Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[CH:17]1(C(O)=O)[CH2:19][CH2:18]1.C(=O)=O>O.S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]([CH:17]2[CH2:19][CH2:18]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(O)C1CC1
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Agent: [Ag+]
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(C2CC2)nc1C(=O)OCC

Procedure:
40 g of pyridine-2,3-dicarboxylic acid diethyl ester are dissolved in a mixture of 400 g of water and 36 g of concentrated sulphuric acid and 6.1 g of silver nitrate (AgNO3). Subsequently, 32 g of cyclopropanecarboxylic acid are added and the reaction mixture is heated to 70°. A solution of 82.1 g of ammonium peroxydisulphate (NH4)2S2O8 in 300 ml of water is added dropwise thereto while stirring vigorously. When the evolution of CO2 has ceased, the reaction mixture is stirred for a further 20 minutes. It is then cooled to 15° and extracted twice with 200 ml of methylene chloride each time. The organic phase is collected, dried over magnesium sulphate, filtered and concentrated by evaporation. The residue is distilled at 13 millibars and the distillate is chromatographed over a column of silica gel with hexane/methylene chloride/ether. After the solvent has been evaporated 11.2 g of the above diester remain behind in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([C:36](Cl)=[O:37])[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([C:36]([N:10]([CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:37])[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=1)#[N:25]
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 300 mg, 1.55 mmol) was dissolved in CH2Cl2 (30 m]L) and to the resultant solution were added DIPEA (440 mg, 3.40 mmol) together with 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 341 mg, 1.55 mmol). The mixture was stirred for 2 h at room temperature, diluted with CH2Cl2 (20 mL) and then washed with water, aqueous KHSO4 solution and finally with brine. The solution was dried over Na2SO4 and then the solvent was evaporated. The residue was chromatographed on silica gel using a mixture of heptane and ethyl acetate as eluent (7:3) and there was obtained 460 mg (78%) of 3-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (400 MHz, CDCl3): 0.8-4.2 (cm, 16H), 4.8-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.7-7.4 (cm, 6H); LCMS: m/z 377 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6](C)=[N:5]1)([CH3:3])[CH3:2].[CH3:25][C@@:26]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:27]5[CH2:28][CH2:29][CH2:30][C@@:26]5([CH3:25])[C:31]([NH2:33])=[O:32])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C[C@@]1(C(N)=O)CCCN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC[C@@]3(C)C(N)=O)cc1OCC2

Procedure:
Following the procedures for Examples 339 and 408, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and (S)-2-methyl-pyrollidine-2-carboxylic acid amide were reacted. The crude product was passed down a Isolute SCX-2 column, eluting with methanol then 2M NH3 in methanol. The basic fractions were concentrated in vacuo and the resultant residue subjected to reverse phase HPLC (C18 column, gradient 15 to 75% Methanol in water+0.1% HCO2H). The appropriate fractions were evaporated to dryness, passed down an Isolute NH2 column, eluting with methanol then further triturated in diethyl ether to give 402 as a white solid. LCMS: RT=2.79 min, [M+H]+=423. 1H NMR 400 MHz (CD3OD) δ: 9.14 (1 H, s), 7.93 (1 H, s), 7.69 (1 H, s), 6.05 (1 H, s), 5.99 (1 H, m), 4.51-4.50 (4 H, m), 3.70 (1 H, m), 3.57 (1 H, m), 3.50 (1 H, m), 2.36-2.33 (1 H, m), 2.10-2.08 (2 H, m), 1.63 (3 H, s), 1.56 (6 H, dd, J=6.63, 2.34 Hz)
Reaction SMILES: Br[CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:21])[C:10]2=[O:28])=[CH:5][CH:4]=1.N[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>ClCCCl.ClCCl.CO>[Cl:27][C:24]1[S:23][C:22]([C:20]([NH:19][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[C:17](=[O:18])[N:9]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:19][C:15]4[CH:16]=[CH:11][C:12]([C:36]5[CH:37]=[CH:32][CH:33]=[CH:34][N:35]=5)=[CH:13][CH:14]=4)=[CH:30][CH:29]=2)[C:10]3=[O:28])=[O:21])=[CH:26][CH:25]=1
