Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Br[C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.BrBr.[C:15](O)(=[O:17])C>>[CH3:15][O:17][C:6]1[N:11]=[C:10]2[S:1][C:2]([NH2:3])=[N:12][C:9]2=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: COc1ccc2nc(N)sc2n1
Temperature: 0 °C

Procedure:
Potassium thiocyanate (156 g, 1600 mmol) is dissolved in acetic acid (1400 mL) and cooled to 0° C. 6-Bromo-pyridin-3-ylamine (50 g, 400 mmol) is dissolved in acetic acid (100 mL) and added dropwise over 10 min. Bromine (25 mL, 480 mmol) is dissolved in acetic acid (100 mL) and added dropwise over 10 min. The reaction is allowed to stir and warm to RT overnight. Acetic acid is removed via concentration. The resulting residue is poured into water (1 L) and adjusted to pH=7 with 1 N sodium hydroxide solution. This is extracted with ethyl acetate. Extracts are combined, washed with brine, and concentrated to a brown sludge. Recrystallization from methanol affords 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a brown solid: 1H NMR (400 MHz, DMSO-D6) δ 3.8 (s, 3 H) 6.7 (d, J=8.8 Hz, 1 H) 7.4 (s, 2 H) 7.6 (d, J=8.6 Hz, 1 H); LC/MS 182.3 (M+1), 180.4 (M−1).
Reaction SMILES: [CH3:1][Br:2].[C:3]([N:7]([CH3:25])[CH2:8][CH2:9][C@@H:10]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>>[Br-:2].[C:3]([N+:7]([CH3:1])([CH3:25])[CH2:8][CH2:9][C@@H:10]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CBr
Reactant: Cc1ccc(O)c([C@H](CCN(C)C(C)(C)C)c2ccccc2)c1
Product: Cc1ccc(O)c([C@H](CC[N+](C)(C)C(C)(C)C)c2ccccc2)c1
Product: [Br-]

Procedure:
Following the general procedure of Example 2 and making non critical variations, but starting with methyl bromide and 2-{(1R)-3-[tert-butyl(methyl)amino]-1-phenylpropyl}-4-methylphenol, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[C:16](CC)[C:15]=1[NH2:25])(=O)[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:25]1[C:15]2[CH:16]=[C:17]([C:18]([O:20][CH2:32][CH3:33])=[O:19])[CH:21]=[CH:22][C:14]=2[N:13]=[C:10]1[CH3:11]
Reactant: CCO
Reactant: CCc1c(C(=O)[O-])ccc(NC(C)=O)c1N
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccccc3Cl)c2c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
2-Chlorobenzyl bromide (100 g) is added to an ethanol (750 ml) solution of 4-acetylamino-3-amino-ethylbenzoate (86.0 g) and potassium carbonate (37.3 g), and the solution is stirred for 14 hours at 60° C. Solids are separated through filtration and the filtrate is concentrated under reduced pressure. 35% hydrochloric acid (38.7 g) is added and the solution is stirred for two hours at 60° C. After solids are separated through filtration and the solution is neutralized with sodium bicarbonate, the ethanol is removed through evaporation under reduced pressure. Ethyl acetate and water are added, and extraction is performed (three times). After the organic layer is washed with water and dried, the solvent is removed through evaporation until the organic layer became. Precipitated crystals are separated through filtration and are recrystallized through ethanol. Thus, 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (54.3 g ) is obtained. Furthermore, crystals are obtained by collecting and concentrating all filtrates. The crystals are recrystallized with ethanol. Thus, 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (18.1 g) is obtained. 1H-NMR (CDCl3, δ): 1.39 (3H, t, J=7.1 Hz), 2.57 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.46 (2H, s), 6.41 (1H. d, J=7.8 Hz), 7.10 (1H, t, J=7.8 Hz), 7.25 (1H, t), 7.47 (1H, d, J=8.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.94 (1H, s), 8.00 (1H, d,=1.5 and 8.4 Hz).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(C)nccn32)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@H](c2nc(Br)c3c(C)nccn32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (cis)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (46.8 mmol, 12.8 g) in N,N-dimethylformamide (100 ml) was added N-bromosuccinimide (46.8 mmol, 8.33 g). After stirring at room temperature for one hour the reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic layers were washed with water twice, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 3% of methanol) to give (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (15.34 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1>CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:30]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Yield: 15.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (3 g), dimethylaluminium chloride in heptane (1.0 molar, 34.62 ml) and 4-aminobenzoic acid (1.58 g) to give the desired 4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-benzoic acid (0.522 g) as a white solid. MS (ESI): 449.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][N:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:6][CH3:7].[Br:20]Br>C(Cl)Cl>[NH2:1][C:2]1[C:17]([Br:20])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][N:5]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:6][CH3:7]
Reactant: CCN(Cc1cc(OC)ccc1N)C1CCCCC1
Reactant: BrBr
Solvent: ClCCl
Product: CCN(Cc1cc(OC)cc(Br)c1N)C1CCCCC1

