Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([OH:10])[N:4]=1.N([O-])=O.[Na+].C(O)=O.[CH:18]([NH2:20])=O>[Pd]>[NH:4]1[C:5](=[O:10])[C:6]2[NH:20][CH:18]=[N:9][C:7]=2[N:8]=[C:3]1[NH2:2]
Reactant: Nc1cc(O)nc(N)n1
Reactant: NC=O
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
29.0 g (0.2 mol) 2,4-diamino-6-hydroxypyrimidine hydrate was nitrosed with 13.8 g (0.2 mol) sodium nitrite and 10.8 g (0.2 mol) 85% formic acid in 150 ml formamide and the pink-coloured suspension obtained was admixed with a further 42.4 g (0.8 mol) 85% formic acid. After stirring in 1.0 g of a palladium catalyst on active carbon according to example 1, it was heated for 3 hours to 120° C. In this process the suspension became colorless and was subsequently heated for 3 hours to 180° C. while removing a small amount of water by distillation. After cooling to 80° C., 100 ml water was added and the solid was suction filtered. The filter cake was washed twice with 50 ml water and dissolved in 320 ml of a 5% sodium hydroxide solution. The insoluble noble metal catalyst was removed by filtration and the filtrate was stirred for 30 minutes at 50° C. with 3 g active carbon. After separating the active carbon, guanine was precipitated by addition of 20% sulphuric acid to pH 9.0, suction filtered, washed twice with 50 ml water and dried in a vacuum at 80° C. 26.7 g (0.174 mol, 87% of theory) 98.4% pure guanine was obtained in this manner.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][N:15]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC1
Reactant: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(COc2ccc3c(c2)CCN(C2CCC2)CC3)cc1
Reaction time: 0.5 h

Procedure:
7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) (25.3 g, 100 mmol) was dissolved in 2.5% acetic acid in dichloromethane (400 ml) at 0° C. and treated dropwise with cyclobutanone (11.2 ml, 150 mmol). The mixture was stirred for 30 minutes and then sodium triacetoxyborohydride (31.8 g, 150 mmol) was added portion wise. The reaction mixture was stirred at room temperature for 4 hours, basified with saturated sodium carbonate solution and extracted with dichloromethane. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was triturated with hexane and filtered to afford the title product (E1). MS (ES+) m/e 308 [M+H]+.
Reaction SMILES: [C:1]([C:5](=[CH:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=O)[CH2:2][CH3:3].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[F:23][C:21]1[CH:22]=[C:17]([CH:16]2[NH:35][C:33]([O:32][CH3:31])=[N:34][C:1]([CH2:2][CH3:3])=[C:5]2[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH:18]=[CH:19][C:20]=1[F:24]
Reactant: CCC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(=O)OCc1ccccc1
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Temperature: 70 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A suspension of benzyl 2-propionyl-3-(3,4,5-trifluorophenyl)-2-propenoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO3 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70° C. for 20h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4×100 mL), brine (200 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (SiO2, EtOAc/Hexane, 10%-30%) to afford benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate as a colorless oil (10.6 g, 58% yield). The product was directly used in the next step after 1H NMR spectroscopy which showed it to be a mixture of amine/imine tautomers.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>>[NH:18]1[C:17]([NH:16][C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)=[O:11])=[N:21][N:20]=[N:19]1
Reactant: Nc1nnn[nH]1
Reactant: CSc1ccc(C(=O)O)nc1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)Nc2nnn[nH]2)nc1
Yield: 34 %

Procedure:
0.36 g of 5-methylthio-2-pyridinecarboxylic acid, 6 ml of thionyl chloride and 0.18 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.17 g of N-(5-tetrazolyl)-5-methylthio-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:31][CH2:30][C:22]4[N:23]=[C:24](S(C)=O)[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH4+:32].[OH-]>O1CCOCC1>[NH2:32][C:24]1[N:25]=[CH:26][C:21]2[CH2:20][N:19]([C:15]3[N:14]=[C:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:18]=[CH:17][CH:16]=3)[CH2:31][CH2:30][C:22]=2[N:23]=1
Reactant: [NH4+]
Reactant: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(S(C)=O)ncc4C3)n2)cc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)n2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A suspension of 6-(2-Methanesulfinyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-pyridine-2-carboxylic acid (4-isopropyl-phenyl)-amide (405 mg, 0.930 mmol) in 1,4-dioxane (10 ml) was treated with NH4OH (3 ml, 28-30%) and the reaction mixture was heated in a sealed tube at 100° C. with stirring for 15 hours. Upon cooling to room temperature, the reaction mixture was concentrated and the residue was taken up in water. The aqueous mixture was extracted with ethyl acetate and the organic extract was dried (MgSO4), filtered, and concentrated. Trituration with MeOH gave the title compound as a yellow, amorphous solid (200 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH2:9]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccccc2F)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(2-fluorophenyl)piperazine (2.5 g, 2.2 mL, 13.9 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.73 g, 14.6 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound M, 3.56 g (85%).
Reaction SMILES: CC1C=CC(S(O[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]#[N:15])(=O)=O)=CC=1.Cl.[NH2:22][CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[O-]CC.[Na+].Cl>C(O)C.O1CCCC1>[NH2:15][C:14]1[CH:13]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[NH:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OC(=CC#N)c2ccco2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(-c2ccco2)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.3 %

