Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Br[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(OCCCCSc3ccccn3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
14.4 gm (0.13 mol) of 2-mercapto-pyridine and 17.9 gm (0.13 mol) of potassium carbonate were stirred into 360 ml of dimethylsulfoxide which had been dried over a molecular sieve, and the solution was admixed with 36 gm (0.12 mol) of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.; prepared from 6-hydroxy-carbostyril and 1,4-dibromo-butane). The mixture was stirred for 15 hours at about 25° C., then poured into 3.6 liters of water, and the aqueous mixture was stirred for 30 minutes. The precipitate formed thereby was collected by suction filtration, thoroughly washed with water, dried and recrystallized from xylene in the presence of activated charcoal, yielding 32 gm (81.2% of theory) of a light yellow crystalline product having a melting point of 123°-124.5° C. It was identified to be the compound of the formula ##STR9##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CN(C)C=O.[Cu]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccn1
Reactant: Ic1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3ccccn3)cc2n1Cc1ccccn1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 26 mg, 0.060 mmol) in dimethylformamide (1 ml) stirring at room temperature, was added cesium carbonate (83 mg, 0.25 mmol) and the reaction stirred for 5 minutes. 2-iodopyridine (0.05 mL, 0.09 g, 0.47 mmol) and then copper powder (7.0 mg, 0.11 mmol) was then directly added and the resulting mixture heated at 100° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100 % EtOAc) to yield the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH:22]=O)=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH3:30].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CCOCC>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:30])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCOCC
Solvent: c1ccccc1
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
A solution of 4.8 g (0.015 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde [see Example 1 a)] in abs. benzene is saturated with ammonia. After cooling of the solution to 0°, an addition is made portionwise, with a light flow of ammonia gas and in the course of 45 minutes, of 14.0 g (0.030 mole) of lead tetraacetate. The reaction mixture is then stirred for a further 24 hours at 25°; it is subsequently diluted with ether and filtered through kieselguhr. The filtrate is washed with 1N hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed through silica gel with the use of ethyl acetate as eluant. The fractions containing the desired nitrile [Rf = 0.63 in the eluant system ethyl acetate/isopropanol (7:1)] are combined, and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.IC>O1CCCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH:32]([CH3:37])[CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CC(=O)C=C1N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round bottomed flask, 50 mg (0.0997 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F) was dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere and cooled to −78° C. To this solution was added by syringe, 0.090 mL (0.9 equiv, 0.0897 mmol) of a 1M solution of LiHMDS in THF. The resulting faint yellow solution was stirred for 1 hr at −78° C. then 0.0155 mL (0.249 mmol) iodomethane was added by syringe. The resulting yellow solution was stirred for 5 min at −78° C. then warmed to RT over 30 min. The reaction was quenched by the addition of 2 mL sat. aq. NH4Cl stirred 5 min then 2 mL water was added. The resulting mixture was extracted with ether (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to provide a yellow oil. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band with Rf˜0.85 was isolated. The resulting yellow oil (48 mg) was purified by prep HPLC on Chiralcel OD eluting with heptanes/absolute alcohol (94/6) to afford the title compound as a mixture of stereoisomers. 1H-NMR (CD3OD) rotamers: δ: 1.2-1.45 (m, 6H), 2.04 (m, 1H), 2.78 (m, 1H), 3.18 (m, 1H), 3.30-4.35 (m, 6H), 4.7-4.9 (m, 2H), 4.95, 5.0 (2d, 1H), 6.95-7.02 (m, 2H), 7.10-7.22 (m, 2H), 7.62 (s, 1H), 7.80 (s, 1H), 7.83 (s, 1H)ppm. MS: 516.2 (MH+) observed.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1.[NH2:31][C:32]1[C:37]2[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=2[CH:35]=[CH:34][CH:33]=1>C1COCC1.CN(C=O)C>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:3]=1[CH2:2][NH:1][C:24]([NH:31][C:32]1[C:37]2[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=2[CH:35]=[CH:34][CH:33]=1)=[O:25]
Reactant: CN(C)CCOc1cc(C(F)(F)F)ccc1CN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1OCC(=O)N2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1OCC(=O)N2
Temperature: 70 °C
Yield: 35 %

Procedure:
To a solution of 27b (1.48 g, 5.64 mmol) in THF (25 mL) was added CDI (2.1 mol eq, 1.92 g) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×30 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (pale yellow oil, 1.91 g, 95% yield). The oil obtained (0.95 g, 2.68 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.35 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (8:2 EtOAc:MeOH) to obtain the product as a white solid (0.33 g, 35% Yield). 1HNMR (DMSO, 400 MHz) δ 2.27 (s, 6H), 2.71 (t, 2H), 4.20 (t, 2H), 4.32 (d, 2H, J=6), 4.62 (s, 2H), 6.50 (dd, 1H), 6.80 (t, 1H), 7.29 (m, 3H), 7.40 (d, 1H), 7.70 (dd, 1H), 8.18 (s, 1H), 10.65 (bs, 1H). [M+1] 452.91 (C21H23F3N4O4 requires 452.43).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[CH3:34][C:35]1([CH3:41])[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:37]3[CH2:38][CH2:39][CH2:40][C:35]([CH3:41])([CH3:34])[CH2:36]3)=[CH:4][CH:5]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:32][CH:31]=1
Reactant: CC1(C)CCCNC1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Product: CC1(C)CCCN(Cc2ccc([C@H](c3ccc(Cl)cc3)N3CC(=C(c4cc(F)cc(F)c4)S(C)(=O)=O)C3)cc2)C1
Yield: 69.5 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane and 0.025 g of 3,3-dimethylpiperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then eluting with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.040 g of 1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 0.94 (s, 6H), 1.21 (mt, 2H), from 1.50 to 1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27 (unresolved complex, 2H), 2.81 (s, 3H), 3.36 (s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[CH3:11]S(C)=O.CI>O>[CH3:11][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CS(C)=O
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1ccccn1
Temperature: 25 °C

