Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(OCC)(=O)C.CO>[CH:26]1([NH:29][CH2:2][CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:28][CH2:27]1
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCCNC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
The compound (300 mg, 1.59 mmol) obtained in Example 25b was dissolved in ethyl acetate (16 mL), triethylamine (0.323 mL, 2.39 mmol) and methanesulfonyl chloride (0.147 mL, 1.90 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Insoluble matter was removed by filtration through celite, the solvent was evaporated under reduced pressure, the resulting residue was added dropwise to a solution of cyclopropylamine (1.82 g, 31.8 mmol) in methanol (3 mL) under ice cooling, and the mixture was stirred at 60° C. for 72 hours. The solvent was evaporated under reduced pressure, 1 N sodium hydroxide was added to the resulting residue, and the mixture was extracted with ethyl acetate (×3). The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1→10:1, v/v) to give the title compound (215 mg; yield, 59%) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@@:7]2([CH3:24])[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:8]2=[O:23])=[CH:4][CH:3]=1.[C:27]([Cu])#[N:28]>CN(C=O)C>[C:27]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]2([CH3:24])[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:8]2=[O:23])=[CH:25][CH:26]=1)#[N:28]
Reactant: N#C[Cu]
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Temperature: 140 °C
Yield: 77.4 %

Procedure:
(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-imidazo[1,2-α]-imidazol-2-one (13.5 g, 29.9 mmol) was dissolved in anhydrous DMF (70 mL) and CuCN (3.22 g, 35.9 mmol) was added. The reaction mixture was heated to 140° C. under argon for 40 h. When the reaction was complete, the solvent was removed under reduced pressure and the residue was diluted with CH2Cl2. The organic solution was washed four times alternately with 5% aqueous pyridine then water. The organic layer was dried over Na2SO4 and filtered through a diatomaceous earth pad. The filtrate was concentrated and purified by silica gel column chromatography using a mixture of CH2Cl2-hexane (10:1) as an eluent to afford 9.19 g of (R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-imidazo[1,2-a)-imidazol-2-one.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:21]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH:22]=1.[ClH:29].[CH3:30]COCC>>[ClH:29].[C:22]1([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH2:23][CH2:24][CH2:25][CH2:21][CH:30]=1
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Reactant: OB(O)C1=CCCC1
Reactant: CCOCC
Agent: Cl
Product: C1=C(c2cnc3ccc(NCCCN4CCOCC4)nn23)CCCC1
Yield: 75 %

Procedure:
Prepared from the product of step A (example 16) and 1-cyclopenteneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (82 mg, 75%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.66 (d, J=9.7 Hz, 1H), 7.47 (s, 1H), 7.13-7.12 (m, 1H), 6.78 (d, J=9.7 Hz, 1H), 3.89-3.87 (m, 4H), 3.49 (t, J=6.4 Hz, 2H), 3.21-3.17 (m, 6H), 2.51-2.49 (m, 2H), 2.32-2.30 (m, 2H), 2.17-2.12 (m, 2H), (1.84-1.81 (m, 2H), 1.75-1.70 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 155.4, 137.2, 131.1, 128.3, 126.6, 126.2, 124.8, 115.0, 65.4, 57.0, 53.6, 39.9, 27.9, 26.7, 24.3, 23.8, 23.2; HPLC tR=9.1 min (Synergi), 98%; ES-MS: (M+H)=342 m/z.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8]1([CH2:14][CH2:15][CH:16]=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[C:8]1([CH2:14][CH2:15][C@H:16]2[O:5][C:4](=[O:6])[CH2:3][C@@H:2]([CH3:7])[O:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CCCc1ccccc1
Reactant: C[C@@H](O)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CC(=O)O[C@H](CCc2ccccc2)O1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of (R)-3-hydroxybutanoic acid (7.8 g), 3-phenylpropionaldehyde (6.71 g) and pyridinium toluene-4-sulphonic acid (ca. 10 mmol %) in dichloromethane (300 ml) was stirred, under reflux, for 48 hours with removal of water. The reaction mixture was cooled to room temperature, washed three times with saturated sodium bicarbonate, dried (MgSO4) and evaporated under reduced pressure. The residue was crystallised from ether/pentane to give (2R,6R)-2-(2'-phenylethyl)-6-methyl-1,3-dioxan-4-one (7.0 g), m.p. 49.7°-50.9° C.; [α]DR.T. =15.2(c=1.05; CHCl3).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:22])[CH:11]=[N:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[CH:17][N:18]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:23]1([S:29]([N:19]2[C:16]3=[CH:17][N:18]=[C:13]([N:12]=[CH:11][N:10]([CH3:22])[CH3:9])[CH:14]=[C:15]3[C:21]([Br:1])=[CH:20]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C=Nc1cc2cc[nH]c2cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=Nc1cc2c(Br)cn(S(=O)(=O)c3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
1-Bromo-pyrrolidine-2,5-dione (5.34 g, 30 mmol) was added to a stirred solution of N,N-dimethyl-N′-(1H-pyrrolo[2,3-c]pyridin-5-yl)-formamidine (Preparation #10b, 6.00 g, 31.9 mmol) in DMF (200 mL) at about 0° C. The reaction was allowed to warm to ambient temperature then stirred for about 1 hour. Benzenesulfonyl chloride (3.83 mL, 30.0 mmol) and Na2CO3 (6.36 g, 60.0 mmol) were added and the mixture was warmed at about 60° C. for about 1 hour. The reaction mixture was concentrated under reduced pressure and the dark solids were triturated with EtOAc (2×100 mL) and filtered. The combined EtOAc layers were passed through a 6 inch silica gel column, eluting with EtOAc. The product fractions were combined and concentrated to yield N′-(1-benzenesulfonyl-3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)-N,N-dimethylformamidine (4.29 g, 35%) as a tan solid. RP HPLC (Table 1, Method e) Rt=2.18, m/z: (MH)+ 407/409.
