Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[C:2]([CH:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:1])[CH3:11]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl 3-oxobutanoate (20.0 g) in tetrahydrofuran (200 mL) was added 60% sodium hydride in oil (556 g) portionwise over 20 minutes in an ice-water bath under N2. After 40 minutes, to the mixture was added ethyl 5-iodopentanoate (35.6 g) at the temperature. After 15 minutes, the mixture was stirred at ambient temperature. After 1 hour, the reaction mixture was heated at 50° C. for 24 hours. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 1 L) eluting with hexane-ethyl acetate=50-1, 20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate (27.3 g, 75.4%) as colorless oil.
Reaction SMILES: C(=O)=O.C(O)(C)C.[CH2:8]([C:15]1[O:16][C:17]2[CH:35]=[CH:34][CH:33]=[CH:32][C:18]=2[C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][C:23]=1[O:30]C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[CH:32]1[C:18]2[C:19]3[C:20]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=4[OH:30])=[C:10]4[C:9](=[CH:8][C:15]=3[O:16][C:17]=2[CH:35]=[CH:34][CH:33]=1)[CH:14]=[CH:13][CH:12]=[CH:11]4
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)O
Solvent: ClCCl
Product: Oc1ccc(-c2c3ccccc3cc3oc4ccccc4c23)c(O)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 38.4 %

Procedure:
To a cold (-76° C. dry ice, isopropanol bath) solution of (2-benzyl-benzofuran-3-yl)-(2,4-dimethoxy-phenyl)-methanone (6.13 g, 16.5 mmol) in anhydrous methylene chloride (60 mL) was added a 1 M solution of boron tribromide in methylene chloride (100 mL, 100 mmol, 6.06 eq) dropwise over a period of 20 minutes under a dry nitrogen atmosphere. The dry ice bath was removed and the reaction mixture was stirred at ambient temperature for 45 hours. After cooling in an ice bath water was carefully added and after quenching the reaction mixture was further diluted with water (300 mL). The organics were extracted with diethyl ether and methylene chloride. The extracts were combined, washed with water and brine, and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (80/20 petroleum ether/ethyl acetate) to provide the title compound as a white solid (2.07 g, 38%): mp 201 -202° C.; NMR (CDCl3); δ8.03 (ddd, J=8, 7, 1 1 H), 8.01 (s, 1 H), 7.82 - 7.79 (m, 1 H), 7.58 - 7.54 (m, 2 H), 7.48 - 7.43 (m, 2 H), 7.20 (d, J=8 Hz, 1 H), 7.18 - 7.15 (m, 2 H), 6.70 (m, 2 H), 5.00 (s, 1 H), 4.70 (s, 1 H); Hi Res MS, Calc. Sample Mass for C22H14O3, 326.0942951, Measured Mass 326.09019, mas deviation 4 mmu. Anal. Calc. for C22H14O3: C, 80.97, H, 4.32, N, 0.00. Found: C, 79.80, H, 4.10, N, 0.07.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:3]1.[NH2:19][C:20]1[N:24](C(OC(C)(C)C)=O)[N:23]=[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)[CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([CH2:33][CH2:32][C:22]2[CH:21]=[C:20]([NH:19][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][CH:6]([CH3:8])[NH:7][CH:2]([CH3:1])[CH2:3]4)=[CH:18][CH:17]=3)[NH:24][N:23]=2)[CH:35]=[C:36]([O:42][CH3:43])[CH:37]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CC(C)NC(C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 10.5 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide was prepared as for Example 94, but starting from methyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 34-54% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (34 mg, 10%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.04 (6H, d), 2.22 (2H, t), 2.53 (2H, d), 2.82 (2H, t), 2.87 (4H, s), 3.71 (1H, s), 3.73 (7H, s), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.94 (2H, d), 7.89 (2H, d), 10.27 (1H, s), 12.07 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:41])=O>ClCCl>[CH3:1][C:2]1[C:3]([S:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([Cl:41])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2c(cc1Sc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: Cc1cc2c(cc1Sc1ccc(C(=O)Cl)cc1)C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
A solution of 1.4 g (4 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoic acid in 100 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 900 μl (4.4 mmol) of dicyclohexylamine were added and the mixture was stirred for one hour. Next, 320 μl (4.4 mmol) of thionyl chloride were added and the mixture was stirred for one hour. The reaction medium was evaporated to dryness, taken up in anhydrous ethyl ether, the dicyclohexylamine salt filtered off and the filtrate evaporated. 1.5 g (100%) of the crude acid chloride was recovered which was used as such in the continuation of the synthesis to follow.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:12]1[C:11]([C:16]([F:18])([F:17])[F:19])=[CH:10][C:9]2[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]3[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=4)[CH:28]=[CH:29][CH:30]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C#N)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M190) (300 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (158 mg, 67%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and 1-propanesulfonyl chloride (Aldrich), to give [4-amino-2-[ 1-(propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-methoxy-phenyl)-methanone. MS (M+H)+, 452.
Reaction SMILES: C(O)C.Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=3)[N:12]=[CH:13][C:6]=12.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29].C(OC(C)C)(C)C>C(#N)C>[CH3:21][C:16]1[CH:15]=[C:14]([N:11]2[C:7]3=[N:8][CH:9]=[N:10][C:5]([NH:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH3:22])=[C:6]3[CH:13]=[N:12]2)[CH:19]=[C:18]([CH3:20])[CH:17]=1
Reactant: COCCOCCN
Reactant: Cc1cc(C)cc(-n2ncc3c(Cl)ncnc32)c1
Solvent: CC(C)OC(C)C
Solvent: CC#N
Solvent: CCO
Product: COCCOCCNc1ncnc2c1cnn2-c1cc(C)cc(C)c1
Temperature: 27.5 °C
Yield: 56.8 %

