Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH:18]=O)[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].Cl.[CH3:21][O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][NH:25][C@H:24]([C:23]([O:22][CH3:21])=[O:27])[CH3:26])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:4]
Reactant: COC(=O)C1(CC=O)CCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C)NCCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
271 mg (1 mmol) 2-(2-oxo-ethyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 154 mg (1.1 mmol) L-alanine methyl ester hydrochloride are suspended in 10 mL toluene and treated with 0.073 mL (1 eq.) triethylamine. The reaction mixture is stirred 10 minutes at room temperature and slowly evaporated in a rotary evaporator. The residue is taken up in 15 mL acetonitrile and 95 mg (1.5 mmol) sodium cyanoborohydride in 2 mL methanol added dropwise. Upon completion of the reaction (TLC, EtOAc/petroleum ether 4:1), the reaction mixture is evaporated and the residue taken up in ethyl acetate and treated with an ice-cold, saturated aqueous ammonium chloride solution, then extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic phases are dried over sodium sulfate, filtered and evaporated to yield the crude desired product as a thick oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=[CH:13]1>C(#N)C>[O:9]1[CH:19]2[CH:18]1[CH2:17][C:16]1[C:21]([CH2:20]2)=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1=CCc2ccccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: c1ccc2c(c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
A solution of metachloroperbenzoic acid (55%, 22.8 g) in acetonitrile (190 ml) was added dropwise over 15 min to a solution of 1,4-dihydro-naphthalene (7.86 g) in acetonitrile (100 ml) at 0° C. The resulting mixture was stirred for 6 hours at room temperature. The mixture was concentrated to about 50 ml under reduced pressure, diluted with methylene chloride and filtered. The filtrate was washed with 10% aqueous sodium sulfite, saturated aqueous sodium hydrogenocarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting solid (8.45 g) was chromatographed (silica gel, 150 g, elution with ethyl acetate:hexane, 1:9) to give the title compound as a solid (5.81 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:21]
Reactant: CCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 2-hydroxy-4-nitrobenzonitrile (0.5 g, 3.04 mmol) in DMF (5 ml) is added potassium carbonate (0.631 g, 4.56 mmol) followed by bromoethane (0.238 ml, 3.19 mmol) and the reaction mixture is stirred at room temperature for 5 days. The solvent is removed in vacuo and the crude is partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer is separated, washed with water (2×100 ml), saturated sodium hydrogen carbonate solution (100 ml) and concentrated in vacuo to afford the titled compound as a pale yellow solid which is used crude in the next step.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:12])/[CH:9]=[CH:10]/[CH3:11].[C:13]1([Si:19]([CH3:22])([CH3:21])Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH:8]([O:12][Si:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])[CH3:21])=[CH:9][CH:10]=[CH2:11]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: C/C=C/C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC=CO[Si](C)(C)c1ccccc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A 250 mL flask, fitted with a magnetic stirrer, a reflux condenser and an addition funnel, was charged with zinc chloride (0.25 g, 1.83 mmol, anhydrous), triethylamine (36.2 mL, 0.260M, distilled from CaH2), crotonaldehyde (21.0 mL, 0.257M, dried over MgSO4 and distilled), and toluene (35 mL, distilled from sodium). 42 mL of phenyldimethyl chlorosilane (0.254M) were added dropwise via the addition funnel over one hour with stirring. The resulting mixture was heated slowly to about 65° and maintained at 65°-75° for a total of 6.5 hours with stirring. The mixture was cooled to ambient temperature and filtered to remove precipitated triethylamine hydrochloride (32 g, 92%) which was rinsed on the filter with 35 mL of dry toluene. The resulting filtrate and rinse were combined and distilled on a water pump at about 110 mm to remove solvent and unreacted starting materials. The resulting residue was distilled on an oil pump to give (1,3-butadienyloxy)phenyldimethylsilane (30.9 g, 59%) as a colorless liquid boiling at 57.8°-59.0°/0.10 mm (13 Pa).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:17]3([O:27][CH3:28])[CH2:21][CH2:20][N:19]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:30][OH:31]>>[OH:31][N:30]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:17]3([O:27][CH3:28])[CH2:21][CH2:20][N:19]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC1(c2cccc(Sc3ccc(C(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Reactant: NO
