Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[O-:18][CH2:19][CH3:20].[Na+]>C(O)C>[CH2:19]([O:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=2)=[CH:4][CH:3]=1)[CH3:20]
Reactant: NCCCCc1nc(-c2ccc(Cl)nc2)c[nH]1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2c[nH]c(CCCCN)n2)cn1
Temperature: 130 °C
Yield: 87 %

Procedure:
To a solution of 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine (825 mg, 3.3 mmoles) in ethanol (15 ml) was added sodium ethoxide (2.24 g, 33 mmoles). The reaction mixture was heated in a sealed vessel in a 130° C. oil bath for 48 hours; upon cooling more sodium ethoxide was added (1.0 g) and the closed vessel was heated at 150° C. for 48 hours more. Upon cooling the reaction mixture was concentrated and than was taken up in dichloromethane (200 ml) and was washed with water (50 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-ethoxy-3-pyridyl)imidazolyl]butylamine (747 mg, 87%). MH+(261).
Reaction SMILES: [CH:1]12[S:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=O)[CH2:2]2.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:3]1[CH2:4][CH:5]2[S:8][CH:1]([CH2:7][CH2:6]2)[CH2:2]1
Reactant: O=C1CC2CCC(C1)S2
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CC4CCC(C3)S4)c[nH]c12
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 A molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([CH:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:36])[C:33]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[S:9])[O:8][C:4]=3[CH:3]=2)=[O:34])[CH2:30][CH2:31]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc2[nH]c(=S)oc2c1
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc2[nH]c(=S)oc2c1)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a stirred solution of 0.3 g (1.8 mmol) of 6-amino-3H-benzoxazole-2-thione [J. Org. Chem., 19; 758. (1954)] and 0.6 ml (4.3 mmol) of triethylamine in 20 ml of chloroform 0.5 g (1.8 mmol) of (4-benzyl-piperidine-1-yl)-oxo-acetyl chloride (Example 38c) in 10 ml of chloroform is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and the organic layer is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.46 g (61.9%) of the title compound. Melting Point: 203° C. (isopropanol)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2C=[CH:19][CH:18]=[CH:17]2)=[CH:12][C:11]=1[Cl:21]>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:17]=[CH:18][CH:19]=[C:2]2[CH:1]=[O:5])=[CH:12][C:11]=1[Cl:21]
Reactant: COC(=O)c1ccc(-n2cccc2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2cccc2C=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMF (0.1 mL) in CH2Cl2 (2 mL) was added dropwise with stirring to a solution of oxalyl chloride (0.2 mL) in CH2Cl2 (16 mL) at −30° C. under N2. The mixture was stirred for 15 min and a solution of 2-chloro-4-(1-pyrrolyl)benzoic acid methyl ester (0.5 g) in DMF (4 mL) was added. The mixture was stirred at that temperature for 3 h and allowed to warm to room temperature. The mixture was stirred overnight and evaporated. The residue was partitioned between EtOAc and 0.2 M NaOAc. The EtOAc layer was separated and the aqueous solution was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 3/1) to yield 2-chloro-4-(2-formyl-1-pyrrolyl)benzoic acid methyl ester (0.41 g). ESMS: 264 (MH+).
Reaction SMILES: Cl[C:2]1([NH2:14])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[N+]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.C(O)C.[Cu]>[O:24]([C:2]1([NH2:14])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: NC1(Cl)C=C([N+](=O)[O-])C=CC1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCO
Product: NC1(Oc2ccccc2)C=C([N+](=O)[O-])C=CC1C(=O)O

