Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccnc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C=O)CC1

Procedure:
To a stirring solution of 2-bromo-3-formylpyridine (XVI, EXAMPLE 1, 2.0 g, 10.80 mmol), and diisopropylethylamine (1.39 g, 10.80 mmol) in THF is added 1-(tert-butoxycarbonyl)-piperazine (Aldrich, 2.01 g, 10.80 mmol). The mixture is heated in a sealed tube at 100° for 16 hr, cooled to 20°-25° and poured into water (100 ml). The aqueous layer is extracted with ethyl acetate (100 ml), the organic layer separated, dried over sodium sulfate and solvent evaporated to dryness. The residue is purified via flash column chromatography (silica gel; hexane/ethyl acetate (4/1)) to give the title compound, mp 88°-89°; NMR (CDCl3) 1.48, 3.42, 3.60, 6.96, 8.01, 8.39 and 10.03δ; MS (EI, m/e) 291 (M+).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]Br)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.S1C(CCCCCCBr)=CC2C=CC=CC1=2.[Mg].BrCCBr.[CH3:39][Si:40]([CH3:49])([CH3:48])[C:41]1[O:45][CH:44]=[C:43]([CH:46]=[O:47])[CH:42]=1>O1CCCC1>[S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:46]([C:43]2[CH:42]=[C:41]([Si:40]([CH3:49])([CH3:48])[CH3:39])[O:45][CH:44]=2)[OH:47])=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: Br[Mg]CCCCCCc1cc2ccccc2s1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: BrCCCCCCc1cc2ccccc2s1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C[Si](C)(C)c1cc(C(O)CCCCCCc2cc3ccccc3s2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-(benzo[b]thien-2-yl)hexylmagnesium bromide (1.22 mmol, prepared from 1.22 mmol 6-(benzo[b]thien-2-yl)-1-bromohexane and 2.44 mmol magnesium, initiated with a catalytic amount of 1,2-dibromoethane) in 1.5 ml tetrahydrofuran at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.167 g., 0.99 mmol) in 1 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes, and then quenched with a 5% ammonium chloride solution. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a pale yellow oil. This material was purified by flash chromatography (silica, 100% hexane to 20% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[CH3:17][Mg]Br>C1COCC1>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([OH:16])[CH3:17])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(C=O)CC2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(C(C)O)CC2)n1
Reaction time: 2 h
Yield: 33.1 %

Procedure:
A solution of 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde (1.1 g, 4.93 mmol) in THF (25 mL) at −10° C. was treated dropwise with methylmagnesium bromide (3M in Et2O, 3.94 mL, 11.8 mmol). The mixture was stirred at −10° C. to −5° C. over a 2 h period. The reaction was carefully quenched by the addition of saturated aqueous NH4Cl and the aqueous was extracted with ether (6 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by chromatography on a silica gel column eluted with 0 to 70% EtOAc/hexanes to give 0.39 g (33%) of (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol as a light yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20]([CH:25]=[CH:26][C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc2occc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2occc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of benzofuran-5-yl-N-methylmethanamine (297 mg, 1.84 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (474 mg, 1.86 mmol), HOBt (252 mg, 1.86 mmol) and DIPEA (1.32 mL, 7.58 mmol) in anhydrous DMF (30 mL) was added EDC hydrochloride (357 mg, 1.86 mmol). The mixture was stirred overnight at 40° C. Water (70 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give a red solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-(benzofuran-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (381 mg, 57%) as a red solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.62 (m, 1H), 8.36-8.33 (m, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.59-7.49 (m, 3H), 7.38-7.17 (m, 2H), 6.94 (m, 1H), 4.89-4.69 (m, 2H), 3.10-2.85 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 362 [C21H19N3O3+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:33])[NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([F:34])[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:33])=[C:19]([F:34])[CH:18]=2)(=[O:15])=[O:16])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)c(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