Procedure:
Also, 2-(methoxymethyl)pyridine is prepared by the following alternative procedure. A mixture of 10.9 g. of 2-pyridinemethanol and 2.4 g. of sodium hydride in 50 ml. of dimethylsulfoxide is warmed on a steam bath for 15 minutes, then cooled to room temperature. Methyl iodide (14.2 g.) is added then the mixture is heated at 40°C. for one hour. Water (150 ml.) is then added and the mixture is extracted with ether. The extracts are dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[N+:28]([C:31]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][C:32]=1[NH2:33])([O-:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].O>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>[NH2:33][C:32]1[CH:34]=[CH:35][C:36]([C:6]2[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:27])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=3)[N:7]=2)=[CH:37][C:31]=1[N+:28]([O-:30])=[O:29]
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 92.5 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (1.0 g, 2.46 mmol) in DME (10 mL) was added 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.97 g, 3.69 mmol), Pd(PPh3)4 (90 mg, 0.12 mmol), Na2CO3 (781 mg, 7.38 mmol) and water (2 mL) with stirring for 40 minutes at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 2-(4-amino-3-nitrophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (900 mg, 93%).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC.O1CCCC1>[CH2:17]([C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of heptanophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction, a solid precipitated out which was triturated with ether and filtered (m.p. 119°-120.5° C.). 1H NMR (CDCl3) δ 0.84 (t, 3 H), 1.1-1.4 (m, 8 H), 1.9-2.0 (m, 2 H), 2.89 (d, 1 H), 2.93 (d, 1 H), 3.24 (d, 1 H), 3.35 (d, 1 H), 7.2-7.5 (m, 5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][C:9]=2[N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].[NH2:31][C:32]1([C:42]([OH:44])=[O:43])[CH:39]2[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:41][CH:33]1[CH2:34]3)[CH2:38]2>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:31][C:32]3([C:42]([OH:44])=[O:43])[CH:39]4[CH2:38][CH:37]5[CH2:36][CH:35]([CH2:34][CH:33]3[CH2:41]5)[CH2:40]4)=[O:15])[CH:11]=[CH:10][C:9]=2[N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:29])[CH3:30]
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1ccc(N2CCCC2=O)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Product: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)C4CC5CC(C4)CC3C5)ccc2N2CCCC2=O)ccc1Cl
Product: Cl
Yield: 83.9 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 391 mg (0.91 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate and 265 mg (1.36 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 241 mg of 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:53][CH3:54]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:52]=[CH:51][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:53][CH3:54])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Yield: 47.8 %

Procedure:
A mixture of 0.0628 g (0.19 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0542 g (0.285 mmole) of toluenesulfonic acid monohydrate, 0.0527 g (0.19 mmole) of 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 25 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (90:10:1) and then recrystallization from acetonitrile to give 0.0519 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-255) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]([N:30]1[CH2:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][C:32]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:31]1=2)=[O:29]>O1CCCC1>[Cl:45][C:43]1[CH:42]=[CH:41][C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]([C:28](=[O:29])[CH2:27][NH:26][C:10](=[O:12])[CH2:9][CH2:8][NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:3])[CH3:13])[C:31]=2[CH:44]=1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(1,1-dimethylethoxy)carbonyl]-β-alanine (0.72 gram) in anhydrous tetrahydrofuran (20 mL) at 5° C. under a nitrogen atmosphere was added, in portions, 1,1'-carbonyldiimidazole (0.67 gram). The reaction was stirred at 5° C. for 30 minutes, and then at room temperature for 90 minutes. To the reaction was then added 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (1.00 gram), and the reaction was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was partitioned between saturated aqueous sodium bicarbonate (50 mL) and chloroform (50 mL). The layers were separated, and the aqueous layer was extracted with chloroform (50 mL), and the chloroform extracts were combined, washed with 25 mL each of saturated aqueous sodium bicarbonate, water, and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 3:1 ethyl acetate:hexane. The yield of the title compound was 1.23 grams (77%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:44])=[O:43]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:52][CH2:51]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OCC(F)(F)F)c1

Procedure:
[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 739.4 [(M+H)+]
Reaction SMILES: C([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N+:7]([O-:23])[CH2:6][C:5]1=[O:24])C=C.[Mn]([O-])(=O)(=O)=[O:26].[K+].[CH3:31][C:32]([CH3:34])=[O:33]>O>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([CH2:31][CH:32]([OH:33])[CH2:34][OH:26])[C:5](=[O:24])[CH2:6][N+:7]([O-:23])=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:14]=1
Reactant: CC(C)=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=CCN1C(=O)C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Agent: [K+]
Solvent: O
Product: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
3.3 g of 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide are dissolved in acetone and treated dropwise with a solution of 1.6 g of potassium permanganate in water. After the addition, the mixture is stirred for a further 25 minutes at room temperature. Then the mixture is filtered off under vacuum from manganese dioxide, whereupon the manganese dioxide is washed with acetone and the filtrate is freed from acetone on a rotary evaporator. The aqueous phase is extracted with ethyl acetate and the organic phase is washed with water, concentrated and dried azeotropically with benzene. By chromatography on silica gel with ethyl acetate/methanol (9:1) there is isolated from the residue 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide. For analysis, a sample is recrystallized from ethyl acetate; melting point 165°-166°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([N:36]=[C:37]=[S:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[S:38])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: S=C=Nc1ccccc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=S)Nc2ccccc2)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin 3-yl]-phenyl-methanone and phenyl isothiocyanate according to the procedure of Example 65. MS (ESI) m/z 526.