Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24]C(C)=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH3:24])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C

Procedure:
The concentrated solution (1.88 g) containing (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid, which was prepared by concentrating the ethyl acetate portion, was obtained in the same manner as Example 1. To the solution, 24 ml of acetone were added to prepare an acetone solution. 3.1 g of methyl iodide and 0.60 g of potassium carbonate were added to the solution with stirring, and then the mixture was further stirred for 5 hours at room temperature. After 24 ml of water was added to the solution, the solution was extracted with two portios of 30 ml of ethyl acetate. The ethyl acetate portions were combined and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation in vacuo to give 1.2 g of methyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate as an oil (optical purity: 98% ee; purity: 79%).
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13]>O.CO>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])/[CH:11]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(/C=C/c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.8 %

Procedure:
To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL) was added benzaldehyde (0.746 g, 7.03 mmol) and then a solution of 5-chloro-2-hydroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room temperature, and it was stirred for 24 hours. The bulk of the organic solvent was removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc (3×30 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo. The residue was dissolved in a minimum volume of CH2Cl2, and n-pentane was added which resulted in precipitation. The obtained suspension was filtered and the precipitate was washed with little cold pentane, and dried in vacuo to afford Compound (XVI) (695 mg, 46%) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/1)=[O:5].[CH:31](B(OCCCC)OCCCC)=[CH2:32].[F-].[Cs+]>CO.COCCOC.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>[C:12]([C:10]1[N:9]([CH3:16])[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)/[C:7](=[N:6]/[C:4](=[O:5])[C:3]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:2]=2[CH:31]=[CH2:32])/[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1C[C@H]1CCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: C=Cc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Temperature: 130 °C
Yield: 86 %

Procedure:
To the mixture of Example 88, tetrakis(triphenylphosphine)palladium (0.231 g, 0.200 mmol), dibutyl vinylboronate (0.863 ml, 4.00 mmol) and cesium fluoride (1.82 g, 12.0 mmol) in MeOH (1 mL) and DME (2 mL) was added tetrakis(triphenylphosphine)palladium (0.231 g, 0.200 mmol). The mixture was heated in a sealed tube at 130° C. for 20 min. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was diluted with EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3 and brine and then concentrated. Purification by column chromatography (silica gel, 5-30% gradient of 9:1 MeOH/Et3N in EtOAC) provided the title compound 1.5 g (86% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H) 1.62-1.95 (m, 4H) 3.59-3.68 (m, 1H) 3.70-3.81 (m, J=7.14, 7.14 Hz, 1H) 3.90 (s, 3H) 4.11-4.22 (m, J=6.15, 4.16 Hz, 1H) 4.26-4.46 (m, 2H) 5.31 (d, J=12.29 Hz, 1H) 5.76 (d, J=17.85 Hz, 1H) 6.85 (s, 1H) 7.54-7.68 (m, 2H) 7.76 (d, J=8.33 Hz, 1H) 8.04 (d, J=1.59 Hz, 1H); MS (ESI) m/z 436 (M+H)+, 434 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].CN(C=O)C.CC#N.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][CH:34]1[CH2:36][CH2:35]1
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OCC2CC2)c(Cl)c1)C1CCCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one ((25 g, 0.099 mol, from Step 2) in 1:1 DMF/CH3CN (200 mL) was treated with K2CO3 (15 g, 0.109 mol, 1.1 equiv), and the mixture stirred for 15 min. A solution of (bromomethyl)cyclopropane (17.4 g, 0.129 mol, 1.3 equiv) in DMF (50 mL) was added dropwise, and the reaction mixture heated to 100° C. for 1 h. The volatiles were removed in vacuo. The residue was dissolved in a minimal amount of ethyl acetate, and this solution washed with water, dried over Na2SO4, filtered, and evaporated. Chromatographic purification of the residue on silica gel using hexanes/ethyl acetate afforded 29.12 g (96%) of the title compound. 1H NMR (CDCl3) δ 0.32 (m, 2H), 0.58 (m, 2H), 1.23 (m, 1H), 1.64 (m, 8H), 2.70 (m, 5H), 3.8 (d, J=6 Hz, 2H), 6.78 (d, J=9 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 7.13 (s, 1H). MS calcd for C18H23ClO2, 306.83, found [M+1)]: 307.0
Reaction SMILES: CN(C1C=CC=CN=1)C.[O:10]=[N:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14].S(Cl)(C)(=O)=O.Cl.[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29]>O1CCCC1.ClCCl.C(N(CC)CC)C>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:16](=[O:18])[C@H:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[O:10]
Reactant: CC(C)[C@H](N=O)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N=O)C(C)C
Temperature: -20 °C

