Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([O:32]C)=O)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH3:41]COCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH:30]([OH:32])[CH3:41])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: COC(=O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A solution of 0.330 g (0.71 mmol) of methyl (1RS,2RS,3RS,5SR)-4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxymethyl]-biphenyl-2-carboxylate in 10 ml of ether was slowly added dropwise to a suspension of 33 mg of lithium aluminium hydride in 5 ml of ether and the mixture was stirred at room temperature for 4 hours. After the addition of aqueous ether and subsequently water the phases were separated, the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 140:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There was obtained 0.210 g (68% of theory) of [4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxymethyl]-biphenyl-2-yl]-ethanol as a colourless foam, Rf : 0.18 (methylene chloride:methanol:ammonia=140:10:1), MS: 434 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CCN(CC)CCN
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Solvent: CC#N
Product: CCN(CC)CCNCCC(=O)Nc1nc(C)c(-c2ccnc(Nc3ccc(Cl)cc3)n2)s1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with N1,N1-diethyl-ethane-1,2-diamine. Anal. RP-HPLC: tR=11.8 min (10-70% MeCN, purity >97%). 1H-NMR (DMSO-D6) δ: 1.20 (t, 6H, J=7.0 Hz, CH3), 1.53 (d, 2H, J=6.5 Hz, CH2), 2.52 (s, 6H, CH3), 3.18 (m, 4H, CH2), 3.28 (m, 4H, CH2), 7.13 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 7.30 (m, 2H, Ph-H), 7.81 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.82 (brs, 1H, NH).
Reaction SMILES: C1NCCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH-].[Na+].C(#N)C=C.C(C[N:35]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][C:49]#[N:50])[CH2:43][CH2:42][N:41](CC(O)=O)[CH2:40][CH2:39][N:38](CC(O)=O)[CH2:37][CH2:36]1)(O)=O>O.CO>[C:49]([CH2:48][CH2:47][N:44]1[CH2:45][CH2:46][NH:35][CH2:36][CH2:37][NH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43]1)#[N:50]
Reactant: N#CCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C=CC#N
Solvent: O
Product: N#CCCN1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Into a 100 ml round bottom flask containing 5.2 g of DO3A dissolved in 22 ml of H2O (pH adjusted to 8.25 with dilute NaOH) was added 1.35 ml of acrylonitrile. The reaction was allowed to stir at room temperature for 14 hours. After 14 hours, HPLC analysis indicated complete conversion to 1,4,7-tris(carboxymethyl)-10-(2'-cyanoethyl)-1,4,7,10-tetraazacyclododecane. The reaction mixture was taken to dryness on a rotary evaporator to yield a glassy solid. The solid was dissolved in methanol and then taken to dryness on a rotary evaporator to yield 5.9 g of crude 1,4,7-tricarboxymethyl)-10-(2'cyanoethyl)-1,4,7,10-tetraazacyclododecane as a white solid. 3.0 g of the crude 1,4,7-tris(carboxymethyl)-10-(2'-cyanoethyl)-1,4,7,10-tetraazacyclododecane was dissolved in 150 ml of H2O, and the solution acidified with 6 ml of concentrated HCl. The solution was then added to a 500 ml hydrogenation vessel containing 1.5 g of 10% Pd/C and the reaction mixture hydrogenated at 50 psi H2 at room temperature for 14 hours. After 14 hours the catalyst removed over a Celite bed and the filtrate taken to dryness on a rotary evaporator. The sample was dissolved in 200 ml of H2O and applied to a 2.5×20 cm column of Dowex 50X-2 (H+ form). The column was eluted with 4 L of 0.5 H2O and the material eluted off the column with 1.0 L of 0.5M NH4OH. The eluant was concentrated to dryness on a rotary evaporator, the residue dissolved in methanol and taken to dryness on a rotary evaporator to yield 3.8 g of the ammonium salt of 1,4,7-tris(carboxymethyl)-10-(3'-aminopropyl)-1,4,7,10-tetraazacyclododecane.