[1-(3-Fluoro-4-phenethylcarbamoyl-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.38 g, 0.7 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum, then azeotroped with methanol and suspended in diethyl ether. The resulting solid precipitate was then collected by filtration, washed with diethyl ether and dried under vacuum to afford the title compound (0.24 g, 80% yield) as a white solid. Tr=1.20 min, m/z (ES+) (M+H)+ 406.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:12]([NH2:14])=[O:13]>CN(C)C1C=CN=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(N(C)C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]([NH2:14])=[O:13])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: NC=O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(C(N)=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.255 g of bis(triphenylphosphine)-palladium(II) chloride, 7.36 g of 1-bromo-4-tert-butylbenzene, 3.12 g of formamide, 4.64 g of 4-dimethylamino-pyridine and 25 ml of dimethyl acetamide are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the solution is diluted with diethylether and water, and extracted. The aqueous phase is extracted by shaking 3 times with diethylether, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 33% (part of the product remains in the water phase). 1H-NMR: 1.35 (s, CMe3), 6.21 (br, NH2), 7.45 (d, Ph—H), 7.77 (d, Ph—H); 13C-NMR: 31.5 (CMe3), 35.4 (C—Me), 125.9 (2 Ph—CH), 127.6 (2 Ph—CH), 130.9 (Ph—C), 155.1 (Ph—C), 169.9 (CONH2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([OH:12])[CH3:11].[N+:13]([C:16]1[C:21](O)=[CH:20][CH:19]=[CH:18][N:17]=1)([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:21]1[C:16]([N+:13]([O-:15])=[O:14])=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: C[C@@H](O)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol (12 g, 57.42 mmol) was dissolved in tetrahydrofuran (110 mL), 2-nitro-3-hydroxypyridine (8.84 g, 63.16 mmol) and triphenylphosphine (21.06 g, 80.39 mmol) were added, and the reaction mixture was stirred for 1 h at room temperature. Diisopropyl azodicarboxylate (16.26 g, 80.39 m mol) was added dropwise under the cooling of ice bath. The temperature of the reaction liquid was raised to 30° C., and the reaction was stirred overnight. After TLC test has showed that reaction was completed, the reaction liquid was concentrated under reduced pressure;
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=S)[NH2:2].NC1C=CC([C@H](C)C(OC)=[O:26])=CC=1.[O-]C#N.[Na+]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:26])[NH2:2]
Reactant: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Reactant: COC(=O)[C@@H](C)c1ccc(N)cc1
Agent: N#C[O-]
Agent: [Na+]
Product: COC(=O)[C@@H](C)c1ccc(NC(N)=O)cc1

Procedure:
Following the same procedure described for (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate and starting from methyl (2S)-2-(4-aminophenyl)propanoate (98 mmol) and sodium cyanate (128 mmol), after workup (S)-methyl 2-[4-(carbamoylamino)phenyl]propanoate was isolated as white solid (59%). 1H-NMR (CDCl3): δ 8.90 (bs, 1H, CONH), 7.55 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.50 (bs, 2H, CONH2), 3.75 (m, 1H), 3.60 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([O:20]CC)=[O:19].[Li+].[OH-]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCOc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1[nH]c2ccccc2c1CCCOc1cccc(Cl)c1

Procedure:
A mixture of EXAMPLE 3B (0.035 mg) and LiOH (0.1 g) in methanol/water (1:1, 5 mL) was heated at 150° C. under microwave (CEM Discover) conditions (70 W) for 10 minutes. The reaction mixture was concentrated, diluted with water (2 mL), treated with 5 MHCl, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB, C-18, 20% to 100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (400 MHz, DMSO-d6) δ 12.88 (brs, 1H), 11.40 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 7.24 (m, 2H), 6.92 (m, 4H), 3.97 (t, 2H), 3.20 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=4)[NH:20]C(=O)N[C:17]3=[O:22])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[OH-:36].[Na+]>>[NH2:20][C:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=1)([CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17]([OH:36])=[O:22]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C2(CC3c4ccccc4Oc4ccccc43)NC(=O)NC2=O)cc1OC