Agent: Cl
Product: COC1(c2cccc(Sc3ccc(C(C)=NO)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[3-(4-acetylphenylthio)phenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{3-[4-(1-hydroxyiminoethyl)phenylthio]phenyl}-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine in 63% yield, m.p. 86°-88° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[C:2]=[O:3].[CH3:13][CH:14]([CH3:37])[CH:15]([NH:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:22])[C:16]([O:18][CH3:19])=[O:17]>>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][C:2](=[O:3])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:25]4[S:24][C:23]([C:21]([NH:20][C@@H:15]([CH:14]([CH3:37])[CH3:13])[C:16]([O:18][CH3:19])=[O:17])=[O:22])=[N:27][CH:26]=4)=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1ccc2c(c1)CCC2
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 5-isocyanato-2,3-dihydro-1H-indene (0.599 mmol) and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ ppm 8.891 (s, 1H), 8.732-8.704 (d, 1H), 8.602 (s, 1H), 8.347 (s, 1H), 7.717-7.689 (d, J=8.4 Hz, 2H), 7.575-7.547 (d, J=8.4 Hz, 2H), 7.289 (s, 1H), 7.172-7.101 (m, 2H), 4.349-4.299 (t, J=7.2, 7.8 Hz, 1H), 3.681 (s, 3H), 2.859-2.770 (m, 4H), 2.328-2.204 (m, 1H), 2.054-1.952 (m, 2H), 0.965-0.923 (d, J=6.3 Hz, 6H); MS (ESI) m/z 491 (M−H), 493 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Product: COc1cc(C)c(F)cc1C(=O)c1ccc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 43) and 1-(4-amino-piperidin-1-yl)-ethanone (prepared as described in D. Manefti et al, Biorg. Med. Chem. Lett., 13 (2003), 2303-2306) using the procedure described in Step B. Example 6. HRMS, observed: 401.1084, Calcd for (M+H)+: 401.1084.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Cl)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-chlorophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH2:12][NH2:13]>C1COCC1>[NH:12]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: COC(=O)c1ccc(F)nc1
Reactant: NN
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NN)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of methyl 6-fluoronicotinate (13.9 g, 89.60 mmol) and hydrazine (5.625 ml, 179.2 mmol) in THF (200 mL) were heated at 56° C. for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and water (200 mL) was added. The suspension was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with water and dried to give methyl 6-hydrazinylnicotinate (13.4 g, 89.5%) as a solid.
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(COC)OC>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: OB(O)c1cccnc1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)oc2c(-c3cccnc3)csc12
Temperature: 180 °C
Yield: 1.2 %

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 0.16 mmol), 3-pyridylboronic acid (29 mg, 0.24 mmol), cesium carbonate (103 mg, 0.32 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (9 mg, 0.008 mmol), and dimethoxyethane (1 mL). The reaction mixture was magnetically stirred and heated via microwave irradiation for 15 minutes at 180° C. Upon cooling to room temperature, the reaction was concentrated in vacuo and purified using high-pressure liquid chromatography to give 5-morpholino-3-(pyridin-3-yl)-7H-thieno[3,2-b]pyran-7-one (3) (6 mg, 1.9 μmol) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CC(O)C.C(N(CC)CC)C>CCCCCCC>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (150 g; 90% ee) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5° C., held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25° C. for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48° C. for two and half days to give 227 g (90.1%) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94% ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([CH:14]=[CH:15][C:16]2[S:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH2:21][C:19]2[S:20][C:16]([CH:15]=[CH:14][CH:11]3[CH2:13][CH2:12]3)=[CH:17][CH:18]=2)=[O:8])=[CH:4][N:3]=1
Reactant: NCc1ccc(C=CC2CC2)s1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCc2ccc(C=CC3CC3)s2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
