Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20][OH:21]>>[CH3:20][O:21][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Reactant: CO
Product: COCC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
To a solution of 176 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane in 10 ml of methanol was added 2 g of dry neutral alumina, and the mixture was heated under reflux for 16 hours. After filtration of the alumina, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 96 mg of (2RS, 3S)-3-carbobenzoxyamino-2-hydroxy-5-methylhexyl methyl ether as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[CH2:12]([Zn]CC)C.ICI.[Cl-].[NH4+]>ClCCl.O>[CH3:11][C:2]1([CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[OH:4])[CH2:12][CH2:1]1
Reactant: C=C(C)C(O)c1cccnc1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: ICI
Product: CC1(C(O)c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.3 %

Procedure:
In dichloromethane (40.0 mL) was dissolved 2-methyl-1-(pyridin-3-yl)prop-2-en-1-ol (1.04 g, 6.95 mmol) obtained in Step 1. Diethylzinc (1.09 mol/L solution in n-hexane, 31.9 mL, 34.7 mmol) and diiodomethane (2.80 mL, 34.7 mmol) were added dropwise at −10° C. and the mixture was stirred at 0° C. for 2.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give (1-methylcyclopropyl)(pyridin-3-yl)methanol (888 mg, 78% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:21][N:20]1[C:15]2[C:14](=[O:25])[NH:13][C:12]([CH2:11][C:10]3[CH:26]=[CH:27][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)=[N:17][C:16]=2[C:18]([CH2:22][CH2:23][CH3:24])=[N:19]1
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NS(C)(=O)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (43 μl, 0.00055 mol) was added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (150 mg, 0.0005 mol) in pyridine (5 ml), and the reaction stirred at room temperature, under a nitrogen atmosphere for 2 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:20]([O:22][CH3:23])=[O:21]>CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cccs1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cccs1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(2-thienyl)-propionate (Bachem), the title compound was prepared as a solid (mp=145-147° C.). The reaction was monitored by tlc (Rf=0.9 in 100% EtOAc) and the product was purified by preparative tlc using EtOAc as the eluent.
Reaction SMILES: N1C=CC=CC=1.C(O[C:11](=[O:13])[CH3:12])(=O)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[N:22]2[CH2:25][C:24](=[CH:26][S:27]([CH2:30][C:31]3[CH:32]=[C:33]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH:34]=[CH:35][CH:36]=3)(=[O:29])=[O:28])[CH2:23]2)=[CH:17][CH:16]=1>C(OCC)(=O)C.O>[C:11]([N:40]1[CH2:41][CH2:42][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][S:27]([CH:26]=[C:24]3[CH2:23][N:22]([CH:21]([C:18]4[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=4)[C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[CH2:25]3)(=[O:28])=[O:29])[CH:32]=2)[CH2:38][CH2:39]1)(=[O:13])[CH3:12]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 23 h
Yield: 89.4 %

Procedure:
2 cm3 of pyridine and then 11.5 mg of acetic anhydride are successively added, at a temperature close to 20° C., to 54 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 23 hours at a temperature close to 20° C., the reaction medium is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 30° C. The residue obtained is taken up in 5 cm3 of ethyl acetate and 2 cm3 of water. After separating after settling out, the organic phase is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 52 mg of 4-acetyl 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a beige foam [1H NMR spectrum (300 MHz, CDCl3), δ in ppm): 2.16 (s, 3H), 2.77 (s, 3H), from 3.10 to 3.25 (mt, 4H), 3.63 (broad t, J=5.5 Hz, 2H), 3.78 (broad t, J=5.5 Hz, 2H), 3.82 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8 Hz, 1H), 6.92 (dd, J=8 and 2 Hz, 1H), 7.02 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][O:11][CH3:12])[C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1ccc(F)cc1
Solvent: C1CCOC1
Product: COCCN(C(=O)n1ccnc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 28 h

Procedure:
To a 50 mL round-bottomed flask was added 4-fluoro-N-(2-methoxyethyl)-benzenamine (512 mg, 3026 μmol, from step 1), 1,1′-carbonyldiimidazole (736 mg, 4539 μmol, Aldrich), THF (2 mL). The reaction mixture was stirred at 80° C. for 28 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(4-fluoro-phenyl)-N-(2-methoxyethyl)-1H-imidazole-1-carboxamide. MS (ESI pos. ion) m/z: 264 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:4]([O:6]N1C(=O)CCC1=O)=O.[NH2:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:3]([C:4]([NH:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:6])[C@@H:2]([CH3:1])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
20.2 g of Z-Thr(tBu)-OSU, 13.3 g of H-Phe-Pro-OH (monohydrate) and 6.54 ml of triethylamine are dissolved in 80 ml of dimethylformamide, allowed to stand overnight at about 20° C. and then concentrated in a high vacuum until a sticky mass forms. The latter is dissolved in 500 ml of ethyl acetate and washed five times with 200 ml at a time of 5 % strength tartaric acid solution and subsequently with water until neutral. The organic phase is concentrated to dryness and the remaining solid foam is powdered and dried in a high vacuum at 40° C. On twice reprecipitating from ethyl acetatepetroleum ether 13.3 g of amorphous chromatographically pure tripeptide derivative having an unsharp melting range at about 75°- 85° C. are obtained. In a thin layer chromatogram on silica gel Rf115 = 0.68; Rf121A = 0.57.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1cc2ccccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2nc1-c1ccccc1OC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 2-chloroquinoline-3-carboxylate (2.01 g, 10 mmol), prepared as described in the Journal of Organic Chemistry 2003, 68, 9517-9520, 2-methoxyphenylboronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=1[O:4][CH2:3][C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1OCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccccc1OCC(F)(F)F