Agent: Cl
Agent: [Na+]
Product: COc1cc(C(N)(CC2c3ccccc3Oc3ccccc32)C(=O)O)ccc1C(=O)O

Procedure:
A suspension of 5-(9H-xanthen-9-ylmethyl)-5-(3-methoxy-4-methoxycarbonylphenyl)hydantoin (1.04 g, 2.27 mmol) in aqueous sodium hydroxide (2M, 6.8 ml) was heated at 120° C. in a teflon lined stainless steel sealed tube for 3 days with stirring. After cooling, aqueous hydrochloric acid (5M, 3 ml) was added followed by purification on ion exchange (Dowex50×8-100 resin). The column was eluted sequentially with water, water-tetrahydrofuran (1:1), water and 10% pyridine in water. Fractions collected after the pyridine-water elution were combined, evaporated to dryness, redissolved in water and freeze-dried to give 2-amino-2-(4-carboxy-3-methoxyphenyl)-3-(9H-xanthen-9-yl)propanoic acid as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.CN(C1CCNCC1)C.CCN=C=NCCCN(C)C.[CH3:35][CH:36]([CH2:40][CH3:41])[C:37](O)=[O:38]>C(Cl)Cl>[CH3:35][CH:36]([CH2:40][CH3:41])[C:37]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:38]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C1CCNCC1
Solvent: ClCCl
Product: CCC(C)C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
tert-butyl piperidin-4-ylcarbamate (1 g, 5 mmol), 4-(N,N-dimethylamino)piperidine (0.73 g, 6 mmol) and EDCI (1.15 g, 6 mmol) were added into a solution of 2-methylbutanoic acid (0.612 g, 6 mmol) in CH2Cl2 (200 mL). The reaction was stirred overnight at rt. The reaction was quenched with the addition of 0.1 M HCl. The organic layer was further washed with sat. NaHCO3 solution followed by sat. NaCl solution. The organic layers was concentrated under vacuo. The product was purified by flash chromatography (Hex:EtOAc/1:1) yielding final product 15 (1.3 g, 4.6 mmol, 91.5% yield). H-NMR (DMSO-d6) ∂ 0.79 (q, J=5 Hz, 3H), 0.95 (m, 3H), 1.2-1.3 (m, 2H), 1.38 (s, 9H), 1.50 (m, 2H), 1.73 (t, J=15 Hz, 1H), 2.6-2.7 (m, 2H), 3.06 (t, J=12 Hz, 1H), 3.46 (m, 1H), 3.88 (d, J=12 Hz, 1H), 4.26 (m, 1H), 6.85 (d, J=8 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6](=[NH:10])[O:7][CH2:8][CH3:9].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH2:21]([O:20][C:18]([N:10]=[C:6]([O:7][CH2:8][CH3:9])[CH2:5][CH2:4][O:3][CH3:2])=[O:19])[CH3:22]
Reactant: CCOC(=N)CCOC
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N=C(CCOC)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Ethyl 3-methoxypropanimidate hydrochloride (1.0 g, 6.0 mmol) was suspended in DCM (12 mL) and cooled to 0° C. Pyridine (2 mL, 24.7 mmol) was added dropwise and the mixture was stirred for 15 min. Ethyl chloroformate (0.97 g, 9.0 mmol) was added dropwise and the mixture was diluted with DCM (20 mL), allowed to warm to RT, and stirred for 12 h. The mixture was diluted with a mixture of EtOAc and hexanes (1:1, 200 mL) and the solids were removed by filtration through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to afford ethyl N-ethoxycarbonyl-3-methoxy-propanimidate (1.0 g, 83%) as a light green solid. 1H NMR (400 MHz, DMSO-d6): δ 4.08 (q, J=7.0 Hz, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.19 (s, 3H), 2.57 (t, J=6.4 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([N+:15]([O-])=O)[CH:8]=2)[CH2:3][CH2:2]1.[N:18]([C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[CH2:23][CH2:22]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:14]=[CH:13][C:10]3[C:9]([CH:8]=2)=[N:15][N:18]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[CH2:23][CH2:22]2)[CH:11]=3)[CH2:3][CH2:2]1
Reactant: C[C@@H](CO[C@H]1CC[C@H](N=[N+]=[N-])CC1)NC(=O)OC(C)(C)C