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[C:31]([NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[C:32]5[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]5=[N:34][C:35]=4[CH2:36][CH3:37])=[O:27])[CH:21]=3)=[O:19])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:50][N:51]([CH3:56])[CH2:52][CH2:53][NH:54][CH3:55].[CH2:57]1COCC1>>[CH2:41]([N:38]1[C:33]2=[N:34][C:35]([CH2:36][CH3:37])=[C:30]([CH2:29][NH:28][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([NH:17][CH2:16][C:11]4[CH:10]=[C:9]([C:5]5[CH:4]=[CH:3][CH:8]=[C:7]([CH2:50][N:51]([CH2:52][CH2:53][N:54]([CH3:57])[CH3:55])[CH3:56])[CH:6]=5)[C:14]([F:15])=[CH:13][CH:12]=4)=[O:19])[CH:21]=3)=[O:27])[C:31]([NH:43][CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[C:32]2[CH:40]=[N:39]1)[CH3:42]
Reactant: CNCCN(C)C
Reactant: C1CCOC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CCl)c3)c2)c1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN(C)CCN(C)C)c3)c2)c1

Procedure:
N-{[3′-(Chloromethyl)-6-fluoro-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol) and N,N,N′-trimethyl-1,2-ethanediamine (0.025 g, 0.25 mmol) were combined in THF (1 mL) and microwaved at 150° C. for 1 h. Purification on a Gilson HPLC using a TFA system was followed by passing the product though a quaternary ammonium hydroxide cartridge to give the free base, the title compound, as a white solid. LC-MS m/z 748.8 (M+H)+, 1.43 min (ret time); mp 126-129° C. Analytical HPLC shows 99.1% purity, (ret time 9.788 min).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[Cl:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:28]=[N:29][C:2]2[CH:1]3[CH2:7][CH:4]([C:3]=2[CH:16]=1)[CH2:5][CH2:6]3
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cccc(Cl)c1Cl)OC
Reactant: O=C1C(=O)C2CCC1C2
Solvent: O
Product: Clc1cccc(-c2cc3c(nn2)C2CCC3C2)c1Cl

Procedure:
yellow viscous oil. MS (ESI): 291.0 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2,3-Dichloro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)CC=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27].F[C:29](F)(F)[C:30]([OH:32])=[O:31]>ClC(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl.C(#N)C>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:29][C:30]([OH:32])=[O:31])=[C:11]([CH2:12][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH3:27])[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(C2=CCc3ccc(Cl)cc32)c1OC
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(Cc2cc(Cl)ccc2CC(=O)O)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
701.6 mg of sodium periodate (3.28 mol) and 3.6 mg of ruthenium(III) chloride monohydrate (0.02 mol) are introduced into 3 ml of water. 229.4 mg of the compound from Example 24A (0.80 mol) dissolved in 2 ml of tetrachloromethane are added and, after addition of 2 ml of acetonitrile, the reaction mixture is stirred at room temperature for 16 h. For working up, the mixture is poured into 20 ml of a 5% strength aqueous trifluoroacetic acid solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate, and the solvent is removed in a rotary evaporator. The residue is stirred with 5 ml of ethyl acetate and 2 ml of n-heptane and stored at 5° C. for 3 h. The deposited product is filtered off, washed with m-pentane and dried under high vacuum. 119.0 mg (44% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[N:12](OCCC(C)C)=[O:13].Cl.O1CCOCC1>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12][OH:13])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)C(=NO)C2

Procedure:
6-Methyl-1-indanone (40.4 g) and isoamyl nitrite (40.6 mL) were dissolved in ethanol (300 mL), and 4N hydrogen chloride-dioxane (10 mL) was added dropwise under ice-cooling. After the completion of the reaction, the precipitated crystals were collected by filtration and washed with ether to give 6-methyl-2-hydroxyimino-1-indanone (37 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>CO.C(OCC)(=O)C>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:21]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1CN1CCOCC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
