Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1([CH2:22][O:23][C:24]([NH:26][CH:27]([PH:29](=[O:31])[OH:30])[CH3:28])=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH2:15][P:29]([OH:31])([CH:27]([NH:26][C:24]([O:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:25])[CH3:28])=[O:30])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(NC(=O)OCc1ccccc1)[PH](=O)O
Reactant: C=C(Cc1ccc(Br)cc1)C(=O)OCC
Product: CCOC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)NC(=O)OCc1ccccc1
Yield: 90 %

Procedure:
The process is performed according to the operating conditions described in 5.3., starting with 2.6 g (9.67 mmol) of ethyl 4-bromo-α-methylenebenzenepropanoate and 2 g (8.23 mmol) of [1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinic acid. 3.79 g of product are recovered (yield=90%).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[CH3:14][O-:15].[Na+]>C(Cl)Cl>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:15][CH3:14])[N:12]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
1.00 g of ethyl 2,6-dichloronicotinate was dissolved in 10 mL of methylene chloride, and 1.05 g of sodium methoxide (28 wt % of methanol solution) was added thereto at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 511 mg of methyl 6-chloro-2-methoxynicotinate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[N:11][CH3:12])=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[C:16](=[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20])=[O:17].N12CCCC1=NCCC2>C1(C)C=CC=CC=1.O>[OH-:17].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N+:7]3[C:16]([OH:17])=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19](=[O:20])[N:11]([CH3:12])[C:8]=32)=[CH:4][CH:3]=1
Reactant: CN=C1NCc2ccc(Cl)cc21
Reactant: O=C=C(C(=O)Cl)c1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c2[n+](c(O)c(-c3ccccc3)c1=O)Cc1ccc(Cl)cc1-2
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of 5.42 g of 6-chloro-1-(methylimino)isoindoline (prepared from the hydrochloride by treatment with 1.5 equivalents of 2N sodium hydroxide solution) and 120 ml of toluene was treated dropwise under argon at 0°-5° within 10 minutes with 5.96 g of α-carbonyl-phenylacetyl chloride. The mixture was stirred for 30 minutes, 4.47 g of 1,5-diazabicyclo[4.3.0]non-5-ene in 30 ml of toluene were subsequently added dropwise thereto, the mixture was stirred at 0°-5° for a further 90 minutes, then treated with 50 ml of water and the separated crystals were filtered off under suction and washed with 35 ml of methylene chloride and, after drying, there was obtained 3.66 g of 9-chloro1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3-phenyl-6H-pyrimido[2,1-a]isoindol-5-ium hydroxide (internal salt) with a m.p. of 245° (decomposition). This product was recrystallized from N,N-dimethylformamide and then had a m.p. of 288°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])C>>[CH3:36][O:35][C:28]1[CH:29]=[CH:30][C:31]([CH2:33][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][CH2:17][C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)[CH:8]=3)[CH2:3][CH2:2]2)=[CH:32][C:27]=1[C:26]([OH:37])=[O:25]
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(CCc4ccsc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1 g (3.2 mmol) of 3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.15 g (4.2 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up and purification, 1.16 g (76% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18]([OH:31])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:21]2[CH:20]=[CH:19][C:18]([OH:31])=[CH:17][C:16]=2[CH3:15])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1sc(Br)nc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(O)cc2C)nc1C(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of 2-bromo-4-isopropyl-thiazole-5-carboxylic acid ethyl ester (834 mg, 3 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.4 g, 6 mmol) and K2CO3 (828 mg, 6 mmol) in 1,4-dioxane/H2O (30 mL/5 mL) is bubbled nitrogen gas for 10 minutes. To this solution is added tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol). The reaction mixture is stirred at 100° C. overnight. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and 1N HCl. The organic phase is concentrated and purified by column chromatography (gradient: 0 to 15% EtOAc in hexanes) to give the title product (730 mg, 80%). 1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.68 (d, 1H), 6.68, 6.72 (m, 2H), 4.26 (q, 2H), 3.88 (m, 1H), 2.50 (s, 3H), 1.26 (t, 3H), 1.23 (d, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:13]#[N:14])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(OCC)C>[CH:7]1([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:13][NH2:14])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cccc(C(C#N)C2CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(C(CN)C2CCCC2)c1
Yield: 85.8 %

