Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Br:31])[N:9]=1)=[O:7])(C)(C)C.O[Li].O.C(OCC)(=O)C>O1CCCC1.O.CCCCCC>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Br:31])=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Yield: 94.7 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (376) (14 g, 27.723 mmol) in tetrahydrofuran-water (15:7, 220 mL) was added LiOH.H2O (11.644 g, 277.228 mmol). The reaction mixture was refluxed for 16 h while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.1). After completion of the reaction, all volatiles were removed and the residue was diluted with water (50 mL) and neutralized to pH 7 with 1N HCl. The mixture was filtered and the resulting solid was dried to get 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (377) (11.8 g, 94.65%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].[H-].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[CH:7][N:8]2[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1cc2c(I)c[nH]c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A solution of 6-fluoro-3-iodo-1H-indole-5-carboxylic acid (650 mg, 2.13 mmol) in DMF (5 mL) at 0° C. was treated with NaH (60% dispersion in mineral oil, 0.213 g, 5.33 mmol). After 30 minutes at 0° C., TsCl (0.447 g, 2.34 mmol) was added in 1 portion and the reaction mixture was warmed slowly in the ice bath (reached ca. 10° C.). After 1.5 h, the reaction mixture was poured onto ice, and the pH adjusted to pH 5 with 2 N HCl causing precipitation of the product. It was then collected by filtration, washing with water on a sintered glass frit, transferred to a flask and dried on a lyopholizer for 5 h affording 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carboxylic acid (858 mg, 1.87 mmol, 88% yield) as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 459.8 (M+H)+. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](OC)=[O:35].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>O1CCCC1>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2]([OH:1])=[C:7]([O:8][CH3:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[CH3:12]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCc1c(C)cc(OC)c(OC)c1O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoate (3 g) in tetrahydrofuran (30 ml) is added lithium aluminum hydride and the mixture is stirred at room temperature for 1 hour. Under ice-cooling, 10% aqueous solution of sulfuric acid is added to the reaction mixture. The mixture is subjected to extraction with ether. The extract is washed with water and dried. The solvent is distilled off under reduced pressure, whereby 6-(22-hydroxydocosyl)-2,3-dimethoxy-5-methylphenol is obtained as colorless needles. m.p. 78° C.-81° C.
Reaction SMILES: [N:1]1([N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:4]1[CH2:3][CH2:2][N:1]([N:7]3[CH2:12][CH2:11][CH2:10][NH:9][C:8]3=[O:13])[CH2:6][CH2:5]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C1NCCCN1N1CCNCC1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCN(N2CCCNC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
1-(Piperazin-1-yl)tetrahydropyrimidin-2(1H)-one obtained in Example 25b) (0.55 g), (2S)-3-[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.94 g) and HOBt (0.46 g) were dissolved in DMF (20 mL), WSC was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=5/1), and recrystallized from ethyl acetate-methanol to obtain the title compound (0.88 g, 61%) as a colorless powder.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH3:17][O:16][C:4]1[CH:3]=[C:2]([N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH2:27][CH2:28]2)[C:10]2[O:9][C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=1
Reactant: COc1cc(Br)c2oc(C(=O)N(C)C)cc2c1
Reactant: c1ccc(CCN2CCNCC2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(CCc3ccccn3)CC2)c2oc(C(=O)N(C)C)cc2c1

Procedure:
7-Bromo-5-methoxy-N,N-dimethylbenzofuran-2-carboxamide (0.20 g, 0.67 mmol), 1-(2-pyridin-2-yl-ethyl)piperazine (0.13 g, 0.67 mmol), Pd2 dba3 (0.031 g, 0.030 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (0.032 g, 0.070 mmol) and sodium t-butoxide (0.14 g, 1.41 mmol) were heated in toluene (1 mL) at 100° C. for 2 h. The mixture was allowed to cool. Ethyl acetate was added and the mixture was filtered through a pad of Celite. The filtrate was washed with water and brine, dried over MgSO4 and the solvent was removed by rotary evaporation. The crude product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-3%) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Fc1cc(F)cc(-c2cc(CCl)ccn2)c1
Product: COc1ccc(N(Cc2ccnc(-c3cc(F)cc(F)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,5-difluorophenyl)pyridine (240 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH:19]([CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C(OC1C=CC(/C=C2/C(=O)N(CCCNC(=O)OC(C)(C)C)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH:19]([CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)NCC(Br)CNC(=O)OC(C)(C)C
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)C2=O)cc1
Yield: 23.9 %