Procedure:
60.0 ml of ethanol and 10.0 g (0.038 mol) of 4-chloro-1-(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound No. 79) were charged into a 250 ml of 4 necked round bottom flask connected to a mechanical stirrer, thermometer socket, condenser and addition funnel. 22.40 g (0.18 mol) of 2-(2-Methoxy-ethoxy)-ethyl amine was charged at 25-30° C. under stirring. Reaction mass temperature was raised to reflux. Maintained the mass temperature at reflux for 5 hours. Reaction mass temperature was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 60 min. Reaction mass temperature cooled to 0-5° C. Maintained the mass temperature at 0-5° C. for 60 min. Solid does not formed. Distilled off Ethanol completely under vacuum. Crude oily mass was obtained. Oily mass was dissolved in 45 ml of acetonitrile. 300.0 ml of isopropyl ether was added. Solid was formed. Solid was filtered and solid was washed with 50.0 ml of isopropyl ether. Compound was dried under vacuum at 60-65° C. Dry weight of the compound: 7.50 g (yield—56.80%). Melting point: 90.4° C.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:38][C:35]2([CH2:34][CH2:33][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=3)[CH2:37][CH2:36]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: COc1ccc(CCC2(N)CC2)cc1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CCC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 191 mg (1 mmol) 1-[2-(4-methoxy-phenyl)-ethyl]-cyclopropylamine. Yield: 55 mg (11%, trifluoroacetate); mass spectroscopy: [M+H]=399.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[N-:12]=[N+:13]=[N-:14].[Na+].[CH2:16](OC(OCC)OCC)C>C(O)(=O)C>[N:3]1([CH:4]2[CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)[CH:16]=[N:14][N:13]=[N:12]1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: c1nnnn1C1CN2CCC1CC2
Temperature: 100 °C
Yield: 60.4 %

Procedure:
A suspension of 3-aminoquinuclidine dihydrochloride (19.94 g, 0.1 mol), sodium azide (7.8 g, 0.12 mol) and triethylorthoformate (22 mL, 0.15 mol) in glacial acetic acid (50 mL) is heated at an oil bath temperature of 100° C. for 3 hours. The solvent is removed and the oily residue is partitioned between aqueous concentrated potassium carbonate solution and chloroform. The organic layer is dried (potassium carbonate) and concentrated to an oil. The oil is purified by column chromatography (silica gel eluting with chloroform-methanol 8:2) to give 10.82 g of the title compound; mp 83°-84° C. as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>C(O)C>[Br:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCCCc1ccccc1CBr
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1CCCBr)(NC(C)=O)C(=O)OCC

Procedure:
To a stirred solution of 0.61 g (27 mmol) Na in 40 mL of dry ethanol was added portionwise 5.86 g (27 mmol) of solid diethyl acetamidomalonate. This mixture was stirred at reflux under nitrogen for 2 h, then cooled to 0°-10° C. on an ice bath. Then, 8.0 g (27 mmol) of 2-(3-bromopropyl)benzyl bromide in 40 mL of dry ethanol was rapidly added. The reaction mixture was stirred for 2 h at 0°-10° C., then 24 h at room temperature. The precipitated inorganic salt was removed by filtration, and was washed with 20 mL of ethanol and discarded. The combined solvents were removed under reduced pressure yielding an orange colored oil. This oil was chromatographed on a column of silica gel with hexane-ethyl acetate (3:1) as eluant. The combined fractions were concentrated under reduced pressure to yield an oil which solidified upon standing, yield 9.5 g (82%), mp 73°-74.5° C. IR(nujol): 1745, 1648 cm-1 (C=O). 1H NMR(D2O) δ 1.3 (t, 6H); 1.9-2.4 (m, 5H); 2.7 (t, 2H); 3.4 (t, 2H); 3.75 (5, 2); 4.3 (q, 4); 6.6 (s, 1H); 7.0-7.3 (m, 4H). Anal Calcd. for C19H26NO3Br: C, 53.28; H, 6.12; N, 3.27; Br, 18.66. Found: C, 53.33; H, 6.13; N, 3.23; Br, 18.67.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[N:7]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1ccc(CNc2cc(C(F)(F)F)cc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccccc3C(F)(F)F)n2)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of (6-chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine (7.26 g, 22.9 mmol, prepared as described in STEP A above) in DME (100 mL) and water (50 mL) was treated with 2-trifluoromethylphenylboronic acid (5.66 g, 29.8 mmol), and Cs2CO3 (11.2 g, 34.4 mmol). The resulting mixture was degassed via heating under a stream of Ar. Cl2Pd(dppf).DCM (1.13 g, 1.38 mmol) was added, and the mixture was heated to 80° C. for 4 h. The cooled mixture was diluted with water (100 mL) and extracted twice with EtOAc (150 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE column (Flow rate=30 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield (4-methoxy-benzyl)-[4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]amine as a yellow oil, which solidified upon standing. 1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.8 Hz, 1H), 7.57-7.63 (m, 1H), 7.47-7.55 (m, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.85-6.91 (m, 3H), 6.57 (s, 1H), 5.11 (t, J=5.2 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 3.80 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N2OF6: 427.1 (M+H); Measured: 427.2.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C1(C)C=CC=CC=1>ClCCl>[CH3:31][CH:30]([O:29][C:27](=[O:28])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:16])[CH2:6]1)[CH3:32]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 2 h