Procedure:
To a solution of 2-cyano-1-(2-furyl)vinyl 4-methylbenzenesulfonate (10.48 g) and diethyl aminomalonate hydrochloride (7.67 g) in a mixed solvent of ethanol (120 mL)-tetrahydrofuran (64 mL) was added dropwise a solution (36.9 mL) of 20% sodium ethoxide in ethanol under ice-cooling. After stirring at room temperature for 12 hrs, the reaction mixture was poured into ice water (350 mL) and adjusted to pH 7 with 1N hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mL×3). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=3:1→1:1) and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (2.66 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([N:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][NH2:29])[CH3:24].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH3:31])[CH2:23][CH3:24])=[O:12])[CH2:7]1
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Reactant: CCN(CC)CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNC(=O)N1CCC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 78 h

Procedure:
A stirred solution, 13 g (0.05 mole) of 3-(3-chlorophenoxy)-1-pyrrolidinecarbonyl chloride in 100 ml of chloroform was treated with 25 mg of ice and 12.8 g of sodium carbonate after 5 min. This mixture was treated with 7.15 g (0.055 mole) of N,N-diethyl-1,3-propanediamine dropwise and allowed to stir for 78 hours. The reaction mixture was transferred to a separatory funnel and enough water was added to form two distinct phases. The organic phase (chloroform) was separated and washed with 50 ml of water; the organic portion was extracted with 50 ml of 3N hydrochloric acid, separated and washed with 2×25 ml of water. All the aqueous portions were combined and the pH adjusted to neutral with 3N sodium hydroxide and extracted with 4×30 ml of chloroform. The extract was combined, washed with water, dried over magnesium sulfate and concentrated on a rotary vacuum to a pale yellow oil (12 g). The oil was dissolved in chloroform, treated with 1.5 g of charcoal and filtered hot. This was then slurried with 25 g of silica gel and filtered. The chloroform was discarded and the silica gel washed with methanol to give, after concentrating, 4 g of pale yellow oil. This was dissolved in ethyl ether and filtered through celite.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cnc(-c2ccccn2)nc1Cl
Product: COc1cccc(Nc2nc(-c3ccccn3)ncc2OC)c1

Procedure:
The title compound was prepared from 4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (100 mg, 0.451 mmol) and m-anisidine (51 μl, 0.451 mmol) similar to Example 13 and isolated as a tan oily liquid (63 mg, 45%). 1H NMR (CDCl3): 8.76-8.74 (m, 1H), 8.37 (dd, J=1.1, 8.0 Hz, 1H), 8.05 (s, 1H), 7.79-7.73 (m, 2H), 6.65-6.62 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]4[N:32]=[C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])[NH:33][C:28]=4[CH:27]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: COc1cc2nccc(N3CCOc4ccc(-c5ccc(N)c(N)c5)cc4C3)c2cc1OC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5cc(OC)c(OC)cc35)CCO4)cc2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A solution of 4-{-4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-2-nitroaniline (56 mg, 0.12 mmol) in methanol (20 mL) was hydrogenated at 30 psi over 10% Pd—C (25 mg) for 4 h. The catalyst was filtered off, and the filtrate was concentrated to give 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}benzene-1,2-diamine (40 mg, 77% yield) as a brown oil. MS (EI) for C26H26N4O3: 443 (MH STEP 5: To a solution of 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}benzene-1,2-diamine (40 mg, 0.09 mmol) in acetic acid (2 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (19 mg, 0.09 mmol) and the reaction mixture was stirred at 80° C. for 30 min. After cooling to room temperature the mixture was concentrated, and purified by preparative reverse phase HPLC to provide methyl (6-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-yl)carbamate (17 mg, 25% yield) as a brown solid. 1H NMR (400 MHz, CD3OD): 8.30 (d, 1H), 7.78 (m, 2H), 7.68 (m, 2H), 7.60 (m, 1H), 7.27 (d, 2H), 7.11 (d, 1H), 7.04 (d, 1H), 5.17 (s, 2H), 4.64 (m, 2H), 4.25 (m, 2H), 4.01 (s, 3H), 3.96 (s 3H), 3.63 (s, 3H); MS (EI) for C29H27N5O5: 526 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C>[F:9][C:8]([F:10])([F:11])[CH:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: OC1CCC(C(F)(F)F)CC1
Yield: 86.9 %

Procedure:
4-Hydroxybenzotrifluoride (5 g, 30.8 mmol) was placed in a hydrogen reaction vessel, dissolved in acetic acid (15 ml), and Pt−2O (500 mg) was added. The hydrogen reaction vessel was pressurized with hydrogen (50 psi), and reacted for 16 h. After the reaction finished, the reaction mixture was filtered through Celite, and to the filtrate was added 1N-NaOH, extracted with diethylether, dried over MgSO4, and concentrated in vacuo at rt to give the title compound (4.5 g, 87%).
Reaction SMILES: C[O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)=[N:13][C:14]=3[C:19]([O:21]C)=O)[CH2:5][CH2:4]1.[NH2:40]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=1N[C@H]1CC[C@@H](OC)CC1>ClCCl>[OH:2][C@@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:13][C:14]=3[C:19]([NH2:40])=[O:21])[CH2:7][CH2:8]1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(N[C@H]2CC[C@@H](OC)CC2)c1N
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@@H](OC)CC1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@@H](O)CC1