Procedure:
The title compound 21e was prepared from compound 2 (292 mg, 1.17 mmol) and di-tert-butyl (2-bromopropane-1,3-diyl)dicarbamate (413 mg, 1.17 mg) in a manner similar to that described for 21a. Yield=23.9%, 130 mg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([CH3:31])[CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(C)cc(C)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,5-dimethylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, dd, J=2.6, 0.3 Hz), 8.24 (1H, d, J=7.3 Hz), 8.16 (1H, d, J=3.0 Hz), 8.00 (2H, dd, J=6.6, 1.8 Hz), 7.42 (2H, d, J=8.4 Hz), 6.94 (1H, s), 6.77 (2H, s), 5.42–5.32 (1H, m), 3.90 (3H, s), 2.36 (6H, s), 1.58 (3H, d, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>CO.O.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>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(Br)ccc1F
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: CO
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ccc1F
Temperature: 105 °C
Yield: 90.2 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (400 mg, 2.000 mmol) and (Ph3P)4Pd (116 mg, 0.100 mmol) were mixed in a microwave tube (20 mL) and flushed with nitrogen. Toluene (5 mL), 2 M aqueous sodium carbonate (2.270 mL, 4.54 mmol) and a solution of 3,4-dichlorophenylboronic acid (519 mg, 2.72 mmol) in MeOH (3 mL) were added. The mixture was heated in an oil bath at 105° C. for 4.5 h. After cooling to room temperature, the reaction was diluted with water (10 mL) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL), and combined organic phases were washed with water (2×10 mL), 5% aqueous NH4OH (10 mL), and brine (10 mL). The organic phase was dried over Na2SO4 and the solvent was removed. The residue was chromatographed on silica gel eluting with hexane containing 0, 2, 3% ethyl acetate to afford 480 mg of product as a white solid which was about 76% pure by LC/MS. This was used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccnc2cn[nH]c12
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccnc3cn[nH]c23)cc1
Yield: 55 %

Procedure:
A solution of 7-chloro-1H-pyrazolo[4,3-b]pyridine (215 mg, 1.4 mmol) in aniline (1.3 ml) was heated under reflux under nitrogen for 16 h. The mixture was cooled, and the white solid which separated was collected, washed with 60°-80° petrol and water, then dried. The solid was then dissolved in 60% aqueous methanol (25 ml). The solution was filtered, adjusted to pH9 with 10% sodium carbonate solution, and on cooling the product crystallised, to give the title compound as needles (161 mg, 55%), m.p. 222°-224° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([N:12]2[C:7](=[O:9])[C:3]3[C:2](=[N:1][CH:6]=[CH:5][CH:4]=3)[C:10]2=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Solvent: C1CCOC1
Product: O=C1c2cccnc2C(=O)N1c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2,3-pyridinedicarboxylic acid anhydride (19.4 g) in tetrahydrofuran (260 mL) was added aniline (11.8 mL) and the mixture was refluxed 2 hours. The reaction mixture was concentrated. Acetic anhydride (65 mL) was added to the reaction mixture, which was refluxed for 1.5 hours. After cooling in ice bath, the reaction mixture was poured in ice water (200 mL) and stirred for 1 hours. The precipitate was collected by filtration. It was washed with water and then washed with ethanol on heating to give the title compound (20.9 g) having the following physical data.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:27][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])[CH3:4].[CH3:28]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:27][C:11]2[N:12]([CH3:28])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 3.0 g, 0.075 mole) in 25 ml of dry dimethylformamide, was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxycyclopent[b]indole-2-carboxylic acid ethyl ester (23.5 g, 0.07 mole) in 100 ml of dry dimethylformamide. After stirring at ambient temperature for two hours, a solution of methyl iodide (4.7 ml, 0.075 mole) in 20 ml of dimethylformamide was added, and the mixture was stirred at 70° C. for five hours. After cooling, the mixture was poured into 500 ml of water, stirred for five minutes, and then extracted with ethyl acetate (3×). The organic layer was washed successively with water and saturated sodium chloride solution, and dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a brown oil (~25 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fraction was concentrated to a thick brown oil, 20.6 g, which solidified on cooling, m.p. 90°-95° C. A sample of this material was recrystallized from ethanol to give the product as an off-white solid, m.p. 109°-110° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([Cl:33])[CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][CH:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)CO1
Yield: 17 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with 3,5-dichlorophenylboronic acid yielded the title compound (17% yield) as a white solid. MS (ISP): m/z=475.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.C[Si]([N:38]=C=O)(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26]([NH2:38])=[O:27])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(N)=O

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate and trimethylsilyl isocyanate, and in the same manner as in Example 10, the title compound was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][C:5](=[O:9])[NH:6]OC.[Cl:13][C:14]([Cl:22])([Cl:21])[CH2:15][O:16][C:17]([NH:19][NH2:20])=[O:18]>>[NH2:1][C@H:2]([C:10]([NH:20][NH:19][C:17]([O:16][CH2:15][C:14]([Cl:22])([Cl:21])[Cl:13])=[O:18])=[O:12])[CH2:3][CH2:4][C:5](=[O:9])[NH2:6]
Reactant: NNC(=O)OCC(Cl)(Cl)Cl
Reactant: CONC(=O)CC[C@H](N)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Yield: 46.4 %