A solution of 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.079 g, 0.300 mmol) in methanol (1.2 mL) was added with 1H-indole-3-carboxaldehyde (0.0523 g, 0.300 mmol) and piperidine (0.00255 g, 0.0300 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain an orange crude product as a solid. This solid was suspended in ethyl acetate and thereby washed to obtain the objective (Z)-2-[(1H-indol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0128 g, 10%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10][C:11]3([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:4]=12.[BH-](O[C:44]([CH3:46])=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.ClCCCl.C(Cl)Cl>[CH2:17]([N:14]1[CH2:13][CH2:12][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][NH:1][CH:46]3[CH2:44][CH2:12][CH2:11][CH2:10]3)[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10]2)[CH2:16][CH2:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CN)cccc43)c21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC5CCCC5)cccc43)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of cyclopentone (0.036 mL, 0.40 mmol) in THF (0.15 mL) was added to a stirred solution of (R)-tert-butyl 4-(aminomethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (30 mg, 0.067 mmol) in DCE (0.6 mL) The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH was added, and the reaction allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give (R)-N-((1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)cyclopentanamine (34 mg, 98%) as an oil. LCMS (APCI+) m/z 518 [M+H]+; Rt=2.91 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:16])[C:14]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:16][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:8])[C:14]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 66.2 %

Procedure:
General procedure C was followed using N-methylpiperazine (27 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (44 mg, 65%), umax (CHCl3)/cm−1 2942, 2849, 2803, 1558, 1449, 1289, 1151; m/z (ESI) C10H14Cl2N3 requires 246.0559, found [M+H]+ 246.0560.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:2]1.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].C[C@H]1NCCNC1.[NH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31]>>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:12]([OH:14])=[O:13])[CH2:31][C@H:30]([NH2:29])[C:32]([OH:34])=[O:33])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Agent: CC(=O)C(=O)[O-]
Agent: C[C@@H]1CNCCN1
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
In a specific embodiment, L-tryptophan is converted to D-tryptophan using a tryptophan racemase. D-tryptophan then reacts with pyruvate via a broad specificity D-aminotransferase to produce indole-3-pyruvate and D-alanine. Indole-3-pyruvate then reacts with an R-specific aldolase and pyruvate to form R-α-keto acid monatin (R-MP). R-MP then reacts with a broad specificity D-aminotransferase and D-alanine to produce R,R monatin and pyruvate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].[CH3:16]N(C)CCN(C)C.[Cl-].[NH4+]>O1CCCC1.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:16][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:2]1=[O:10]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800 cm3) was cooled to −20° C. then n-butyllithium (2.5M in hexanes, 152 cm3, 0.38 mol) was added slowly followed by N,N,N′,N′-tetramethylethylenediamine (51 cm3, 0.38 mol,). After 15 min. 1,5-dilodopentane (174 g, 0.54 mol) was added slowly and the mixture was allowed to warm to room temperature. After stirring for 16 h. saturated aqueous ammonium chloride solution (1L) and EtOAc (1L) were added. After 15 min., the layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organic layers were extracted with hydrochloric acid (1N), then washed with brine (500 cm3), dried (MgSO4), and concentrated to obtain an oil. The oil was triturated with hexane (200 cm3) and benzene (20 cm3). The precipitate was collected and dried in vacuo to obtain the subtitled compound (26.3 g, 69.6%) as colorless crystals: mp 110-114° C.; 1H NMR (DMSO-d6) δ 1.67 (m, 10H), 6.84 (d, 1H, J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44 (d, 1H, J=8 Hz), 10.3 (S, 1H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH:11]1[CH2:14][NH:13][CH2:12]1.Cl.[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2([CH2:31][C:30]3[C:25](=[N:26][CH:27]=[C:28](/[CH:32]=[CH:33]/[C:34](O)=[O:35])[CH:29]=3)[NH:24][C:23]2=[O:37])[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH:11]1[CH2:12][N:13]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:28]2[CH:29]=[C:30]3[C:25](=[N:26][CH:27]=2)[NH:24][C:23](=[O:37])[C:20]2([CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH2:31]3)[CH2:14]1