Procedure:
By working in a way similar to that described in example 29 but using LiAlH4 (1.01 g, 26.57 mmoles) in anhydrous ethyl ether (20 ml) and cyclopentyl-(3-methoxy-phenyl)-acetonitrile (5.72 g, 26.57 mmoles), obtained as described in example 32, 5 g of the title compound were obtained (yield: 85.8%).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[CH:6]([CH:8]=[O:9])=[O:7]>>[OH:7][CH:6]1[CH:8]([OH:9])[O:4][CH:2]([CH3:3])[CH2:1][O:5]1
Reactant: CC(O)CO
Reactant: O=CC=O
Product: CC1COC(O)C(O)O1
Yield: 93 %

Procedure:
1 mol of 1,2-propanediol is stirred with 40% strength by weight aqueous glyoxal solution at 50° C. for 3 hours. Water is then distilled off at 70° C. and 100 mbar, leaving 125 g (93% of theory) of 2,3-dihydroxy-5-methyl-1,4-dioxane in the form of a clear, colorless oil which crystallizes on prolonged standing.
Reaction SMILES: [OH:1][CH:2]([CH2:15][S:16][C:17]1[S:18][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:20][CH:21]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[OH:1][CH:2]([CH2:15][S:16][C:17]1[S:18][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:20][CH:21]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CSc1ccc(CN2CCCCC2)s1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(O)CSc1ccc(CN2CCCCC2)s1

Procedure:
8.60 g (20 mmol) of 2-[2-hydroxy-3-[5-(1-piperidylmethyl)-2-thienylthio]propyl]-1H-isoindole-1,3-dione and 3.3 ml of hydrazine hydrate (80%) are boiled in 80 of ethanol for 3 hours. The residue obtained after the mixture has been concentrated by evaporation is taken up in 50 ml of water. 8 ml of conc. hydrochloric acid are added and the mixture is filtered. The filtrate is adjusted to pH 12 with conc. sodium hydroxide solution and extracted with 3×40 ml methylene chloride. The organic phase is dehydrated with Na2SO4 and concentrated by evaporation under vacuum. 4.9 g (82% of theoretical) of the title compound are obtained in the form of a light green oil.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:41]2[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.CO.C(Cl)Cl>[ClH:1].[ClH:1].[O:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:6][CH2:5]3)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (70 mg, 0.187 mmol) in chloroform (5 ml) and methanol (0.2 ml) at room temperature under argon was treated with triethylamine (0.078 ml, 0.561 mmol) and stirred for 0.25 h. Everything went into solution; 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144 Example 2(c) or WO03/087098 Example 19(d))) (30.9 mg, 0.187 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (119 mg, 0.561 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h 1 eq more of sodium triacetoxyborohydride was added. After 1 h sat NaHCO3 (50 ml) was added followed by 20% MeOH/DCM (50 ml) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% MeOH/DCM (2×50 ml). The combined organic extracts were dried on MgSO4, filtered and evaporated to afford 90 mg of crude product which was purified by silica chromatography using a 0-20% methanol/dichloromethane gradient to afford the free base of the title compound as a pale yellow gum (60 mg, 71%).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)C.[CH2:30]([NH2:33])[CH2:31][CH3:32]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:33][CH2:30][CH2:31][CH3:32])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CCCN
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (48 mg) in anhydrous DMF (1 ml) is cooled in an ice bath and stirred while triethylamine (28 μl) and propylamine (12.4 μl) are added. The resulting solution is allowed to warm to room temperature (25° C.) and kept there for 1 hour. The solution is diluted with ethyl acetate (10 ml), washed with water (5×2 ml), pH 3 phosphate buffer (2 ml), 5% NaHCO3 (2 ml), and brine, dried with MgSO4, filtered, and evaporated in vacuo to provide benzyl 6-(1-hydroxyethyl)-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[O:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][C:24]1=2.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.CCOC(C)=O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:30]4[CH:31]=[CH:32][C:24]5[O:23][CH2:28][CH2:27][O:26][C:25]=5[CH:29]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccc3c(c2)OCCO3)OC1(C)C
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: C[C@@H](Oc1nc(-c2ccc3c(c2)OCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 105 °C