Reaction SMILES: C(NC[C@@H]1C[C@H](O)C1)C1C=CC=CC=1.[OH:15][C@@H:16]1[CH2:19][C@H:18]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[CH3:37][S:38]([O:15][C@H:16]1[CH2:19][C@@H:18]([CH2:20][N:21]([C:22]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:28])[CH3:29])[CH2:17]1)(=[O:40])=[O:39]
Reactant: CN(C[C@H]1C[C@@H](O)C1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O[C@H]1C[C@@H](CNCc2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Intermediate 5, tert-Butyl [(cis-3-hydroxycyclobutyl)methyl]methylcarbamate (22.6 g, 105 mmol) and triethylamine (36 mL, 250 mmol) were dissolved in CH2Cl2 (50 mL). MsCl (9.75 mL, 126 mmol) was added dropwise at −20° C. under stirring in argon. The temperature was brought to ambient within 1 h. Water (100 mL) was added, and the layers were separated. The organic one was washed with water, brine, dried with Na2SO4, and evaporated. The title compound (29 g, 96%) was obtained as a yellow oil. This crude product was used for the next stage without additional purification. 1H NMR-data (DMSO-d6): 4.76-4.88 (m, 1H); 3.23 (d, 2H, CH2, J=6.6 Hz); 3.12 (s, 3H, MS); 2.76 (s, 3H, NCH3); 2.38-2.48 (m, 2H); 2.00-2.12 (m, 1H); 1.86-97 (m, 2H); 1.38 (s, 9H, Boc).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17](=[O:19])[NH2:18])[CH2:12]1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:30]([O:37][C:38]([N:14]1[CH2:15][CH2:16][CH:11]([C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])[CH2:9][CH3:10])[CH2:12][CH:13]1[C:17](=[O:19])[NH2:18])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C1CCNC(C(N)=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h

Procedure:
To a chilled (0° C.) solution of [(S)-1-(2-carbamoyl-piperidin-4-yl)-propyl]-carbamic acid tert-butyl ester (780 mg, 2.73 mmol) in methylene chloride (25 mL) was added DIPEA (0.41 mL, 2.9 mmol) followed by benzylchloroformate (723 μL, 4.1 mmol). After 1 hour, the reaction was diluted with dichloromethane (200 mL), washed with saturated ammonium chloride, brine, dried over sodium sulfate, filtered and concentrated to afford 4-((S)-1-tert-butoxycarbonylamino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[Al](C)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:21]=[C:22]([C:33](OCC)=[O:34])[N:23]([CH3:32])[C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(Cl)Cl>C1(C)C=CC=CC=1.CCCCCC>[N:2]1([NH:1][C:33]([C:22]2[N:23]([CH3:32])[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[Cl:12])[N:21]=2)=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 0.33 mL (3.05 mmol) of 1-aminopiperidine in 2 mL of dry toluene under N2, 1.5 mL (3.05 mmol) of 2M trimethylaluminum in hexane was added with cooling in ice bath. The cold bath was removed, reaction was stirred for 1 h and 0.5 g (1.22 mmol) of ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate in 3 mL of toluene, and 1.5 mL of CH2Cl2 was added. The mixture was heated in a 60° C. bath for 2 h, cooled, quenched with water and the pH was adjusted to 5 with 1.2 N HCl. The solution was extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography using 30% EtOAc/hexane as an eluant to isolate the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]([NH:22][C@H:23]([C:28](O)=[O:29])[CH2:24][CH2:25][S:26][CH3:27])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[CH2:15]([O:14][C:12]([NH:22][C@@H:23]([CH2:24][CH2:25][S:26][CH3:27])[C:28]([NH:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:29])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCC2(CC1)OCCO2
Reaction time: 8 h
Yield: 64.7 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-amine (5.03 g, 32.0 mmol, 1 eq.), CBZ-L-methionine (10.90, 38.4 mmol, 1.2 eq.), 1-hydroxybenzotriazole hydrate (HOBT) (5.19 g, 38.4 mmol, 1.2 eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI) (7.36 g, 38.4 mmol, 1.2 eq.), triethylamine (8.92 mL, 64.0 mmol, 2 eq.) and methylene chloride (150 mL) were stirred at room temperature under nitrogen for 72 hours. Worked up by rinsing 3 times with saturated sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate and stripped to give an amber oil which solidified. The solids were triturated with diethyl ether (100 mL) and stirred overnight. The solids were filtered to give 8-((2S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-1,4-dioxaspiro[4.5]decane (8.75 g) as a white solid. Yield=64%. Mass Spec (ESI) detects (M+H)+=423.22.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+]>O.ClCCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(C)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Yield: 12.3 %