Procedure:
Methyl 9-(cis-4-methoxycyclohexyl)-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-6-(cis-4-methoxycyclohexylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate (0.223 g, 0.422 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.547 g, 3.38 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using biotage chromatography (0 to 65% EtOAc in hexanes) to afford the title compound (0.210 g, 90%). MS (ESI) m/z 555.5 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[CH:24]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:24]([N:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:2]2=[O:1])[CH2:39][CH2:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared as described in Example 28B, reacting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E) with 1-benzhydrylpiperidin-4-amine (Example 48A). 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.43 (m, 20H), 6.58 (d, J=8.1 Hz, 1H), 4.24 (s, 1H), 4.01 (s, 2H), 3.72-3.84 (m, 1H), 3.53 (t, J=6.4 Hz, 2H), 2.70-2.77 (m, 2H), 2.58-2.63 (m, 2H), 1.97-2.08 (m, 2H), 1.76-1.91 (m, 5H), 1.41-1.50 (m, 1H); MS (ESI+) m/z 558 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc2C1
Yield: 12.4 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (130 mg, 0.55 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (160 mg, 0.55 mmol) were coupled to provide (1S,2S,3R,4R)-3-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-bicyclo-[2.2.1]hept-5-ene-2-carboxylic acid amide (34 mg, 12%) following preparative reverse-phase chromatography; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.82 (s, 1H), 7.07 (s, 1H), 6.32 (m, 1H), 6.08 (m, 1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.88 (s, 3H), 3.70 (m, 2H), 3.40 (m, 2H), 3.05 (s, 1H), 2.80 (s, 1H), 2.60 (q, J=7 Hz, 2H), 1.60 (d, J=8 Hz, 1H), 1.50 (t, J=7 Hz, 3H); MS (m/e) 498 (M+1); mp 165° C. (dec.).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.C(O)C>O.[OH-].[Na+]>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:2][OH:3])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(Cl)cc1
Yield: 75.7 %

Procedure:
To a solution of 50 g of hydroxylamine hydrochloride in 300 ml of water was added a suspension of 20 g of 4-chlorobenzaldehyde in 200 ml of 10% aqueous sodium hydroxide solution. Ethanol was then added until the mixture was clear. The solution was heated on a steam bath for 25 minutes, then cooled in an ice bath. The solid which separated was collected by filtration and dried in a vacuum desiccator. A second fraction was obtained by adding water just to the cloud point. This solid was collected and dried and the two products combined to give 16.75 g of 4-chlorobenzaldoxime, m.p. 108°-109°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[N+:5]([O-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:12][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc[n+]([O-])c(C)c1OC
Product: COc1ccnc(COC(C)=O)c1OC
Reaction time: 1 h
Yield: 90 %

Procedure:
4.8 g (28 mmol) of 3,4-dimethoxy-2-methylpyridine 1-oxide are metered into 25 ml of acetic anhydride at 85° C. in the course of one hour, the mixture is stirred at the same temperature for one hour and concentrated completely in vacuo. The brown oily residue is distilled in a bulb tube still under 1 Pa. 5.3 g (90% of theory) of 2-acetoxymethyl-3,4-dimethoxypyridine are obtained; b.p. 125°-130° C.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[C:13]=1[Cl:14])=[O:8])C.Cl>C(O)C>[Cl:14][C:13]1[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:7]([OH:8])=[O:6]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
A mixture of 12N aqueous solution of sodium hydroxide (0.5 ml), water (2 ml) and ethanol (4 ml) was added to 5-chloro-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (120 mg), and stirred at 80° C. for four hours. After the reaction, 1N hydrochoric acid aqueous solution was added under ice-cooling, the precipitated solid was washed with ethyl acetate to give 5-chloro-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[N:10]([CH3:17])[CH2:9][CH:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[O:7][C:6]2=1.[O:25]=[C:26]1[NH:31][C:30]2[CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[N:10]([CH3:17])[CH2:9][CH:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:36]([C:33]4[CH:34]=[CH:35][C:29]5[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=5[CH:32]=4)=[O:37])[CH2:20][CH2:19]3)[O:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3C
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CN3C

Procedure:
The titled compound is prepared as an off-white lyophilizated powder following Scheme 7 and in analogy to Example 47 using trans-4-(6-methoxy-1-methyl-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]4[NH:29][CH2:28][CH2:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=4[CH:34]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>C1COCC1>[CH:1]([N:29]1[C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][O:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[CH:34][C:24]=2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]1)=[O:3]
Reactant: CC(=O)O
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2NCC1
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.2 ml) was added dropwise formic acid (0.1 ml), under ice-cooling, and the mixture was heated to stir under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (5 ml), and then to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) in THF (15 ml). The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) as pale yellow crystals.