Procedure:
2-Amino-3-bromo-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11]C1C2C(=CC=CC=2)CCC1>C(O)(C)C>[ClH:1].[N:10]1[C:2]([NH2:11])=[C:3]2[C:7]([N:6]=[CH:5][NH:4]2)=[N:8][CH:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NC1CCCc2ccccc21
Solvent: CC(C)O
Product: Cl
Product: Nc1ncnc2nc[nH]c12
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 6-chloropurine (1.546 g, 10 mM) and 1-aminotetralin(1.472 g, 10 mM) in isopropanol (60 ml) is heated to reflux for about 20 h. The resulting salt suspension is then cooled to room temperature, filtered and the residue washed with ice-cooled isopropanol to give almost pure title compound in 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NS(=O)(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 98.9 %

Procedure:
A solution of 39 (0.08 g, 0.21 mmol), benzenesulfonyl chloride (0.07 g, 0.42 mmol), triethylamine (0.06 g, 0.63 mmol), and a catalytic amount of DMAP in CH2Cl2 (40 mL) was stirred at room temperature for 18 h. Absolute MeOH was then added and the solution was washed with 10% HCl (3×25 mL) and saturated NaCl (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield a crude solid. The solid was purified by flash column chromatography (eluent: n-hexanes/EtOAc, 1:1). Removal of the solvent under reduced pressure gave 0.11 g (97%) of 43 as a white solid, mp 271-273° C. (EtOAc/n-hexanes): 1H NMR (acetone-d6): δ 0.98 (3H, s); 1.29 (3H, s); 1.52 (2H, m); 1.65 (1H, m); 1.70 (1H, ddd, J=3.0, 3.0, 12.6); 1.82 (1H, ddd, J=1.8, 5.1, 13.5); 1.95 (1H, ddd, J=6.3, 6.3, 10.2); 2.09 (1H, d, J=13.2); 2.22 (1H, dd, J=2.7, 11.7); 2.29 (1H, ddd, J=3.3, 6.9, 13.5); 2.62 (1H, s); 2.96 (1H, dd, J=3.5, 13.4); 3.66 (3H, s); 4.19 (1H, m); 5.47 (1H, dd, J=5.4, 12.0); 6.53 (1H, dd, J=0.9, 1.5); 6.69 (1H, d, J=8.4); 7.38 (1H, m); 7.40 (1H, d, J=6.9); 7.44 (1H, dd, J=2.1, 3.0); 7.60 (2H, m); 7.80 (2H, m); 13C NMR (acetone-d6): δ 15.7, 16.8, 19.4, 35.5, 36.4, 39.1, 43.4, 44.3, 51.5, 52.2, 54.8, 61.2, 64.7, 72.4, 110.0, 127.5, 128.2, 130.1, 133.5, 141.2, 142.4, 145.1, 171.7, 173.0, 205.3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1.CO>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc([N+](=O)[O-])ccc1CO
Temperature: 80 °C
Yield: 102.5 %

Procedure:
To a solution of 2-methyl-4-nitrobenzoic acid (5 g, 27.6 mmol, Aldrich) in THF) (95 ml) was added dropwise 1.0 M borane-tetrahydrofuran complex (55 ml, 55.0 mmol, Aldrich) at ambient temperature under nitrogen. The resulting red solution was heated to 80° C. for 2 h. To the solution at ambient temperature was added methanol (30 ml) and then heated to 80° C. for 30 min. The solvent was evaporated in vacuo to leave a yellow oil. The residue was dissolved in methanol (80 ml) and the solvent evaporated in vacuo to leave (2-methyl-4-nitrophenyl)methanol as a yellow solid (4.73 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[N:60]1([CH:66]2[CH2:71][CH2:70][CH:69]([C:72]3[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=3)[CH2:68][CH2:67]2)[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:78][C:75]4[CH:76]=[CH:77][C:72]([CH:69]5[CH2:68][CH2:67][CH:66]([N:60]6[CH2:61][CH2:62][O:63][CH2:64][CH2:65]6)[CH2:71][CH2:70]5)=[CH:73][CH:74]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc(C2CCC(N3CCOCC3)CC2)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCC(N6CCOCC6)CC5)cc4)nn23)c1