Procedure:
To a mixture of methyl 2-(3,4-methylenedioxyphenyl)propionate (1.0 g, 4.8 mmol), 4-nitrobenzoic acid (1.6 g, 9.6 mmol) and 1,2-dichloroethane (35 mL) was added P2O5 (4 g) and the mixture obtained was heated to reflux for 12 h. Water was added to the reaction mixture and it was neutralized to pH=7-8 by NaHCO3 solution. It was extracted with EtOAc and washed with brine. The product (211 mg, 12.3%) was obtained by a chromatographic purification (EtOAc:Hex=1:4). 1H NMR (CDCl3) 8.31 (d, J=8.7, 2H), 7.94 (d, J=8.7, 2H), 7.00 (s, 1H), 6.73 (s, 1H), 6.06 (s, 2H) 4.15 (q, J=7.1, 1H), 3.59 (s, 3H), 1.51 (d, J=7.1, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][CH2:28][OH:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=[O:33].Cl[O-].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:33])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CCO)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Reaction time: 0.33 h

Procedure:
2-[2-({4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)pyridin-3-yl]ethanol (10.0 g) was suspended in acetonitrile (100 ml) and the aforementioned phosphate buffer (70 ml) and 2,2,6,6-tetramethyl-1-piperidinyloxyradical (131.2 mg) was added at 25° C. To the obtained mixture were simultaneously added dropwise a solution of 5% sodium hypochlorite (355 mg) in water (5 ml) and a solution of sodium chlorite (5.43 g) in water (15 ml) at 25° C. and the mixture was stirred for 1 hr. 0.2N-Sodium hydroxide was added to adjust the reaction solution to pH 8, and a solution of sodium sulfite (7.260 g) in water (100 ml) was dropwise added. The reaction solution was stirred for 20 min. and acetonitrile was evaporated under reduced pressure. Toluene (100 ml), tetrahydrofuran (50 ml) and 2N-sodium hydroxide (12 ml) were added to the residue to partition the mixture. The organic layer was extracted with water (50 ml), and aqueous layers were combined and washed with a mixture of toluene (100 ml) and tetrahydrofuran (50 ml). 6N Hydrochloric acid was dropwise added to adjust the aqueous layer to pH 7.0, and toluene (150 ml) and tetrahydrofuran (70 ml) were added 6N Hydrochloric acid was added to adjust the mixture to pH 6.5 and the mixture was partitioned. The organic layer was washed with 5% brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Tetrahydrofuran (20 ml) was added to the obtained crystals and the mixture was refluxed. Isopropyl ether (20 ml) was added to the obtained solution, and after stirring for 1 hr., the mixture was stirred under ice-cooling for 2 hrs. The obtained crystals were filtrated, washed with isopropyl ether (20 ml) ice-cooled in advance, and dried under reduced pressure at 40° C. to give 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid as white crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:4])=[O:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: 4.0 g of trans-2,4-dibenzyl glutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][C:13]=3[O:12][CH2:11][C:10]=12)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:15]1[CH:16]=[CH:17][C:18]2[C:9]3[C:10](=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=[CH:7][CH:8]=3)[CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: CC(=O)Nc1nccc2c1COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nccc2c1COc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-((4-acetamido-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.329 mmol) in CH2Cl2 (10 mL) at room temperature was added TFA (0.025 mL, 0.329 mmol) and the solution was stirred at room temperature for 3 h. The solution was concentrated under reduced pressure and the sample was purified by preparative HPLC (0.1% TFA in water and methanol) yielding (S)—N-(8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (40 mg, 0.113 mmol, 33% yield for three steps) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=5.3 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 6.77 (m, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.94 (s, 2H), 4.03 (m, 1H), 3.85 (m, 1H), 3.33 (m, 1H), 2.21 (s, 3H), 1.81 (m, 1H), 1.43 (m, 2H), 0.99 (m, 6H); LCMS (ESI) m/e 356.2 [(M+H)+, calcd for C20H26N3O3 356.2]; LC/MS retention time (Method C): tR=1.26 min; HPLC retention time (method A): tR=8.02 min; HPLC retention time (method B): tR=9.08 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([OH:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(O)c2)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