Procedure:
15.1 g of dimethylaminopyridine were added to a solution of 13.0 g of the ketovaline obtained in step a) in 100 ml of tetrahydrofuran. While stirring, 22.7 g of triethylamine were added dropwise, and the reaction mixture was cooled to -20° C. Subsequently a solution of 14.1 g of mesyl chloride in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for a further 20 minutes. Then a solution of 20.4 g of leucine methyl ester hydrochloride in 150 ml of dichloromethane was added dropwise, and the mixture was again stirred for 20 minutes. The mixture was then allowed to warm slowly to room temperature, undissolved constituents were separated by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was taken up in distilled water and extracted with dichloromethane. The collected organic phases were then dried over sodium sulfate and, after filtration, the solvent was removed under reduced pressure. 14.7 g of the title compound remained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:25]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(N(C)S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(4-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in an analogous manner to Step 2d and was isolated as a tan solid (0.038 g, 33%). MP=202-204° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.9 Hz, 1H), 8.06 (d, J=7.4 Hz, 2H), 7.58 (d, J=7.1 Hz, 1H), 7.52 (d, J=7.4 Hz, 2H), 7.36 (s, 1H), 7.25-7.19 (m, 1H), 7.00-6.95 (m, 2H), 6.83 (s, 1H), 6.59 (d, J=8.4 Hz, 1H), 3.39 (s, 3H), 3.30-3.25 (m, 4H), 2.90 (s, 3H), 2.63-2.58 (m, 4H), 2.37 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.[NH2:13][C@H:14](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CCC(=O)O>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:14][NH2:13]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Arg, Gln, Glu
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[NH2:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])(C)C)=[O:39])[CH2:34]1>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([NH:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:44]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:39])[CH2:34]2)=[O:29])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 18.2 %

Procedure:
Following a procedure similar to that described in Preparation 19, but using 6.4 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 2.40 g of N,N'-carbonyldiimidazole and 2.7 g of (3R)-3-amino-1-t-butoxycarbonylpyrrolidine, 750 mg of the title compound were obtained as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[O:11][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Yield: 86 %

Procedure:
2-Phenylbenzoxazole-7-carboxylic acid was prepared from 3-aminosalicyclic acid and benzoyl chloride using a procedure identical to that described in Step A of Example 1. This material was obtained in 86% yield as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.30 (dd, J=7.2, 2.1 Hz, 2H), 7.98 (dd, J=12.9, 7.8 Hz, 2H), 7.60(m, 3H), 7.48 (t, J=7.8 Hz, 1H); MS (APCI) m/z 240 [M+H]+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C=O)C>[N:19]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc(CCl)n1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCCC2)n1
Temperature: 80 °C
Yield: 67.4 %