Procedure:
To a solution of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (210 mg) in methylene chloride (1 ml) were added triethylamine (186 μl) and methanesulfonyl chloride (83 μl) with stirring under ice cooling, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (2/1) as eluent to give 273 mg of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methansulfonate melting at 40.5°-42.0° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]([Br:15])=[CH:13][N:14]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[Br:15][C:12]1[S:11][C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[N:14][CH:13]=1
Reactant: CC(=O)N1CCN(c2ncc(Br)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Brc1cnc(N2CCNCC2)s1
Yield: 87.7 %

Procedure:
4-Acetyl-1-(5-bromothiazol-2-yl)piperazine (2.0 g) was dissolved in 6N hydrochloric acid and refluxed under heating for 4.5 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (1.5 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (1.1 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.C([O:13][C:14]1[CH2:18][CH2:17][C:16](=O)[CH:15]=1)C.Cl>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:16]2[CH2:17][CH2:18][C:14](=[O:13])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCOC1=CC(=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-methoxyphenylmagnesium bromide (1M in THF) (30 ml, 30.0 mmol) was added dropwise 3-ethoxycyclopent-2-en-1-one (3.56 ml, 30.0 mmol). The reaction mixture was stirred at RT overnight. 1M aqueous hydrochloric acid and EtOAc were added. There was emulsion. The biphasic mixture was filtered through a Celite® pad. Extracted filtrate three times with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The Celite®/filtered solids were stirred in EtOAc/combined aqueous layers. The solids were filtered, separated filtrate layers, and extracted aqueous once more with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The two crude product batches were combined and purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. Mass spectrum (ESI) 189.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (200 mg, 0.42 mmol) in DCM (5 mL) solution were added ethyl 2-aminoacetate (65 mg, 0.63 mmol), HATU (238 mg, 0.63 mmol) and iPr2NEt (0.22 mL, 1.25 mmol). The mixture was stirred at room temperature for 16 hs. The solvent was removed under vacuum. The residue was purified via silica gel column (EtOAC/Hexanes 20% to 40%) to give ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (240 mg, 100%) as white solid. LC-MS (Condition A), MS m/z 565.1 (M++H).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[C:7](OCC)(=[O:10])[C:8]#[CH:9]>CN(C=O)C>[CH3:1][C:2]1[NH:6][C:7](=[O:10])[CH:8]=[CH:9][C:3]=1[C:4]#[N:5]
Reactant: C#CC(=O)OCC
Reactant: C/C(N)=C\C#N
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
(Synthesis 1991, 894-896.) 3-Aminocrotonitrile (29, 2.9 g, 36 mmol) and ethyl propiolate (30, 3.0 mL, 36 mmol) were dissolved in dry DMF (17 mL). The reaction mixture was stirred for 1 h at room temperature, and the mixture was heated at reflux for 3 d. The precipitate formed after cooling to room temperature was collected, washed with methanol (5 mL), ether (10 mL), and dried to yield 131 (1.5 g, 31%): mp>300° C. 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.58 (d, J=9.6 Hz, 1H), 6.23 (d, J=9.6 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:15]Br>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Br:15])[CH:8]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(O)c(Br)c1
Reaction time: 0.08 h