Reactant: c1ccc2oc(C3CNC3)cc2c1
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC(c4cc5ccccc5o4)C3)cnc1NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 3-(benzofuran-2-yl)azetidine hydrochloride (30 mg, 0.086 mmol) and (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (20 mg, 0.059 mmol) in dry DMF (4 mL) were added EDCI.HCl (17.02 mg, 0.089 mmol), HOAt (12.09 mg, 0.089 mmol) and DIPEA (51 μL, 0.296 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and H2O, the layers were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic layers were washed with brine (3×3 mL), dried over Na2SO4 and concentrated. The residue was chromatographic purified (silica gel, eluent dichloromethane/7M NH3 in MeOH 98:2 to 95:5). The residue was further purified by preparative LCMS (Waters X-Bridge 50×19 mm 5 μm ODB in combination with Waters X-Bridge guard 10×19 mm 5 μm, at 25 ml/min flow rate; detection of product by mass and UV signal; eluent 10 mM ammonia in milliQ water to 10 mM ammonia in MeCN 5% to 95% gradient), to yield the title compound (2.6 mg, 9.6%).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][CH:57]=2)[CH:53]([NH:58][C:59](=[O:73])[CH2:60][C:61]2[N:62]=[C:63]([C:66]4[CH:71]=[CH:70][CH:69]=[C:68]([OH:72])[CH:67]=4)[S:64][CH:65]=2)[C:52]3=[O:74])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:72][C:68]1[CH:67]=[C:66]([C:63]2[S:64][CH:65]=[C:61]([CH2:60][C:59]([NH:58][CH:53]3[C:52](=[O:74])[N:51]4[CH:54]3[S:55][CH2:56][CH:57]=[C:50]4[C:48]([OH:49])=[O:47])=[O:73])[N:62]=2)[CH:71]=[CH:70][CH:69]=1
Reactant: O=C(Cc1csc(-c2cccc(O)c2)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(Cc1csc(-c2cccc(O)c2)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 99.1 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8n (152 mg, 0.261 mmol), Et3SiH (0.417 mL, 2.61 mmol), and trifluoroacetic acid (0.804 mL, 10.4 mmol) in dry ClCH2CH2Cl (4 mL) at 0° C. under nitrogen to give 9n (108 mg, 99%) as a white solid after crystallization from THF/Et2O/hexane. mp 195° C. (dec); IR (KBr) 3600-2600 (br), 3343, 1787, 1682, 1532 cm-1 ; 1H NMR (DMSO-d6) δ3.49 (1H, dd, J=19.0 and 6.0 Hz), 3.59 (1H, dd, J=19.0 and 2.6 Hz ), 3.73 (2H, s, CH2), 5.01 (1H, d, J=4.9 Hz), 5.73 (1H, dd, J=8.3 and 4.9 Hz), 6.45 (1H, dd, J=6.0 and 2.6 Hz), 6.88 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.28 (1H, d, J=7.8 Hz), 7.29 (1H, s), 7.38 (1H, s), 9.05 (1H, d, J=8.3 Hz, NH), 9.68 (1H, s, OH), 13.15 (1H, br s, CO2H); FDMS m/z 417 (M+), 418 (M+ +1); Anal. Calcd for C18H15N3O5S2 : C, 51.79; H, 3.62; N, 10.07. Found: C, 51.95; H, 3.66; N, 9.80
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][O:7][C:6]2[C:9]([C:13](O)=O)=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OC(=O)C)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:4]2[C@@H:3]([CH2:2][OH:1])[CH2:8][O:7][C:6]3[C:9]([C:13]4[NH:33][C:28]5[CH:27]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:31]=[CH:30][C:29]=5[N:32]=4)=[CH:10][CH:11]=[CH:12][C:5]2=3)=[N:17][CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: COc1ccc(N2c3cccc(C(=O)O)c3OC[C@@H]2CO)nc1
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
Solvent: CCOC(C)=O
Product: COc1ccc(N2c3cccc(-c4nc5ccc(C(F)(F)F)cc5[nH]4)c3OC[C@@H]2CO)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of (S)-3-(hydroxymethyl)-4-(5-methoxypyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid 3.2 g (10 mmol) of step 7 in dimethylformamide 50 mL were 4-(trifluoromethyl)benzen-1,2-diamine 1.9 g (11 mmol), diisopropylethylamine 3.5 mL (20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 5.7 g (15 mmol), followed by stirring at room temperature for 3 hrs. The reaction mixture was diluted with ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, dried over magnesium sulfate and concentrated in a vacuum. The concentrate was dissolved in acetic acid/toluene (90 mL/10 mL), heated at 75° C. for 4 hrs with stirring, cooled to room temperature and concentrated in a vacuum. The concentrate was dissolved in ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by column chromatography (developing solvent: ethylacetate/hexane=2/3) afforded 4.1 g of the title compound (yield 82%).