Procedure:
2-Chloro-4-nitroanthranilic acid (40.2 g, 0.2 mol) is stirred in nitrobenzene (250 mL) with 3-nitrophenol (31 g, 0.22 mol), potassium carbonate (42 g, 0.3 mole), copper bronze (1 g) and cuprous iodide (1 g) at 155° C. for 6 hours. The pure product is obtained by recrystallization in ethyl alcohol to give 2-phenoxy-4-nitroanthranilic acid. (See Goldberg, Walker, J. Chem. Soc. (1953), 1348).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:10])=[O:11]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenol (642 mg, 2.0 mnol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (690 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 7.92 (d, J=8.0 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.34 (t, J=8.0 Hz, 1 H), 6.62 (s, 1 H), 6.55 (s, 1 H),6.50(s, 1 H),4.02(t,J=6.0Hz,2H),3.82(t,J=5.7Hz,2H),2.26(s,3 H), 1.99 (m, 2 H), 1.58 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:31]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[CH:30][C:29]([F:47])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(OCC)(=O)C>[F:47][C:29]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[C:14]4[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[C:31]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:44])([CH3:45])[CH2:39][C:40]=43)[C:33]2=[O:46])[CH:30]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 135 °C
Yield: 37.2 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 146a (210 mg, 0.6 mmol), 230a (460 mg, 0.9 mmol), 1,2-dimethoxyethane (8 mL) and 1M aqueous sodium carbonate (2 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (36 mg, 0.03 mmol) was added. The mixture was heated in microwave to 135° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride/diethyl ether/methanol to afford a 37% yield (140 mg) of 246a.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[C:17]1([CH2:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8]([NH:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(=O)Cl)(c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC(C(=O)NCc2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
1-Methyl-4-phenyl-4-piperidinecarbonyl chloride (0.49 mol) was added portionwise at room temperature to a stirring mixture of benzenemethanamine (0.49 mol) and triethyl amine (1.223 mol) in CH2Cl2 (2500 ml). The mixture was stirred at room temperature for 1 hour. K2CO3 (150 g) and H2O were added. The mixture was stirred and separated into its layers. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding 144 g of 1-methyl-4-phenyl-N-(phenylmethyl)-4-piperidinecarboxamide (95%) (interm. 12).
Reaction SMILES: F[C:2]([F:7])(F)[C:3](O)=O.[F:8][C:9]1[C:14]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(OCCF)(=O)=O>C(#N)C>[F:8][C:9]1[C:14]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:3][CH2:2][F:7])[CH2:17][CH2:16]2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: Fc1nccnc1C1CCNCC1
Reactant: O=C(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FCCN1CCC(c2nccnc2F)CC1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
In a glass microwave vial containing 2-fluoro-3-(piperidin-4-yl)pyrazine 2,2,2-trifluoroacetate (0.2 g, 0.68 mmol), cesium carbonate (0.12 mL, 1.5 mmol) was added 2-fluoroethyl tosylate (0.22 mL, 1.0 mmol) and Acetonitrile (2.5 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N C) at 120° C. for 10 min (300 watts, Powermax feature on), then at the same temperature for another 10 min. LCMS showed desired product formation 104960-15-1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9]CO)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C(C)=CC=CC=1C.[F:20][C:21]([F:34])([F:33])[S:22]([O:25]S(C(F)(F)F)(=O)=O)(=[O:24])=[O:23]>ClCCl.C(OCC)C>[F:20][C:21]([F:34])([F:33])[S:22]([O:25][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])(=[O:24])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOP(=O)(CCO)OCC
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
5.01 ml diethyl-(hydroxyethyl)-phosphonate are dissolved in 50 ml dichloromethane, combined with 4.42 ml of 2,6-lutidine and cooled to −50° C. Then a solution of 6 ml trifluoromethanesulphonic acid anhydride in 10 ml dichloromethane is slowly added dropwise. Within 1.5 hours the mixture is allowed to come up to 0° C. and then diluted with 300 ml cold diethyl ether. Any solids precipitated are filtered off and the filtrate is washed twice with ice water, once with 1 N hydrochloric acid and once with saturated sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo.
Reaction SMILES: [CH2:1](N(CC)CC)C.[NH2:8][C@H:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][OH:11].[Cl:15][C:16]1[C:21]([S:22]([N:25]([O:27][CH3:28])[CH3:26])(=[O:24])=[O:23])=[C:20]([OH:29])[C:19]([NH:30][C:31]2[C:34](=O)[C:33](=[O:36])[C:32]=2[O:37]CC)=[CH:18][CH:17]=1>CCO>[Cl:15][C:16]1[C:21]([S:22]([N:25]([O:27][CH3:28])[CH3:26])(=[O:23])=[O:24])=[C:20]([OH:29])[C:19]([NH:30][C:31]2[C:32](=[O:37])[C:33](=[O:36])[C:34]=2[NH:8][C@@H:9]([CH2:10][O:11][CH3:1])[CH:12]([CH3:14])[CH3:13])=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: CCN(CC)CC
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Solvent: CCO
Product: COC[C@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O)C(C)C
Temperature: 85 °C

Procedure:
To a stirred solution of triethylamine (1.192 ml, 8.55 mmol) and (R)-2-Amino-3-methyl-butan-1-ol (Intermediate H) in EtOH (36 ml) was added 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1.67 g, 4.27 mmol). The reaction mixture was heated at 85° C. for 18 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) and NaHCO3 (aq). The NaHCO3 (aq) layer was extracted with EtOAc. The EtOAc layers were combined and concentrated in vacuo. The residue was purified using flash chromatography (0-10% MeOH in DCM) to furnish a brown solid [M+H]+ 462.0.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:7][N:6]1[CH2:20][C:21]([O:23]C)=O)=[N+]=[N-].O>CO.[Ni]>[CH:17]1([C:14]2[N:15]=[CH:16][C:11]([O:10][C@H:8]3[CH2:7][N:6]4[CH2:20][C:21](=[O:23])[NH:1][CH2:4][C@@H:5]4[CH2:9]3)=[N:12][CH:13]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)CN1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 201B (203 mg, 0.611 mmol) in methanol (20 mL) was added to Raney®-nickel 2800, water slurry (2030 mg, 34.6 mmol) in a 50 mL pressure bottle. The mixture was stirred at ambient temperature for 16 hours under hydrogen (30 psi). The mixture was filtered and concentrated in vacuo to give the title compound. MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](ON3C(=O)CCC3=O)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.O>C(=O)([O-])[O-].[Na+].[Na+]>[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([NH:1][C@@H:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=3)[C:3]([OH:5])=[O:4])=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
(S)-2-Amino-3-(3-fluoro-4-hydroxyphenyl)propanoic acid (H-Tyr(3-F)-HH, SP449) (7.2 g, 36.2 mmol) was dissolved in a 10% aqueous sodium carbonate solution (250 ml), N-(9-fluorenylmethoxycarbonyloxy)-succinimide (12.2 g, 36.2 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Water (120 ml) was added to the reaction solution, and the mixture was then washed with 200 ml of diethyl ether twice and with 100 ml of diethyl ether once. The aqueous layer was made acidic (pH=2) by adding a 6 N aqueous HCl solution thereto, and then extracted with 250 ml of ethyl acetate twice and with 200 ml of ethyl acetate once. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (SP450, 15.3 g, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1>C(O)CCC>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cccc(N)c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncc(C)cc2[N+](=O)[O-])c1

