate and p-toluenesulfonic acid in ethanol). The mixture of the acid chloride and the primary amine was stirred at room temperature overnight, and poured carefully into cold water. The organic layer was separated, dried over anhydrous magnesium sulfate, and then all solvent removed. The residue was dissolved in tetrahydrofuran, and then dilute HCl solution (1N) was added until the acidic mixture remained homogeneous. This mixture was stirred at room temperature for one hour, and then most of the volatile solvent was removed. The aqueous solution was neutralized with NaHCO3, extracted with ethyl acetate, and the organic extract was washed with water and brine. All volatiles were removed, and the residual solid was crystallized from methanol-hexanes to give N-(3-formyl-phenyl)pyridine-2-carboxamide.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: CCCCCCC=O
Reactant: CN(C)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCCNc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 3.50 g of N,N-dimethyl-p-phenylenediamine, 4.592 g of heptanal, 9.095 g of triacetoxyborohydride, 1.841 g of acetic acid and 257 ml of dichloromethane was stirred at room temperature for one hour. A saturated sodium hydrogen carbonate solution is added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue obtained was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 2.819 g of N,N-dimethyl-N'-heptyl-p-phenylenediamine (yield: 39%, oily product, IR (film): 3375, 2927, 1519 cm-1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([NH2:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:36]=[CH:35][C:24]([CH2:25][N:26]2[C:30]([CH2:31][C:32](O)=[O:33])=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([NH:14][C:32](=[O:33])[CH2:31][C:30]2[N:26]([CH2:25][C:24]3[CH:35]=[CH:36][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)[CH:27]=[N:28][CH:29]=2)[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Reactant: COC(=O)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5-amino piperidine (134 mg, 0.520 mmol), [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid (147 mg, 0.520 mmol), HOBT (73,8 mg, 0.546 mmol), EDC (104 mg, 0.546 mmol), and Et3N (65.2 uL, 0.468 mmol) were dissolved in DMF (4 mL) and stirred at ambient temperature overnight. The solution was concentrated under reduced pressure and the residue was chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4OH) to give the title compound. 1H NMR (CDCl3) d 7.64 (d, 2H, J=8 Hz), 7.52 (s, 1H), 7.19 (d, 2H, J=8 Hz), 6.90-7.05 (m, 1H), 6.98 (s, 1H), 5.22-5.35 (m, 2H), 3.78-3.91 (m, 2H), 3.69 (s, 3H), 3,57-3.64 (m, 1H), 3.45-3.56 (m, 1H), 3.34 (s, 2H), 3.05-3.30 (m, 1H), 2.55-2.68 (m, 1H), 2.05-2.13 (m, 1H), 1.55-1.70 (m, 1H), 1.42 (s, 9H). FAB MS 482 (M+1)
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[N:27][CH:28]=1)[CH2:2][CH2:3][CH3:4].[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[N:27][C:26]([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 5 h

Procedure:
To a solution of 2-(5-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile (0.48 g) and rhodium acetate (dimer, 0.044 g) in toluene (5 mL) was added dropwise ethyl diazoacetate (0.52 mL), and the mixture was stirred for 5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.26 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[O:23][CH3:24])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[O:23][CH3:24])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(OC)c1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of 1.3 (2.22 g, 6.52 mmol) dissolved in pyridine (14 mL) was added 2,4-dichlorobenzenesulfonyl chloride (1.76 g, 7.17 mmol). The resulting red solution was stirred at room temperature for 30 min., after which time LC-MS indicated no 13 remained. The reaction solution was concentrated in vacuo on a rotary evaporator and the concentrate partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic separation was washed with water then brine. The organic extract was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford an orange oil. The product was isolated by chromatography on silica gel, eluting with ethyl acetate/hexane gradient, to afford a faint yellow solid. LC-MS ESI (pos.) m/z: 549.0 (100%), 551.0 (68%), 550.0 (28%) (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:31])C(=O)C1>CN(C)C=O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][C:3]=1[Cl:31]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)cnc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(Cl)c2Br)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E18) (409 mg, 1 mmol) was dissolved in N,N-dimethylformamide (DMF) (5 mL) and NCS (147 mg, 1.100 mmol) was added. The solution was stirred at RT for 24 h. Solvents were removed in vacuo and the residue was purified by flash chromatography (Isolera, 25 g, 0-100% ethyl acetate/iso-hexane) to afford crude product. This was further purified by MDAP to afford desired product in 215 mg.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([CH:11]([O:15][CH2:16][CH3:17])[O:12]CC)=[CH:7][C:8](=[O:10])[N:9]=2)[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>ClCCl>[Br:18][C:7]1[C:8](=[O:10])[NH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]=1[C:11]([O:15][CH2:16][CH3:17])=[O:12]
Reactant: CCOC(OCC)c1cc(=O)nc(C2CC2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1nc(C2CC2)[nH]c(=O)c1Br

Procedure:
To a solution of 2-cyclopropyl-6-(diethoxymethyl)-4(1H)-pyrimidinone (i.e. the title product of Step A) (2.9 g, 12.1 mmol) in dichloromethane (75 mL) was added N-bromosuccinimide (4.76 g, 26.8 mmol). The reaction mixture was stirred overnight. The solvent was removed with a rotary evaporator. The residue was purified by MPLC (1→4% methanol in dichloromethane as eluant) to afford the title compound as a white solid (2.68 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:14](=O)[CH2:15]Br)([CH3:10])([CH3:9])[CH3:8].N.O>C(O)C>[C:22]([C:19]1[CH:18]=[C:13]([C:14]2[N:1]=[C:2]3[N:6]([CH:15]=2)[CH:5]=[CH:4][S:3]3)[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:20]=1[OH:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1nccs1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2cn3ccsc3n2)cc(C(C)(C)C)c1O
Yield: 38.3 %

Procedure:
In 20 ml of ethanol were dissolved 1.2 g of 2-aminothiazole and 3.9 g of 3,5-di-tert-butyl-4-hydroxyphenacyl bromide, and the solution was refluxed for 2 hours. The reaction mixture was neutralized by the addition of aqueous ammonia and added 30 ml of water. The crystals thus precipitated were recovered by filtration and recrystallized from ethanol to provide 1.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]thiazole.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:50])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:40](=[O:49])[NH:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:29][CH:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])C)C1C=CC=CC=1>CO>[CH2:42]([NH:41][C:40]([N:28]1[CH2:29][CH:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:24]2[N:23]([C:21](=[O:22])[CH:16]([NH:15][C:14](=[O:50])[CH:12]([NH:10][CH3:9])[CH3:13])[C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:27][CH2:26][CH:25]12)=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)NCc1ccccc1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)NCc1ccccc1)C(C)(C)C
Reaction time: 1 h

Procedure:
A solution containing 50 (0.53 mmol) and NH4OAc (25 mg, 0.27 mmol) in MeOH (10 mL) was treated with 10% Pd-on-carbon (wet, 60 mg, 0.05 mmol) and the stirred mixture was purged with hydrogen. After 1 h stirring under a balloon of hydrogen, TLC analysis (10:1 DCM/MeOH) indicated the reaction was complete. The catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 10-60% ACN/water containing 0.1% HOAc over 25 min; Flow: 40 mL/min). Fractions containing pure product were combined, frozen, and lyophilized to provide 251 mg (84%, 2 steps) of 51 as a floculent white powder.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[C:16]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][CH3:16])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC1CCN(C)C(=O)N1c1nnc(C)s1

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxy-2(1H)-pyrimidinone.