Procedure:
K2CO3 (66 g, 0.48 mol) was added to a solution of methyl 6-(chloromethyl)picolinate 71 (45.0 g) and pyrrolidine 72 (34 g, 0.48 mol) in DMF (300 mL). The reaction mixture was heated at 80° C. for 12 h. H2O (300 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 73 (36 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[C:44]([O:43][C:41]([N:35]1[CH2:40][CH2:39][N:38]([C:13](=[O:15])[CH2:12][CH2:11][C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)[CH2:37][CH2:36]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (2.07 g, 10 mmol), prepared as described in Example 1 above, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloide (2.3 g, 12 mmol), anhydrous 1-hydroxybenzotriazole (1.62 g, 12 mmol) and N,N-diisopropylethylamine (1.75 ml, 10 mmol) were mixed together in 50 ml of dichloromethane and stirred for one hour at room temperature. Tert-butyl 1-piperazinecarboxylate (2.24 g, 12 mmol) was added to the mixture and stirred at room temperature overnight. The reaction mixture was concentrated and the syrup was dissolved in dichloromethane then purified by flash chromatography, eluting with dichloromethane followed by (dichloromethane: methanol 50/1, 30/1) to give 4-[3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (4.45 g, 86% pure).
Reaction SMILES: C(OCC)(=O)C(OCC)=O.COC1C=CC(N2CCOCC2)=CC=1N.C([O:28][C:29](=[O:47])[C:30]([NH:32][C:33]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:34]=1[O:45][CH3:46])=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:49]>C1(C)C(C)=CC=CC=1>[CH3:46][O:45][C:34]1[CH:35]=[CH:36][C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:38][C:33]=1[NH:32][C:30](=[S:49])[C:29]([OH:28])=[O:47]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C(=O)Nc1cc(N2CCOCC2)ccc1OC
Agent: COc1ccc(N2CCOCC2)cc1N
Solvent: CCOC(=O)C(=O)OCC
Solvent: Cc1ccccc1C
Product: COc1ccc(N2CCOCC2)cc1NC(=S)C(=O)O
Temperature: 180 °C

Procedure:
In accordance with scheme 1, the compounds of formula I are prepared as follows: Diethyl oxalate (2) is heated to about 120° C. 2-Methoxy-5-morpholin-4-yl-phenylamine (1) is added very cautiously in small quantities and the mixture is heated for 90 minutes at about 180° C. After cooling to room temperature and filtration n-hexane is added. The resulting precipitate is collected by filtration. After washing with hexane and drying N-(2-methoxy-5-morpholin-4-yl-phenyl)-oxalamic acid ethyl ester (3) is obtained. Then, to the obtained compound of formula (3) in boiling xylene is added phosphorus pentasulfide in small portions over a period of about 30 minutes. The mixture is refluxed for about 5 hours, cooled to room temperature and filtered. The solution is extracted with 1N NaOH. The aqueous phase is washed with toluene, filtered, and treated at 0-5° C. with concentrated hydrochloric acid until pH 1 was reached. Filtration of the precipitate yielded (2-methoxy-5-morpholin-4-yl-phenylamino)-thioxo-acetic acid (4).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-])=O.C(OC(NC1C=CC(CC(O)=O)=CC=1)=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:31]([C:29]2[O:30][C:26]([C:23]3[CH:24]=[CH:25][C:20]([NH2:17])=[CH:21][CH:22]=3)=[CH:27][CH:28]=2)=[O:32])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Product: CC(C)(C)c1cc(NC(=O)c2ccc(-c3ccc(N)cc3)o2)cc(C(C)(C)C)c1O
Yield: 56 %

