Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O.O1CCOCC1>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: Oc1ccccc1
Agent: BrBr
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 61 %

Procedure:
A mixture of 4.00 g (40 mmol) of hydantoin, 6.4 g (40 mmol) of bromine, 0.01 g of methanesulfonic acid, and 30 ml of dioxane was heated to a temperature of 100° C. with stirring for 3 minutes. The reaction mixture was further stirred at a temperature of 50° C. until bromine disappeared. To the reaction mixture was then added 7.52 g (80 mmol) of phenol. The reaction mixture was then heated to a temperature of 50° C. with stirring for 4 hours. The reaction mixture was then allowed to cool to room temperature. The reaction mixture was further cooled over an ice bath for 2 hours. The resulting crystal was recovered by filtration, washed thoroughly with water, and then air-dried to obtain 4.69 g (24.4 mmol; yield: 61%) of 5-(p-hydroxyphenyl)-hydantoin in the form of white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20].Cl.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
38.80 g. of ethyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyrate and 50 ml. of 25% strength hydrochloric acid are warmed to 125° for 45 minutes. The cooled solution is adjusted to pH 5 with sodium acetate and extracted with chloroform. The organic extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is recrystallized from chloroform/ether, whereupon 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyric acid, m.p. 115°, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=[S:15])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.[CH3:18]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([S:15][CH3:18])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CSC1=Nc2ccc(F)cc2Nc2sc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Stir 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (61.5 g, 0.233 mol) and DMF (310 mL) under nitrogen for 15 minutes at ambient temperature. Add powdered potassium carbonate (67.7 g, 0.490 mol); stir 15 minutes at ambient temperature. Add iodomethane (22 mL, 0.35 mol); stir 4 hours at ambient temperature. Cool to 0-5° C. and add deionized water (150 mL) dropwise, keeping the temperature below 15° C. Extract the product with ethyl acetate. Wash the organic solution with brine four times, then dry over magnesium sulfate, filter and concentrate under reduced pressure to give 74.0 g of crude product. Purify by flash chromatography, eluting with 2:1/methylene chloride:heptane, then methylene chloride to give 55.0 g (85%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.11 (bs, 1H), 6.87 (m, 1H), 6.73 (m, 1H), 6.50 (s, 1H), 6.44 (m, 1H), 2.41(s, 3H), 2.25 (s, 3H). HRMS (ES) exact mass M+H calcd for C13H11FN2S2 279.0426; found 279.0416.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([NH:35][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-(4-chloro-phenyl)-C-phenyl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C25H24ClNO5 [M+H]+: 454.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[CH2:36][O:37][CH2:38][C:39]#[CH:40])[O:7][C@@H:6]1[CH2:41][O:42][C:43](=[O:45])[CH3:44])(=O)C.O[Li].O>C1COCC1.CO.O>[C:43]([O:42][CH2:41][C@@H:6]1[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([OH:15])[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[CH2:36][O:37][CH2:38][C:39]#[CH:40])[O:7]1)(=[O:45])[CH3:44]
Reactant: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#CCOCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethoxybenzyl)-2-((prop-2-ynyloxy)methyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (prepared using methods analogous to those in Example 1 and Example 5 above, 251 mg, 0.39 mmol) in THF:MeOH:H2O (2:3:1, 6.0 mL) at 15° C., was added LiOH.H2O (16.4 mg, 0.39 mmol). After stirring for 5 h at room temperature, the reaction was complete, as indicated by HPLC. The reaction mixture was concentrated and the residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed with brine (20 mL), 5% KHSO4 in brine (20 mL), dried over anhydrous sodium sulfate, evaporated, and the residue was purified by preparative TLC (PE:EtOAc:MeOH=8:80:1, Rf=0.45) to afford 160 mg of title compound as a white solid (yield 79.2%; purity 99.1%, as determined by HPLC). 1H-NMR (CD3OD, 400 MHz) δ 7.48 (s, 1H), 7.40 (s, 1H), 7.12 (s, 4H), 4.85 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.51 (d, J=9.2 Hz, 1H), 4.23 (s, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.96 (q, J=6.8 Hz, 2H), 3.88 (d, J=12.4 Hz, 1H), 3.71-3.67 (m, TH), 3.52-3.41 (m, 4H), 2.94 (s, 1H), 2.15 (s, 3H), 1.34 (t, J=6.8 Hz, 3H); LC-MS (m/z) 519 [(M+1)+], 563 [(M+45)−].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:18])[CH:12]([N+:15]([O-:17])=[O:16])[CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:19](OC(=O)C)(=[O:21])[CH3:20].[C:26](Cl)(=[O:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([O:18][C:26](=[O:28])[CH3:27])[CH:12]([N+:15]([O-:17])=[O:16])[CH2:13][O:14][C:19](=[O:21])[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(O)C(CO)[N+](=O)[O-])cc1OC
Product: COc1ccc(C(OC(C)=O)C(COC(C)=O)[N+](=O)[O-])cc1OC
Temperature: 50 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
A mixture of 12.85 g (0.05 moles) of 1-(3,4-dimethoxyphenyl)-2-nitro-1,3-propanediol, 20.4 g of acetic anhydride and 3.92 g of acetyl chloride is stirred at 50° C. for 5 hours. The mixture is cooled and poured onto ice. The resulting oily substance is washed twice with ice-cold water and decanted. Crystallization sets in after adding 20 ml of isopropanol to the substance. The separated crystalline product is filtered off, washed thrice with 5 ml of isopropanol and 10 ml of n-hexane, each, and dried. 11.1 g (65.1%) of the title compound are obtained; m.p.: 85°-88° C.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1)#[N:2].[H][H]>N>[NH2:2][CH2:1][C@H:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1
Reactant: CC1=CC[C@@H](C#N)CC1
Reactant: [H][H]
Agent: N
Product: CC1=CC[C@@H](CN)CC1
Yield: 88 %