Reactant: Nc1ccncc1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCc1ccc(CBr)cc1)C2=O)c1ccc(Cl)s1
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1cccc2c1C(=O)N(CCc1ccc(CNc3ccc(-c4ccccn4)cc3)cc1)C2=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.1 mmol) of N-{2-[4-(bromomethyl)phenethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide are introduced a little at a time into a solution of 37.4 mg (0.4 mmol) of 4-aminopyridine in 4 ml 1,2-dichloroethane. The mixture is stirred at room temperature overnight and then diluted with dichloromethane/methanol (98:2), washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue is crystallized using dichloromethane/ether and the solid is filtered off with suction and dried under high vacuum. Yield: 25.1 mg (37.2% of theory); MS (ESI): m/z (%)=517 (M+H, 100);); LC-MS (Method 7): rt (%)=3.42 (77).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:42]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:25])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:41]([O:43][C:44]3[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=3)=[O:42])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCCCCCCO)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of the alcohol (40.0 g, 88 mmol) produced in Example 4 and pyridine (7.1 ml, 88 mmol) in 300 ml of methylene chloride was added under nitrogen dropwise over one hour to a solution of 4-nitrophenyl chloroformate (17.7 g, 88 mmol) in 300 ml of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for two hours and overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 54.9 g of an off-white solid. Recrystallization from 1:1 ethyl acetatehexane gave 51.6 g (95%) of the title compound as a white crystalline solid, mp 117-120° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2>C(O)(=O)C.O=[Pt]=O>[CH3:1][C:2]1[N:3]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][CH2:18][NH:19]3)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)O)c2ccccc2n1-c1cccc2ncccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)c2ccccc2n1-c1cccc2c1CCCN2
Temperature: 22 °C
Reaction time: 20 h

Procedure:
To a solution of 2-methyl-1-(quinolin-5-yl)-1H-indole-3-carboxylic acid (Example 40) (25 mg) in acetic acid (3 mL) was added PtO2 (50 mg) at 22° C. The reaction was stirred at 22° C. under H2 ball for 20 hrs. Then the mixture was filtered and the filtrate was purified by column chromatography on silica gel eluted with dichloromethane:methanol=70:1 to the title compound as a yellow solid (20 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].[S:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(=O)([O-])O.[Na+].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([CH:15]2[CH2:16][CH2:17][S:12][CH2:13][CH2:14]2)[C:5](=[O:9])[C:4]=1[C:10]#[N:11]
Reactant: OC1CCSCC1
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccn(C2CCSCC2)c(=O)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.00 g), tetrahydro-2H-thiopyran-4-ol (1.18 g), triphenylphosphine (2.62 g) and tetrahydrofuran (30 mL) was added dropwise diisopropyl azodicarboxylate (2.02 g) at room temperature under nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (320 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[C:4]([O:14][CH3:15])[CH:3]=1.[OH:16]S(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([O:14][CH3:15])[CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:16]
Reactant: O=S(=O)(O)O
Reactant: COc1cc(Br)ccc1NC(=O)C=NO
Product: COc1cc(Br)cc2c1NC(=O)C2=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To concentrated H2SO4 (30 ml) at 65° C. was added N-(4-bromo-2-methoxyphenyl)-2-(hydroxyimino)acetamide (5.55 g, 20 mmol) portionwise. The mixture was heated at 90° C. for 1.5 h. The mixture was cooled to room temperature, poured onto ice, and stirred for 10 min. The solid was collected by filtration, washed with water, and air dried to afford 5-Bromo-7-methoxyindoline-2,3-dione (3.6 g, crude, 70% yield). This material was used without further purification. 1H NMR (400 MHz, DMSO-d6): δH 7.93 (s, 1H), 7.38 (s, 1H), 3.94 (s, 3H). MS (ESI) m/e [M+1]+ 256, 258.