Procedure:
The experimental protocol used is the same as that described for intermediate 40.1, 2,6-di-t-butyl-4-aminophenol and 5-(4-nitrophenyl)-2-furan carboxylic acid replacing thiazolidine and 4-(t-butoxycarbonylamino)-benzeneacetic acid respectively. The expected compound is obtained in the form of a colourless oil with a yield of 56%.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[ClH:9].N1C=CC=CC=1>C(#N)C>[Cl:9][CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][C:2](=[O:8])[CH2:1]1
Reactant: Cl
Reactant: CCCCCC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C1CCCC(CCl)C1
Temperature: 82 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The title compound was prepared following the procedure described in (N. Di Bello et al., Synthesis, 1978, 227. To a solution of bicycle[4.1.0]heptan-2-one (13.8 g, 125 mmol) in acetonitrile (300 mL) was added pyridine hydrochloride (43.3 g, 375 mmol) which had been triturated with Et2O and dried under high vacuum. The solution was stirred under N2 at 82° C., overnight. The reaction mixture was partially concentrated, poured into brine (200 mL) and extracted with Et2O (4×100 mL). The ether extracts were combined, washed with brine (100 mL), dried and concentrated. The residual oil was purified on a Biotage flash chromatography system (15% ethyl acetate in hexanes) to yield the title compound (13.4 g, 91 mmol, 73.1% yield) as an oil. LCMS: 147.09 (M+H), 149.10 (M+3, 30% rel. intensity). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.51-1.60 (m, 1 H) 1.62-1.74 (m, 1 H) 1.95-2.02 (m, 1 H) 2.06-2.13 (m, J=13.47, 9.80, 3.62, 3.62 Hz, 1 H) 2.13-2.20 (m, 1 H) 2.20-2.31 (m, 2 H) 2.35-2.43 (m, 1 H) 2.45-2.51 (m, 1 H) 3.45-3.55 (m, 2 H). 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 24.63, 28.75, 40.85, 41.15, 45.39, 210.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][Si](C)(C)C.[CH2:30]([N:32]([CH2:46][CH3:47])[C:33](=[O:45])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:31]>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33]([N:32]([CH2:46][CH3:47])[CH2:30][CH3:31])=[O:45])=[CH:40][CH:39]=1)(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)OCCOCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCOCCO)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 47.6 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 114 from 1.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-[2-(trimethylsilyloxy)ethoxy]ethyl]amino]indol-2-one and 1.03 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent gives 1 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=114°-118° C.
Reaction SMILES: Cl[C:2](OCC)=O.[NH2:7][CH2:8][C:9]1([C:20]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:19]2[C:11](=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:10]1.C(N(CC)CC)C>ClCCl>[CH3:2][NH:7][CH2:8][C:9]1([C:20]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:19]2[C:11](=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:10]1
Reactant: NCC1(C2(O)CCCC2)Cc2cc3sccc3cc21
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCC1(C2(O)CCCC2)Cc2cc3sccc3cc21

Procedure:
A solution of 0.29 ml of ethyl chloroformate in 40 ml of dichloromethane is introduced, at 0° C., to a mixture of 1 g of the product of Example 21, 1.2 ml of triethylamine and 60 ml of dichloromethane. After returning to room temperature, the reaction mixture is washed with 0.1N hydrochloric acid and then with a saturated sodium hydrogen carbonate solution, dried and then evaporated. The resulting residue is dissolved in 20 ml of tetrahydrofuran. The solution is added to a mixture of 1.3 g of AlLiH4 in 60 ml of tetrahydrofuran. The reaction mixture is refluxed for 3 hours and then hydrolysed with 0.65 ml of water, 0.45 ml of 20% sodium hydroxide solution and 2.1 ml of water. After filtration and concentration, the residue is purified by chromatography over silica gel (dichloromethane/ethanol/NH4OH: 95/5/0.5) and recrystallised from isopropyl ether to yield the expected product.
Reaction SMILES: [CH3:1][N:2]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][C:4](O)=O.[CH:20]([OH:22])=[O:21].CC1C=CC=CC=1C.[OH2:31]>>[CH3:4][CH:3]([C:20]([OH:22])=[O:21])[N:2]([CH:1]=[O:31])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O
Reactant: CN(CC(=O)O)C(c1ccccc1)c1ccccn1
Reactant: O=CO
Solvent: Cc1ccccc1C
Product: CC(C(=O)O)N(C=O)C(c1ccccc1)c1ccccn1
Yield: 60.3 %

Procedure:
A mixture of 37 parts of methyl N-[phenyl(2-pyridinyl)methyl]glycine, 36 parts of formic acid and 450 parts of dimethylbenzene was stirred and refluxed for 2 hours. The reaction mixture was poured into water. The product was extracted with 1,1'-oxybisethane. The extract was washed successively with a sodium hydroxide solution 10% and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 24 parts (60.3%) of methyl N-formyl-N-[phenyl(2-pyridinyl)methyl]glycine as a residue.
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]#[N:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O.C1(C)C=CC=CC=1>[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([C:20]#[N:21])=[N:3][OH:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1ccccc1Oc1ccccc1
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(=NO)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78002.1 %

Procedure:
85% Potassium hydroxide (3.96 g, 0.06 mol), toluene (100 ml) and butyl nitrite (6.19 g, 0.06 mmol) were added to 2-phenoxybenzyl cyanide (10.46 g, 0.05 mol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with hydrochloric acid, extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-phenoxy-α-hydroxyiminobenzyl cyanide (11.15 g, Yield: 93.6%, E/Z=11/89).