Procedure:
605 g of 4(5)-cyano-1-methylcyclohexene were dissolved in 500 ml of liquid ammonia in a stirrer autoclave and hydrogenated at 90° C. and at a hydrogen pressure of 100 bar over 40 g of Raney nickel iron. After evaporating the ammonia, the mixture was filtered from the catalyst and distilled under vacuum. 550 g (88%) of 4(5)-aminomethyl-1-methylcyclohexene, b.p.10 78° to 80° C. were obtained. The ratio by weight of the 4- and 5-isomers was about 80:20.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(F)c(F)cc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(F)c(F)cc12

Procedure:
Beginning with (5,6-difluoroindol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-:22].[K+].[K+].Cl>O1CCCC1.O>[CH:13]([O:22][CH:7]([CH3:6])[CH3:2])([CH3:20])[CH3:14].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(C)C
Product: O=[N+]([O-])c1cc(F)ccc1NCc1ccc(Cl)cc1
Yield: 158.3 %

Procedure:
30 g of 2,5-difluoronitrobenzene and 26.7 g of 4-chlorobenzylamine are dissolved in 300 ml of tetrahydrofuran. 40 g of potassium carbonate are added to this solution and the mixture is refluxed for 8 hours. After cooling, the reaction mixture is added to 1.7 l of water and 50 ml of concentrated hydrochloric acid. The crystals obtained are filtered off and washed with water and then with isopropyl ether to give 41.9 g of 2-(4-chlorophenylmethylamino)-5-fluoronitrobenzene in the form of crystals melting at 160° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2)[CH:9]=1.C1C(=O)N([I:46])C(=O)C1>C(#N)C>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:46])=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Solvent: CC#N
Product: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (450 mg, 0.81 mmol) was dissolved in ACN (15 mL) and NIS (200 mg, 0.88 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified with column (silica gel, 10% EtOAc/Hexane) gave the product, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (541 mg) as yellowish oil. HPLC-MS tR=2.96 min (UV254 nm); mass calculated for formula C27H41IN4O5Si2 684.2, observed LCMS m/z 685.2 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[Cl:9][C:7]1[CH:6]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH3:33])=[O:31])[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Methyl 2-(3,5-dichlorophenyl)piperidine-4-carboxylate hydrochloride (4.8 g, 14.79 mmol) was dissolved in DCM (41.5 mL) and DIPEA (6.46 mL, 36.97 mmol). Methyl chloroformate (1.374 mL, 17.74 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with 0.3 M HCl and brine. The organic layer was filtered through a phase separator and evaporated to give dimethyl 2-(3,5-dichlorophenyl)-piperidine-1,4-dicarboxylate (5.3 g) as an oil. MS m/z 346 (M+H)+
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH2:13][CH2:14][CH3:15]>CN(C=O)C>[CH2:13]([N:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1)[CH2:14][CH3:15]
Reactant: c1cc2cc[nH]c2cn1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccc2ccncc21

Procedure:
A solution of 1H-pyrrolo[2,3-c]pyridine (10 mmol) in DMF cooling on an ice bath was treated with NaH (143 mmol). After stirred at room temperature for thr iodopropane (26 mmol) was added dropwise. The mixture was allowed to react at room temperature for further 3 hrs. Upon cooling on an ice bath the mixture was quenched with 20 mL H2O, followed by extraction with diethyl ether (5×50 mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and dried on a high vacuum to give 1-propyl-1H-pyrrolo[2,3-c]pyridine as orange oil. MS (ESI+) m/z 161.1063 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[NH:5][NH:6][C:7](=[O:9])[CH:8]=1)([OH:3])=[O:2].[C:10](OCC)(=O)[CH2:11]C(C(OCC)=O)=O.NN>>[C:1]([C:4]1[N:5]=[N:6][C:7](=[O:9])[CH:8]=1)([O:3][CH2:10][CH3:11])=[O:2]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=C(O)c1cc(=O)[nH][nH]1
Agent: NN
Product: CCOC(=O)C1=CC(=O)N=N1