Procedure:
To a solution of (4-hydroxy-phenoxy)-acetic acid ethyl ester (0.59 g, 3 mmol) in acetic acid (1.5 mL) is added bromine (0.48 g, 9 mmol) in acetic acid (0.5 mL) at room temperature. After 5 min, solvent is evaporated and purified by column chromatography on silica gel giving the title compound (0.6 g).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:12]([I:27])=[C:13]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].[Cu][C:29]#[N:30].[C-]#N.[K+].N>O.C(O)(=O)C>[C:29]([C:11]1[C:12]([I:27])=[C:13]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17])#[N:30]
Reactant: N#C[Cu]
Reactant: CC(=O)NCc1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCc1c(I)c(C#N)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
14 g of sodium nitrite is introduced under stirring into 170 ml of a concentrated sulfuric acid held at +5° C. The mixture is then maintained at +70° C. until solution has occurred, and then cooled to +5° C. After adding dropwise 84 ml of glacial acetic acid under cooling, 93.6 g of 5-amino-3-acetylaminomethyl-2,4,6-triiodobenzoic acid is added in incremental portions, maintaining the reaction temperature between 0° C. and +5° C. The reaction mixture is stirred for another 2 hours, poured on 800 g of ice, and, under cooling, introduced into a solution of 71 g of copper(I) cyanide and 133 g of potassium cyanide in a mixture of 1 1 of concentrated ammonia and 640 ml of water. After several hours of stirring in an ice bath, the precipitated ammonium salt is vacuum-filtered and dissolved in 4 l of water. After filtration over active carbon, the filtrate is adjusted to pH 6 with acetic acid, again extracted with active carbon, filtered, and the filtrate combined with excess concentrated hydrochloric acid. The thus-separated precipitate is dried at 50° C., thus obtaining 80.5 g (=85% theory) of 5-cyano-3-acetylaminomethyl-2,4,6-triiodobenzoic acid as a white powder, mp 271° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](=[O:35])N(OC)C)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:35])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cccc2scnc12
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2sc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)nc12
Yield: 60 %

Procedure:
To a solution of 4-methoxybenzothiazole (413 mg, 2.5 mmol) in THF (10 ml) at −75° C. was added dropwise n-BuLi (2.5M in Hex, 1.1 ml) such that the temperature did not exceed −70° C. The brown solution was stirred at this temperature for 15 min before the dropwise addition of a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (680 mg, 2.5 mmol) in THF (2 ml). The temperature was also kept below −70° C. The brown solution was then gradually allowed to reach RT (over 3 h). The mixture was poured on water and extracted with EtOAc. Organic extracts were washed with brine and dried over MgSO4 and concentrated. Chromatography on SiO2 (hex/EtOAc 2:1) gave 565 mg (60%) of a yellowish solid.
Reaction SMILES: C(O)(=O)C.C([CH2:7][C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1)([CH3:12])[C:9]([OH:11])=[O:10])C.[NH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[SH:30].C([O-])(=O)C.[Na+]>O.C(OCC)(=O)C>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]2[S:30][C:20]([C:17]3[CH:16]=[CH:15][C:14]([O:13][C:8]([CH3:7])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:19][CH:18]=3)=[N:22][C:23]=2[CH:28]=1
Reactant: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Reactant: Nc1cc(Cl)ccc1S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ccc(-c2nc3cc(Cl)ccc3s2)cc1)C(=O)O
Yield: 35.3 %

Procedure:
In an acetic acid (0.37 mL) solvent, a mixture including Compound 97c (78.2 mg, 0.38 mmol), 2-amino-4-chlorobenzenethiol (60.0 mg, 0.38 mmol), and sodium acetate (NaOAc) (93.6 mg, 1.13 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was evaporated under reduced pressure. The produced precipitate was filtered, and washed with methylene chloride to obtain Compound 99 (46.6 mg, 39.6%).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH:9]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([CH2:22][CH2:23][CH3:24])[N:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38]([NH:41]C(C)(C)C)(=[O:40])=[O:39])=[CH:28][CH:27]=1)[C:15]2=[O:46])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[CH:9]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([CH2:22][CH2:23][CH3:24])[N:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38]([NH2:41])(=[O:40])=[O:39])=[CH:28][CH:27]=1)[C:15]2=[O:46])([CH3:10])[CH3:11]
Reactant: CCCC1Nc2ccc(C(C)C)cc2C(=O)N1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCC1Nc2ccc(C(C)C)cc2C(=O)N1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anisole is added to a stirred solution of the compound from Step 1 (0.554 mmol) in trifluoroacetic acid (6 ml) under nitrogen at room temperature. The solution is stirred at room temperature for 8 h then the solvent removed in vacuo. Flash chromatography affords the titled product.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:1])=[O:28])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(C(=O)O)cn2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cnc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
(Trimethylsilyl)diazomethane, 2M in hexanes (4.19 ml, 8.38 mmol) was added dropwise to 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (1.28 g, 4.19 mmol) in toluene (12 ml) and methanol (3.00 ml) at 25° C. over a period of 2 mins under nitrogen. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with the dropwise addition of acetic acid until bubbling ceased, then the reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was removed and the aqueous further extracted with EtOAc (2×50 mL). The combined organics were washed with sodium hydrogen carbonate solution (100 mL), water (100 mL), brine (100 mL) and dried over MgSO4, filtered and evaporated to afford methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (1.182 g, 88%) as a yellow solid. This was used directly with no further purification.