Procedure:
To a 25 ml 3-neck flask with condenser and magnetic stir bar was added (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (100 mg, 0.27 mmol), 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (90 mg, 0.34 mmol) and Pd(PPh3)4 (32 mg, 0.027 mmol) then evacuated and filled with N2 3×. Added 2 mL DME and 2N sodium carbonate (0.41 ml, 0.82 mmol) via syringe and heated in a 105° C. oil bath for ˜2 hrs at which time LC-MS indicated a complete reaction Let cool, added EtOAc and water, separated, washed with brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO 50 g C18 reverse phase 0-30% water/acetonitrile/0.1% TFA. Partially concentrated under reduced pressure added EtOAc and sat.aq.bicarb, separated, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:15][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]2=[N:35][O:36][N:37]=[C:33]2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:35]1[O:36][N:37]=[C:33]2[CH:32]=[C:31]([CH2:30][N:11]3[C:10]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:9]=4[N:8]=[C:7]3[CH2:6][C:2]([CH3:28])([CH3:1])[C:3]([OH:5])=[O:4])[CH:39]=[CH:38][C:34]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc2nonc2c1)C(=O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A suspension of 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)propanoic acid (300 mg, 0.75 mmol), 5-(bromomethyl)benzo[c][1,2,5]oxadiazole (168 mg, 0.75 mmol) and potassium carbonate (310 mg, 2.25 mmol) in DMF (20 mL) was heated to 70° C. for 18 h. The mixture was cooled to RT and concentrated to dryness. The residue was dissolved in THF/MeOH (18 mL, 1:1) and treated with 5% aq. NaOH (2 mL). The mixture was stirred at 40° C. for 16 h. The reaction was allowed to cool to RT and then concentrated to dryness. The residue was diluted with water (30 mL), washed with EtOAc (20 mL), and then treated with 6N aq. HCl to ˜pH 6. The aqueous was then extracted with DCM (2×30 mL). The organics were combined, dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C29H26N6O4, 507.19; m/z found, 507.9 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=8.6, 1H), 8.11-7.98 (m, 3H), 7.85-7.77 (m, 1H), 7.71 (d, J=8.5, 1H), 7.68-7.61 (m, 2H), 7.58-7.52 (m, 1H), 3.35-3.33 (m, 2H), 7.50-7.43 (m, 1H), 7.38-7.33 (m, 1H), 7.21-7.12 (m, 1H), 5.84 (s, 2H), 5.47 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2)[CH2:2][CH3:3].[CH3:17][O:18][CH2:19][C:20](O)=[O:21].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH3:17][O:18][CH2:19][C:20]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:21]
Reactant: COCC(=O)O
Reactant: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)COC

Procedure:
To a mixture of methyl 2-propylindole-6-carboxylate (10 g), methoxyacetic acid (4.6 ml) and carbontetrachloride (13.4 ml) in 1,2-dichloroethane (45 ml) was added slowly triphenylphosphine (16.7 g) in 1,2-dichloroethane (30 ml) over 1 hour under reflux, and the resulting mixture was heated under reflux for additional 8 hours. After evaporation of solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (1:1) and triturated with diethyl ether to give methyl 3-methoxyacetyl-2-propylindole-6-carboxylate (8.11 g).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[C:12](OC(C)(C)C)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1(C)C=CC=CC=1>[C:12]([O:10][C@H:3]1[C@H:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][C@@H:1]([CH3:11])[CH2:2]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 23 °C
Yield: 114.5 %