Procedure:
The title compound was prepared in the following manner: N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (70 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (82.6 mg, 0.231 mmol), N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol), and N,N-Dimethylformamide (2 mL, 20 mmol) and stir at room temperature for half an hour. Added 4-(4-Morpholin-4-yl-cyclohexyl)-phenylamine (280 mg, 1.1 mmol) and stir at 80° C. overnight. The mixture was concentrated and purified using the gilson. The most pure fractions were combined basified with sat. sodium bicarbonate and extracted with DCM, dried filtered and concentrated to give a yellow solid (30 mg, 20%). MP 160-163 C. LCMS (E/I+) 589 (M+H). NMR 1H (DMSO-d6)-9.44 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 8.33-8.40 (m, 1H), 7.86 (d, 1H, J=8.03), 7.59-7.76 (m, 3H), 7.18-7.24 (m, 2H), 6.98 (d, 1H, J=4.8 Hz), 3.60-3.64 (m, 2H), 3.55-3.59 (m, 1H), 2.55-2.64 (m, 1H), 2.49-2.51 (m, 4H), 2.36-2.42 (m, 2H), 2.14-2.19 (m, 1H), 1.89-1.98 (m, 2H), 1.78-1.88 (m, 2H), 1.44-1.54 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH2:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2)[CH3:15].N1CCCCC1>C(O)C>[CH2:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13])[CH3:15]
Reactant: CCc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 32.1 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 80.5 mg 5-ethyl-2-oxindole, and 75 μL of piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by a chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 52 mg (32%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[C:12](Cl)(Cl)=S.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[CH:32]=[C:31]([C:33]([NH:35][NH2:36])=[O:34])[CH:30]=[CH:29][C:27]=2[N:28]=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[CH:32]=[C:31]([C:33]3[O:34][C:12]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=4)=[N:36][N:35]=3)[CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2-amino-5-trifluoromethyl-pyridine (164 mg, 1.01 mmol) in a biphasic solution of CHCl3 (25 mL) and saturated NaHCO3 (25 mL). Add thiophosgene (78 uL, 1.01 mmol) to the organic phase and stir the reaction vigorously for 2.5 hr. Separate the phases and extract the aqueous phase with CHCl3 (25 mL). Concentrate the combined organics and take the concentrate up in DMF (3 mL). Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol) and stir overnight. Add EDCI (298 mg, 1.56 mmol) and heat to 80° C. for 4 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Purify the concentrate by reverse phase HPLC (35-50% ACN/H2O+5 mM NH4OH) to afford the title compound as a cream colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.63-7.68 (m, 1H) 7.70 (s, 1H) 7.72 (d, J=1.77 Hz, 1H) 7.76-7.87 (m, 1H) 7.88-7.94 (m, 1H) 8.04-8.30 (m, 3H) 8.72 (br. s., 1H) 11.87 (br. s., 1H) 13.31 (br. s., 1H); MS m/z=491.8 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](O)=[O:35].[I-].ClC1C=CC=C[N+]=1C.C(NCCCC)CCC>O1CCCC1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:34]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[N:8]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(N)N=C2c1ccccc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCNCCCC
Solvent: C1CCOC1
Product: CCc1cc2c(s1)-n1c(C)nnc1C(NC(=O)c1cc3ccccc3[nH]1)N=C2c1ccccc1Cl
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To 120 ml of tetrahydrofuran were added 5.0 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 2.7 g of indole-2-carboxylic acid, 4.3 g of 2-chloro-N-methyl pyridinium iodide and 6.2 g of dibutyl amine, and the mixture was heated under reflux while stirring for 90 minutes. After the solvent was distilled off under reduced pressure, the residue was washed with diisopropyl ether. Ethanol was added to separate crystals, which were collected by filtration. The thus-obtained crystals were recrystallized from chloroform-ethanol to give 4.9 g of 4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, m.p. 284°-286° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([CH:5]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](O)=[O:21])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:66]([O:73][NH2:74])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C>[CH2:66]([O:73][NH:74][C:20]([CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[C:3]([N:2]([CH3:36])[CH3:1])=[O:4])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)=[O:21])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: NOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
The acid compound 25 (0.85 g, 1.66 mmol) was dissolved in dry DMF (20 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.25 g, 1.82 mmol), EDCI (0.32 g, 1.66 mmol), and triethylamine (0.7 mL, 5.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.3 g, 1.83 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was extracted with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography on silica gel (hexanes:ethyl acetate—1:1 containing 1% acetic acid) yielded the desired benzyl hydroxamate 26 (0.8 g, 78%). 1H NMR (400 MHz, DMSO-d6): 8.06 (d, J=9.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.30-7.36 (m, 5H), 7.29 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.72 (s, 2H), 4.26-4.32 (m, 1H), 2.75-2.82 (m, 3H), 2.68 (s, 3H), 2.57-2.63 (dd, J=13.6 and 7.6 Hz, 1H), 2.35 (s, 3H), 2.25 (t, J=7.2 Hz, 2H).
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.CO.C[O-].[Na+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClCCl>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:31]([C:29]1[O:30][C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)=[CH:27][CH:28]=1)=[O:32])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CN2CCC1CC2)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of (±)3-aminoquinuclidine dihydrochloride, methanol (250 ml), sodium methoxide (5.1 g, 95 mmol) was stirred at reflux for 1 hour. The mixture was evaporated and was mixed with methanol (150 ml) and dichloromethane (100 ml) was added and cooled on ice, and 5-(4-nitrophenyl)-2-furoyl chloride (11.2 g, 44.5 mmol), solved in dichloromethane (200 ml) was added drop-wise at 0° C. The mixture was stirred at room temperature for 21 hours. The mixture was evaporated, water (200 ml) was added and the pH was adjusted to 8.5 with triethylamine. The mixture was extracted with ethyl acetate (3×200 ml) and the pure product was isolated as free base. Yield 5.0 g (33%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1-bromo-4-methylbenzene.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[CH2:39][NH2:40]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:40][CH2:39][C:38]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:36]([O:35][CH3:34])[CH:37]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCc2ccc(OC)c(OC)c2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 58% purity by LC/MS. MS(ESI+): m/z=488.4.