Procedure:
(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 4) (3.165 g, 9.90 mmol) and DIPEA (5.19 ml, 29.7 mmol) were stirred in dichloromethane (DCM) (66.0 ml) under nitrogen. 1M isopropyl chloroformate in toluene (14.85 ml, 14.85 mmol) was added, the mixture stirred for 2 hours, evaporated to dryness, partitioned between ethyl acetate (200 ml) water (70 ml) and the aqueous layer run off. The organic layer was washed (water (50 ml), brine (20 ml)), dried (sodium sulfate), evaporated to dryness, loaded on to a 40+M Biotage silica column and eluted with cyclohexane:ethyl acetate (9:1 to 1:1). The product containing fractions were evaporated to a white solid (3.23 g). LCMS (Method B): Rt=1.03, MH+=371
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: BrCCOCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 21.43 g (0.1 mol) of tert-butyl N-(trans-4-aminocyclohexyl)carbamate in 250 mL of N,N-dimethylformamide were added 16.76 mL (0.12 mol) of bis(2-bromoethyl)ether and 34.85 mL (0.25 mol) of triethylamine, and the mixture was stirred for 6 hours at 70° C. Then solvent was removed under reduced pressure and the residue was treated with ethyl acetate. The organic layer was washed with sodium carbonate aqueous solution and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform alone to chloroform/methanol=30/1) to give 19.92 g (70%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br-:18].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C)(C)C1C=CC=CC=1.C[N+](C)(C)C1C=CC=CC=1>ClCCl.CO>[Br:18][C:17]1[C:2]([OH:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=1
Reactant: [Br-]
Reactant: CCOC(=O)N1CCc2ccc(O)cc2CC1
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(O)c(Br)cc2CC1
Reaction time: 1 h
Yield: 171 %

Procedure:
Under an argon atmosphere, to a mixed solution of 5.0 g of ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 100 ml of dichloromethane and 20 ml of methanol was added portionwise 8.05 g of N,N,N-trimethylanilinium tribromide under ice-cooling, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was extracted by the addition of ethyl acetate and water, and the organic layer was washed with 1 M aqueous hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to obtain 6.67 g of ethyl 7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH3:16])=[N:13][N:14]=[C:10]3[CH2:9]N=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1.[ClH:24].N([O-])=[O:26].[Na+].S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:12]([CH2:15][CH3:16])=[N:13][N:14]=[C:10]2[CH2:9][Cl:24])=[C:6]([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:26])[CH:23]=1
Reactant: CCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCc1nnc(CCl)n1-c1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
According to the similar procedure as described in Example 4, the reaction product of 8-bromo-1-ethyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 6 N hydrochloric acid-sodium nitrite is chlorinated with thionyl chloride to give 4-[4-bromo-2-(2-pyridinecarbonyl)-phenyl]-3-chloromethyl-5-ethyl-4H-1,2,4-triazole as crystals. Recrystallization from acetone gives pale yellow prisms melting at 199° to 201° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:36])=[O:35]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(F)cc4F)cc3)cc2C1=O

Procedure:
The compound of example 83 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 2,4-difluorobenzene sulfonyl chloride. The compound of example 83 was used directly without isolation for the preparation of compound of example 84.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=[O:26])[CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21]([OH:26])([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[CH2:22]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: c1cocn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncco1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Borane-THF complex (1M, 4.5 mL, 4.5 mmol) was added to a solution of oxazole (0.3 mL, 4.5 mmol) in THF (5 mL) and stirred for 1 hour under nitrogen before cooling to −78° C. n-Butyl lithium (2.5M, 1.8 mL, 4.5 mmol) was added and the reaction mixture stirred for a further 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added and the reaction mixture stirred for 30 minutes. 10% acetic acid in IMS (10 mL) was added and the reaction mixture warmed to room temperature and then further to 40° C. for 30 minutes. The solvent was removed by evaporation under vacuum, water and ethyl acetate were added to the residues, the organics extracted, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica eluting with 25-60% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.3 g) as a colourless oil. LCMS m/z 295.2 [M+H]+. R.T.=3.07 min (Analytical Method 3).