A mixture of 3-[4-(3-hydroxy-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (2.83 g, 9.01 mmol), 3-bromo-4-fluorobenzotrifluoride (2.19 g, 9.01 mmol) and 325 mesh potassium carbonate (1.49 g, 10.8 mmol) in dry DMSO (36 mL) is heated to 100° C. and stirred for 5 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.45 g (71%) of the title compound. Rf=0.54 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C26H24O4F3Br 536, found 554 and 556 (M+NH4, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:16]([CH3:18])[CH3:17])=[CH:3]1.Cl.[NH2:20][CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C.C(Cl)Cl.CO>[CH3:28][C:27]1[CH:26]=[C:25]([CH3:29])[NH:24][C:23](=[O:30])[C:22]=1[CH2:21][NH:20][C:11]([C:9]1[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COc1cc(C(=O)O)c2c(c1)c(C(C)C)cn2C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2c(c1)c(C(C)C)cn2C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 1-methyl-3-(1-methylethyl)-5-(methyloxy)-1H-indole-7-carboxylic acid (78 mg, 0.315 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone hydrochloride (59.5 mg, 0.315 mmol), HOAt (64 mg, 0.473 mmol) in DMF (4 mL) was added EDC (121 mg, 0.631 mmol) and N-methylmorpholine (52 μL, 0.473 mmol). The reaction mixture was stirred for 18 hr at room temperature, after which time the contents were evaporated to near dryness. Water (˜5 mL) was added and the solids which precipitated out were isolated. The collected solid was dissolved in DCM/MeOH (4:1, 5 mL), dried over MgSO4, filtered, and concentrated in vacuo to a afford a creme colored solid. The solid was re-dissolved in DCM/MeOH (4:1, 5 mL) and washed with 6N NaOH (1 mL) and water (4 mL). The organic layer was concentrated in vacuo to afford a nearly white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[C:12]3=[O:29])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.O1CCOCC1.CO>C(Cl)Cl.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)[C:12]3=[O:29])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc4[nH]ncc4c3)C2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A flask was charged with (S)-tert-butyl 4-(3-(1H-indazol-5-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (0.300 g, 0.749 mmol), HCl in dioxane (1.87 mL, 7.49 mmol), DCM (10 mL), and methanol (1 mL). The reaction was stirred at ambient temperature for 2 hours. The organic solvents were removed under reduced pressure. The residue was purified using silica gel column chromatography using 50-100% ethyl acetate in hexanes, then 5% ammoniated methanol in DCM, and then 30% ammoniated methanol in ethyl acetate to provide (S)-3-(1H-indazol-5-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one (0.225 g, 100% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][O:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[CH3:13][O:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH:19]=1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: COc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cn(-c2ccc([N+](=O)[O-])cc2OC)cn1
Temperature: 90 °C
Yield: 54.2 %

Procedure:
1-Fluoro-2-methoxy-4-nitrobenzene (0.785 g, 4.59 mmol), 4-methoxy-1H-imidazole (0.45 g, 4.59 mmol) and potassium carbonate (0.697 g, 5.05 mmol) were mixed in dry acetonitrile (10 mL) and heated at 90° C. for 4 days. DCM was added and the mixture was filtrated through a pad of silica eluting with 5% MeOH in DCM. The solvents were evaporated and mixture was purified by column chromatography in silica eluting with a gradient of MeOH and DCM to give the title compound as a gum 0.62 g (54%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][CH:11]=O.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Yield: 70.3 %

Procedure:
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55% strength in water) in 15 mL of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with brine and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70%) of the desired product were isolated in the form of an amorphous white solid.