Procedure:
A solution of (-)-menthol (23.0 g, 147 mmol, 1 equiv) and t-butyl acetoacetate (20.0 mL, 121 mmol, 0.80 equiv) in toluene (50 mL) was heated at reflux for 12 h, then was cooled to 23° C. Volatiles were removed in vacuo and toluene (20 mL) and t-butyl acetoacetate (12.2 mL, 73.5 mmol, 0.50 equiv) were added to the residue. The resulting solution was heated at reflux for 12 h, then was cooled to 23° C. The cooled reaction mixture was concentrated in vacuo and the residue was purified by distillation under reduced pressure (bp 90° C., 30 mmHg) to afford (1R, 3R, 4S)-p-menth-3-yl acetoacetate (1) as a low-melting solid (33.3 g, 94%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I-].[Na+].[C:30]([O:33][CH2:34][C@@H:35]([CH3:38])[CH2:36]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:36][C@H:35]([CH3:38])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(=O)OC[C@@H](C)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 95 °C
Reaction time: 5 h
Yield: 102.9 %

Procedure:
3.87 g of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-yl-pyrimidine (14.1 mmol) were stirred in 30 ml of dimethylformamide at room temperature. 3.18 g of triethylamine (63.1 mmol), 0.235 g of sodium iodide (1.57 mmol), 2.96 g of (R)-(−)-1-acetoxy-3-bromo-2-methyl-propane (15.2 mmol) were added and the reaction mixture was stirred for 5 h at 95° C. The dimethylformamide was evaporated under reduced pressure. The residue was partitioned between 100 ml of dichloromethane and 100 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give a brownish oil (5.64 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][N:20]([CH3:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([N:20]([CH3:30])[CH3:19])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CCCNC(=O)c1nnc2c(-c3ccc(N(C)C)cc3)cccc2c1N
Yield: 91.1 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 4-dimethylaminophenyl boronic acid (160 mg, 0.97 mmol) were reacted to afford the title compound (105 mg, 93.0% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.61 (br, 1H), 7.58-7.85 (m, 5H), 6.88 (d, J=8.8 Hz, 2H), 3.47 (q, J=6.7 Hz, 2H), 3.02 (s, 6H), 1.67 (m, J=7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=350 (M+H) HPLC 2.67 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-hept-6-enoic acid (5.24 mmol), DIPEA (15.7 mmol) and aniline (5.76 mmol) was stirred at RT in DCM (70 ml) for 20 minutes before adding PyBOP (5.24 mmol) and anhydrous DMF (5 ml). The reaction mixture was stirred for 2 hours at RT. The solvent was removed under reduced pressure and the crude reaction mixture was diluted with AcOEt, washed with 5% Na2CO3, water and then with 5% aqueous citric acid and finally with brine. After removal of the solvent under reduced pressure and purification on silica gel (n-hexane/AcOEt: 9/1) the desired adduct was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O.O/[N:63]=[C:64](/[C:72](=[O:74])[CH3:73])\[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66]>O1CCCC1>[O:74]=[C:72]([CH3:73])/[C:64](=[N:63]/[O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH2:3]1)/[C:65]([O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:66]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)/C(=N/O[C@H]1C[C@@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
4-Nitrobenzyl (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylate (3.24 g, 7.28 mmol) and triphenylphosphine (2.29 g, 8.7 mmol) in dry tetrahydrofuran (60 ml) under argon were treated with dimethyl azodicarboxylate (1.28 g, 8.7 mmol) in dry tetrahydrofuran (5 ml). After 5 min tert-butyl (Z)-2-hydroxyimino-3-oxobutyrate (2.59 g, 8.7 mmol) in dry tetrahydrofuran (10 ml) was added and the mixture was stirred under an argon atmosphere for 18 h. The tetrahydrofuran was removed and the residue taken up in ethyl acetate (150 ml) and washed with water containing a trace of acetone (100 ml,×6). The ethyl acetate layer was dried (MgSO4) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane mixture to give the title compound (2.49 g, 55%) as a mixture of two conformers/rotamers; νmax (CH2Cl2) 1735, 1710, 1605, 1525, and 1350 cm-1 ; δH (250 MHz, CDCl3) 1.52 (9H, s), 2.31 (3H, s), 2.40-2.80 (2H, m), 3.75-4.0 (2H, m), 4.66 (1H, approx dt, J ca 9.3, 1.5 Hz), 4.94-5.05 (1H, m), 5.1-5.4 (4H, m), 7.35-7.55 (4H, m), and 8.05-8.25 (4H, m).