Reactant: O=Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[C@H]1CC[C@H](n2cc3ccc(OCCC4CC4)cc3n2)CC1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-cyclopropylethoxy)-2-nitrobenzaldehyde (0.79 g), tert-butyl {(1S)-2-[(trans-4-azidocyclohexyl)oxy]-1-methylethyl}carbamate (1.0 g), triphenylphosphine (3.08 g) and triethyl phosphite (3.08 g) in toluene (10 mL) was refluxed for 3 hr. The reaction mixture was allowed to cool, and concentrated under reduced pressure. To the obtained residue was added triethyl phosphite (4.0 g), and the mixture was stirred at 160° C. for 4 hr. The reaction mixture was allowed to cool, and purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:9][C:6]2[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: Oc1noc2cc(Cl)ccc12
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CCN(C(=O)Oc2noc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
200 mg (1.18 mmol) of 6-chlorobenzo[d]isoxazol-3-ol, 228.7 mg (1.41 mmol) of 4-methylpiperidine-1-carbonyl chloride and 164 μl (2.36 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 147 mg (42%), M+H+: 295.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CCN(C(C)C)C(C)C.[C:17]([O:21][C:22]([NH:24][C:25]1([CH:29]([OH:33])[C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:33][CH:29]([C:25]1([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:28][CH2:27][CH2:26]1)[C:30]([NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:31]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CCC2)n1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52 mmol) was added to a solution of 2-(1-(tert-butoxycarbonylamino)cyclobutyl)-2-hydroxyacetic acid (400 mg, 1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) was added. After approximately 2 hours at RT, LC-MS showed product and no starting material and the solvent was removed by rotary evaporation. The crude product was dissolved in 40 mL EtOAc and washed with 25 mL sat. NaHCO3(aq). The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified on a 25 g silica column on a Biotage Flashmaster, which gave the title product as a white solid (488 mg, 92%). TLC rf: 0.07 in heptane:ethyl acetate 1:1. [M+H]+=325.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11]CCC)[C:5]([OH:7])=[O:6].[C-]#N.[Na+].[C:18]([Cu])#[N:19]>CN(C=O)C>[C:18]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6])#[N:19]
Reactant: N#C[Cu]
Reactant: CCCOc1ccc(C(=O)O)cc1I
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)O)ccc1O
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of the product of Example 44 Step C (0.22 g; 0.72 mmol), NaCN (0.04 g; 0.8 mmol) and CuCN (0.07 g; 0.8 mmol) in anhydrous DMF (2 ml) was stirred at ˜110° C. for 2 h under N2. This was evaporated to dryness in vacuo and the residue was suspended in H2O (10 ml) and pH was adjusted to ˜10 with 1 M NaOH. The insoluble material was removed by filtration and the filtrate was acidified to pH˜3 with diluted HCl and the product was taken up by CH2Cl2 (2×20 ml). The organic phase was dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness under reduced pressure to give the title compound (0.1 g; 67%) as brownish solid. 1H-NMR (CDCl3) 1.06-1.14 (m, 3H); 1.85-1.97 (m, 2H); 4.1-4.18 (m, 2H); 7.02 (d, 1H, J=9 Hz); 8.24 (dd, 1H, J=3, 9 Hz); 8.31 (d, 1H, J=3 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][CH:31]=1>COCCOC.C([O-])(O)=O.[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>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:9]=2[NH:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[C:7]#[N:8])[CH:29]=[CH:28][CH:27]=1
Reactant: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
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
Product: COCCOc1cccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2C)c1
Temperature: 95 °C
Yield: 66 %

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 2-[3-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98 mg, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) in DME (6 mL) and saturated aqueous NaHCO3 (4 mL) was heated at 95° C. for 2 h, cooled to room temperature and partitioned between dichloromethane and water. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo, and the residue was purified by flash column chromatography (MeOH/CH2Cl2, 1% to 5%) to provide 71 mg (66%) of 5-[3-(2-methoxyethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a tan solid. HPLC retention time: 8.3 min.(g); MS: 399.3 (M+H); melting range: 158-160° C.; and HRMS: 399.18291.