Procedure:
A mixture of 2-chloro-5-methyl-3-nitropyridine (13 g, 75 mmol), triethylamine (12.6 mL, 90 mmol), and m-toluidine (9.8 mL, 90 mmol) in 200 mL butanol was heated overnight under nitrogen. The solvent was evaporated, and the residue dissolved in dichloromethane. The organic layer was washed twice with water, brine, dried over magnesium sulfate, filtered, and evaporated (15.5 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]([OH:34])[CH2:35][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]=4[S:18][CH2:17]3)=[CH:4][CH:3]=[C:2]([F:1])[CH:20]=5)[CH2:12][CH2:13]2)=[CH:29][CH:28]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(F)ccc3C(=O)C2=O)cc1

Procedure:
Compound 191 was synthesized using 9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=114-116° C., 400 MHz 1H NMR (DMSO-d6) δ: 7.99-7.95 (m, 1H), 7.46-7.37 (m, 2H), 7.29-7.27 (d, J=8.60 Hz, 2H), 6.86-6.84 (d, J=8.99 Hz, 2H), 4.85 (br s, 1H), 3.96-3.4 (m, 2H), 3.86-3.84 (m, 1H), 3.34 (s, 2H), 2.79-2.74 (m, 3H), 2.50-2.44 (m, 3H), 1.99-1.96 (m, 2H), 1.83-1.81 (m, 2H), 1.24 (s, 9H); LCMS: 526 [M+H]
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22].[C-:24]#[N:25].[K+]>CS(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:24]#[N:25])=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: [C-]#N
Reactant: CCCc1c(OCc2ccc(CBr)cc2)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1c(OCc2ccc(CC#N)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-Hydroxy-3-propyl-4-(4-bromomethylphenylmethoxy)phenyl]ethanone (7.2 g; 0.02 m) and potassium cyanide (2.5 g; 0.04 m) where dissolved in dry dimethylsulphoxide (60 ml) and stirred at room temperature for 2 hours. The solution was poured onto water with stirring and filtered to give a cream solid, which was dried at 60° C. under reduced pressure; Recrystallised from ethanol to give a pale cream crystalline solid m.p. 75°-76° C.
Reaction SMILES: [CH2:1]([C@@H:5]1[NH:11][C@H:10]([CH3:12])[CH2:9][CH2:8][N:7]([C@@H:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:14]([NH2:16])=[O:15])[C:6]1=[O:28])[CH:2]([CH3:4])[CH3:3].[N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH2:39][C:40](O)=[O:41])=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C@@H:5]1[N:11]([C:40](=[O:41])[CH2:39][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:29]=[CH:30][CH:31]=[CH:32]3)[C@H:10]([CH3:12])[CH2:9][CH2:8][N:7]([C@@H:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:14]([NH2:16])=[O:15])[C:6]1=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: CC(C)C[C@@H]1N[C@H](C)CCN([C@@H](Cc2ccc3ccccc3c2)C(N)=O)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(N)=O)CC[C@@H](C)N1C(=O)Cc1ccc2ncccc2c1

Procedure:
(S)-2-[(3S,5R)-3-isobutyl-5-methyl-2-oxo-[1,4]diazepan-1-yl]-3-(naphthalen-2-yl)-propionamide (382 mg, 1 mmol) is added to a solution of 6-quinolylacetic acid (372 mg, 2 mmol), Hünig's base (170 μl, 1 mmol) and EADC (383 mg, 2 mmol) in CH2Cl2 (50 ml). After 16 hours at RT the reaction mixture is extracted with 0.1 N HCl and then with 5% NaHCO3 solution. Pure title compound is isolated after silica gel chromatography using ethyl acetate —>ethyl acetate/MeOH (9/1) as mobile phase. MH+:551.4 (ESI) αD20=−12.5° (c=0.12 95% AcOH)