Procedure:
According to the process of H. Watanabe et al, Chemical Pharmaceutical Bulletin, vol. 22, p. 1889 (1974), 4 g of Gln(OMe) is reacted with 4 g of β,β,β-trichloroethyloxycarbonylhydrazine (hereinafter referred to as "TrocNHNH2 ") to obtain 3 g of GlnNHNH-Troc.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:9][CH:8]([OH:10])[CH2:7]1)=[O:5].[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](O)=[O:29])=[CH:22]2>ClCCl.CN(C)C=O>[CH2:11]([C@H:3]([NH:2][C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=2)=[O:29])[C:4]([N:6]1[CH2:7][CH:8]([OH:10])[CH2:9]1)=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(Cc1ccccc1)C(=O)N1CC(O)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1)c1cc2cc(Cl)ccc2[nH]1
Yield: 38.3 %

Procedure:
2-Amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride (1.18 mmol) and 5-chloro-1H-indole-2-carboxylic acid (1.1 8 mmol) were coupled according to Procedure A (4:1 dichloromethane-dimethylformamide reaction solvent) and the product purified by chromatography on silica gel eluted with 25%, 50%, 75% and 100% ethyl acetate-hexanes giving the title substance as a colorless foam (104 mg, 22%). A mixture (180 mg) of less polar products was also isolated. Title substance: HPLC (60/40) 4.18 minutes (97%); TSPMS 398/400 (MH+, 100%);
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:12](=[O:13])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1)=O.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=1)#[N:17]>O1CCCC1>[NH2:5][C@H:6]([C:12]([C:23]1[C:18]([C:16]#[N:17])=[N:19][CH:20]=[C:21]([NH2:24])[CH:22]=1)=[O:13])[CH2:7][CH2:8][C:9](=[O:10])[OH:11]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)C(=O)O1
Reactant: N#Cc1ccc(N)cn1
Solvent: C1CCOC1
Product: N#Cc1ncc(N)cc1C(=O)[C@@H](N)CCC(=O)O
Temperature: 40 °C
Reaction time: 12 h

Procedure:
Alpha-L-glutamyl-5-aminopyridine-2-carbonitrile is prepared by the method described in J. Med. Chem., 1973, 16, 163-166. A solution of 5.5 g (24.4 mmol) of N-trifluoroacetyl-L-glutamic anhydride and 2.6 g (21.8 mmol) of 2-cyano-5-aminopyridine (prepared according to tetrahydrofuran (20 cm3) is stirred for 12 h at 40° C. The solvent is then removed and the residue is dissolved in a 1% solution of sodium carbonate (80 cm3). The solution is rapidly washed with methylene chloride (3×30 cm3) and then acidified to pH 2-3 with a 6 N solution of HCl. Extraction with a solution of ethyl acetate (3×50 cm3), followed by drying over sodium sulfate and then evaporation of the solvent, gives 5.1 g of a crude product, N-trifluoroacetyl-alpha-L-glutamyl-5-aminopyridine-2-carbonitrile, which is obtained pure (melting point: 157° C.) after recrystallization several times from an ethanol/hexane mixture (40/60). After treatment of this compound with a 7.5% solution of ammonia for 4 h at 20° C., followed by concentration to dryness, alpha-L-glutamyl-5-aminopyridine-2-carbonitrile is finally obtained (quantitative yield, melting point: 152° C.).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@H:25]([N:28]5[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29]5)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].II.[NH4+:37].[OH-]>C1COCC1.[O-]S([O-])=O.[Na+].[Na+].CCOC(C)=O>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@H:25]([N:28]5[CH:32]=[CH:31][C:30]([C:33]#[N:37])=[CH:29]5)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5ccc(C=O)c5)C4)n23)cc1
Reactant: [NH4+]
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5ccc(C#N)c5)C4)n23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
To a solution of 1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde (0.050 g, 0.105 mmol) in THF (2 mL) was added iodine (0.083 g, 0.327 mmol) and aqueous NH4OH (28-30% w/v, 0.733 mL, 5.27 mmol). The reaction mixture was stirred at ambient temperature for about 24 h. The reaction mixture was diluted with saturated aqueous Na2SO3 (30 mL) and EtOAc (30 mL). The layers were partitioned and the organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give 1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbonitrile (0.05 g, 100%): LC/MS (Table 1, Method a) Rt=2.33 min; MS m/z: 472 (M+H)+.