6-Aminonicotinic acid (35 mg, 0.251 mmol), C-(5-(2-cyclopropylvinyl)thiophen-2-yl)methylamine described in Preparation Example 151 (45 mg, 0.251 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (133 mg, 0.301 mmol) and triethylamine (0.042 mL, 0.301 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the solution was stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (30 mL). The organic layer was washed, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo, the obtained residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1), and the title compound (50 mg, 0.167 mmol, 66.6%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[O:21])[N:31]3[CH2:32][CH2:33][CH:28]([C:27]([F:35])([F:34])[F:26])[CH2:29][CH2:30]3)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)C1CCNCC1
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC(C(F)(F)F)CC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 31 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and 4-trifluoromethyl-piperidine hydrochloride gave the titled compound in 31% yield as white foam. MS: 509.13 (MH+, 2Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[N+:20]([O-])=O)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[O:23]=[C:24]1[N:28]2[CH2:29][C:30](=[O:36])[NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[C:26]([C:27]=32)[N:25]1[CH2:37][C:38]([O-])=O.[Na+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC(O)=O>[O:15]=[C:7]1[NH:8][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]21[CH2:5][C:4]1[C:17](=[CH:18][C:19]3[N:20]=[C:38]([CH2:37][N:25]4[C:26]5[C:27]6[N:28]([CH2:29][C:30](=[O:36])[NH:31][C:32]=6[CH:33]=[CH:34][CH:35]=5)[C:24]4=[O:23])[NH:1][C:2]=3[CH:3]=1)[CH2:16]2
Reactant: O=C([O-])Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Cn2c(=O)n(Cc3nc4cc5c(cc4[nH]3)CC3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1
Temperature: 60 °C

Procedure:
A mixture of 5,6-diamino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (30 mg, 0.11 mmol, described in Intermediate 13), sodium (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate (27 mg, 0.10 mmol, described in Intermediate 26), BOP (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.019 mL, 0.11 mmol) was stirred in DMF (0.4 mL) at ambient temperature for 2 h, then AcOH (0.4 mL) was added and the resulting mixture was heated to 60° C. for 18 h. The mixture was allowed to cool and the precipitate was isolated by filtration. This solid was washed with H2O, then MeOH, then CH2Cl2, then dried in vacuo to give the title compound. MS: m/z=478 (M+1). HRMS: m/z=478.1606; calculated m/z=478.1622 for C26H20N7O3.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:55].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:55])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 23n (0.56 g, 0.67 mmol, obtained from the synthetic method described in step 12 of example 23) in tetrahydrofuran (12 mL) were added aqueous sodium bicarbonate (12 mL, 7.4 mmol, 0.6 M), potassium bromide (16 mg, 0.13 mmol) and 2,2,6,6-tetramethylpiperidinooxy (10 mg, 0.07 mmol) in turn at 0° C., and then sodium hypochlorite (9 mL, 10.60 mmol, 3.5% available chlorine) was added dropwise. The mixture was stirred at 0° C. for 2 hours and acidified with aqueous HCl (1 N) till pH becomes 4. The resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 24a (0.6 g, 100%) as yellow oil. This material was not further purified.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)C(C)C(=O)N2C
Yield: 72.1 %

Procedure:
A mixture of 0.092 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41), 0.1 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.095 g of (rac)-4-(9-cyclopentyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-41a) as an off-white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[Cl:12][C:11]1[C:6]([CH:3]([C:4]#[N:5])[NH:2][C:24](=[O:26])[CH3:25])=[N:7][CH:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=1
Reactant: CC(=O)Cl
Reactant: N#CC(N)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C#N)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h

Procedure:
0.67 g of amino[3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile hydrochloride (0.00245 mol) are dissolved in 15 mL of dichloromethane, 0.68 mL of triethylamine are added . After 10 min. at room temperature, 0.18 mL of acetyl chloride (0.00245 mol) are added, the reaction mixture is stirred overnight. The reaction is quenched with 20 mL of water.