Procedure:
3-carboxy-1H-pyrazol-5-one, for example, can thus be prepared by reacting diethyl oxalacetate with hydrazine to yield 3-(carboethoxy)-pyrazol-5-one, followed by refluxing in aqueous HCl solution to hydrolyze the ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10]([NH:12][C:13](=[N:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)OC1C=CC=CC=1)#[N:11].C(=O)(O)[O-].[Na+].C(#N)C>CN1C(=O)CCC1.CCN(C(C)C)C(C)C>[NH2:11][C:10]1[N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:9]=[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=2)[N:12]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CC(=O)Nc1ccc(N=C(NC#N)Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(Nc2nc(N)n(-c3ccnc(Cl)c3)n2)cc1
Temperature: 220 °C
Yield: 85.3 %

Procedure:
A microwave reaction vessel was charged with 1.34 g of (2-Chloro-pyridin-4-yl)-hydrazine (7.48 mmol, 1.1 equiv) and 2.00 g of N-cyano-N′-(4-acetamidophenyl)-O-phenylisourea (6.80 mMol, 1 equiv). The solids were dissolved in 40 mL of NMP and 8 mL of DIEA. The sealed vessel was warmed to 220° C. for 6 min via microwave irradiation. Upon cooling, the resulting solution was poured into 200 mL of saturated sodium bicarbonate. The precipitate was collected and washed with 3×100 mL of water. After azeotropic drying (3×50 mL of acetonitrile) the dark yellow solid (2.0 g, 5.80 mMol, 85% yield) was used without further purification. 1H NMR (500 Mhz, DMSO-d6) δ 9.68 (1 H, s), 9.00 (1 H, s), 8.40 (1 H, d), 7.67 (2 H, m), 7.50 (2 H, d), 7.40 (2 H, d), 6.95 (2 H, s), 2.0 (3 H, s) ppm. LCMS: 2.16 minutes/343.95 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C.CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(OC)n1
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-2,6-dimethoxy-pyrimidine (1.92 g, 11.0 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.64 g, 13.20 mmol, 1.2 equiv) and N-ethyl diisopropylamine (2.24 mL, 1.71 g, 13.20 mmol, 1.2 equiv) in acetonitrile (8 mL) and DMAc (2 mL) was heated by microwave irradiation to 160° C. for 1 h and then to 180° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.22 g (33%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.39-1.48 (m, 2H), 1.46 (s, 9H), 1.97-2.00 (m, 2H), 2.85-2.96 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 3.96-4.02 (m, 3H), 5.52 (d, J=7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 28.16, 31.48, 42.39, 47.95, 53.12, 53.76, 79.24, 100.51, 154.40, 164.60, 164.99, 171.52. MS (ISP): 339.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:9]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:38]([O:37][C:35]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][NH2:14])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reaction time: 18 h
Yield: 97.7 %

Procedure:
A solution of benzyl (5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate (15.5 g, 26.8 mmol) and 10% Pd/C (12.0 g) in EtOH (175 mL, SureSeal from Aldrich), was hydrogenated at 55 psi overnight. After 18 h, another 4 g of 10% Pd/C was added and the reaction hydrogenated at 55 psi for another 18 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (12.0 g). MS 459.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:39][CH3:37])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(C)COC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.4 %

Procedure:
A mixture of {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg), methylamine hydrochloride (100 mg), triethylamine (120 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 62%) as pale yellow prisms. MS 533 (MH+). mp 107-109° C.
Reaction SMILES: Cl[C:2]1[C:6]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[N:5][S:4][N:3]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:7]1([C:6]2[C:2]([O:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:3][S:4][N:5]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Clc1nsnc1-n1ccnc1
Reactant: OCCN1CCCC1
Product: c1cn(-c2nsnc2OCCN2CCCC2)cn1

Procedure:
Following the procedures of Example 1, the title compound is prepared from 3-chloro-4-(1H-imidazol-1-yl)-1,2,5-thiadiazole and 1-(2-hydroxyethyl)pyrrolidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]3)[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-methylthiophenylboronic acid (240 mg; 1.43 μmol) in dichloromethane (6 mL) was treated with activated powdered 4 Å molecular sieves (1.5 g), Cu(OAc)2 (87 mg; 0.477 mmol), tert-butyl 4,4′-bipiperidine-1-carboxylate (128 mg; 0.477 mmol) and triethylamine (134 μL; 0.954 mmol). The reaction vessel was purged with oxygen and the mixture stirred under an oxygen atmosphere at ambient temperature for 18 hr. The now brown mixture was filtered through Celite. The eluant was adsorbed onto silica gel. The silica gel was exhaustively eluted without fractionation (1:1 hex/MTBE). The eluant was evaporated to a yellow oil and chromatographed (PTLC; 2:1 hex/MTBE). The major band was collected affording the title compound. LRMS calc: 390.2 obs: 391.1 (M+H), 291.1 (M-BOC+H).