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:35]>C(OCC)C>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)c2ccc3c(c2)c2c(n3C)CC3CCC2N3)cc1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide) and the product treated directly with 1.25 M HCl in methanol (0.5 mL). After concentration in vacuo the residue was lyophilized to give 2-(4-methoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (49 mg, 34%, AUC HPLC 98.0%) as a light-yellow solid: mp 210-212° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.34 (br s, 1H), 9.04 (br s, 1H), 8.32 (s, 1H), 7.85 (dd, J=7.2, 2.1 Hz, 2H), 7.63 (s, 2H), 7.09 (dd, J=7.2, 2.1 Hz, 2H), 5.35 (d, J=3.9 Hz, 1H), 4.48 (br s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 3.35-3.45 (m, 1H), 3.01 (d, J=17.1 Hz, 1H), 2.18-2.33 (m, 2H), 2.04-2.15 (m, 1H), 1.72-1.86 (m, 1H); ESI MS m/z 383 [M+H]+.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][N:22]([CH2:24][C:25]1[O:26][C:27]([CH2:30][S:31][CH2:32][CH2:33]N)=[CH:28][CH:29]=1)[CH3:23]>C(O)C>[CH3:23][N:22]([CH2:24][C:25]1[O:26][C:27]([CH2:30][S:31][CH2:32][CH2:33][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[CH:14]=3)=[CH:7][N:6]=2)=[CH:28][CH:29]=1)[CH3:21]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccn(C)c(=O)c3)c(=O)[nH]2)o1
Yield: 43.8 %

Procedure:
2-Nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.08 g) and 2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamine (1.82 g) were refluxed in ethanol (10 ml) for 22 hours. The reaction mixture was evaporated under reduced pressure to afford an oil which on trituration with diethyl ether gave a solid. This solid was collected by filtration, washed with diethyl ether and recrystallised from isopropanol to yield 2-[2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamino]-5-(1-methyl- 2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.41 g); recrystallisation from isopropanol afforded material with m.p. 129°-132° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:27][C:2]1([CH3:1])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:21]([CH:26]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CC(C(Nc2cnc3ccccc3c2)c2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccccc3c2)C2CC(C)(C)C2)cc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
To a vial containing 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoic acid (14.0 mg, 0.0390 mmol) was added 3-aminopropionic acid ethyl ester hydrochloric (6.60 mg, 0.0430 mmol), 1-Hydroxy-7-azabenzotriazole (6.40 mg, 0.0470 mmol) and 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (9.00 mg, 0.0470 mmol). Anhydrous methylene chloride (0.390 mL) was added followed by triethylamine (0.007 mL, 0.0510 mmol). After 18 h, the reaction was diluted with methylene chloride and quenched with a saturated solution of ammonium chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give 26.0 mg of crude material. Purification by column chromatography (0-70% ethyl acetate in heptane) provided ethyl 3-(4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzamido)propanoate (11.9 mg, 66% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.48 (d, J=2.7 Hz, 1H), 7.88 (dd, J=8.3, 1.3 Hz, 1H), 7.74-7.67 (m, 2H), 7.46-7.41 (m, 2H), 7.41-7.29 (m, 3H), 6.81 (t, J=6.1 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 4.42 (br. s., 1H), 4.25 (dd, J=9.3, 4.4 Hz, 1H), 4.19-4.08 (m, 2H), 3.70 (q, J=6.0 Hz, 2H), 2.61 (t, J=5.7 Hz, 2H), 2.59-2.45 (m, 1H), 2.07-1.97 (m, 1H), 1.76-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.28-1.21 (m, 3H), 1.13 (s, 3H), 1.09 (m, 3H). MS (M+1): 460.4.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[NH:17][S:18]([CH2:21][C:22]([O:24]CC)=O)(=[O:20])=[O:19])[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:30]>>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[NH:17][S:18]([CH2:21][C:22]([NH2:30])=[O:24])(=[O:19])=[O:20])[CH3:13])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC(=O)OCC)c1
Reactant: N
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC(N)=O)c1
Yield: 53.5 %

Procedure:
A solution of ethyl 2-{[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)anilino]sulfonyl}acetate (Example 41, 0.13 g, 0.38 mmol) in ammonia (2M in methanol, 3.0 ml, 1.5 mmol) was heated to 60° C. for 12 h in a sealed tube. The mixture was cooled, concentrated in vacuo and then purified by chromatography on silica gel eluting with methanol:ethyl acetate (2:98) to give the product as a pale yellow foam (80 mg, 53%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([OH:30])[C:10]2[N:11]([N:14]=[C:15]([CH2:17][CH2:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:20]=3)[N:16]=2)[C:12]=1[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[C:9]([O:30][CH2:2][CH2:3][O:4][CH3:5])[C:10]2[N:11]([N:14]=[C:15]([CH2:17][CH2:18][C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[N:20]=3)[N:16]=2)[C:12]=1[CH3:13]
Reactant: COCCBr
Reactant: Cc1c(Cl)cc(O)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)c(C)n2nc(CCc3nc(N4CCCC4)nn3C)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
1-Bromo-2-methoxyethane (10.7 mg, 7.26 μl, 77.3 μmol, Eq: 1.2) was added to 6-chloro-5-methyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-ol (23.3 mg, 64.4 μmol, Eq: 1.00) and K2CO3 (26.7 mg, 193 μmol, Eq: 3) in dimethylformamide (1 ml). The mixture was stirred at 50° C. for 2 h. The crude material was purified by preparative HPLC to give the desired product (7 mg, 25%) as a white powder. MS: m/z=420.6 (M+H+)
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl.[NH2-].[Na+].O>C1(C)C=CC=CC=1>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:7]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:12][CH2:11][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: ClCCOCCOC1CCCCO1
Reactant: c1ccc2c(c1)CCCc1ccccc1N2
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCCc1ccccc1N2CCOCCOC1CCCCO1
Temperature: 25 °C

Procedure:
To a solution of 5,6,7,12-tetrahydrodibenz[b,g]azocine (2.5 g, 12 mmol, prepared in a similar way as described in Chem. Pharm. Bull. 1978, 26, 942-950) and 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (3.0 g, 14 mmol) in toluene (50 ml) was added a suspension of sodium amide (1.50 g, 19 mmol, 50% wt suspension in toluene). The reaction mixture was heated at reflux temperature for 10 h. The mixture was allowed to cool to room temperature and water (52.5 ml) was carefully added. The phases were separated and the aqueous phase was extracted with toluene (50 ml). The combined organic phases were washed with water (2×5 ml), brine (15 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (150 g) using a mixture of ethyl acetate and n-heptane (1:4) as eluent. Collecting the proper fractions afforded 3.0 g of crude 12-(2-(2 -((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-5,6,7,12-tetrahydrodibenz[b,g]azocine. TLC: rf=0.11 (SiO2 ; ethyl acetate/n-heptane=1:4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)=[CH:10][C:3]=12.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][N:39]([CH2:51][CH3:52])[N:38]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>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.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:37]2[C:41]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=5)=[CH:10][C:3]=34)=[CH:40][N:39]([CH2:51][CH3:52])[N:38]=2)=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: O=Cc1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
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: CN(C)C=O
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a sealed pressure tube was added 4-bromo-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (1.6 mmol), 3-(4-nitrophenyl)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.7 mmol), N,N-dimethylformamide (15 mL), aqueous saturated sodium bicarbonate (4 mL) and tetrakis(triphenylphosphine)palladium(0) (0.09 mmol). The reaction was purged with nitrogen, capped, and stirred at 100° C. for 8 h. After cooling to room temperature, the reaction was concentrated under vacuum, taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to dryness under vacuum. Purification by silica gel flash chromatography (5-10% ethyl acetate/methylene chloride) gave the title compound as a yellow solid (81%). ESMS [M+H]+: 578.3
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20](=O)[CH2:19][CH2:18][C:17](=O)[C:16]=2[CH:24]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:24]=1
Reactant: O=C1CCC(=O)c2cc(Br)ccc2N1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCCN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
To a slurry of LAH (0.14 g, 3.69 mmol) in 10 mL of THF was added AlCl3 (0.46 g, 3.45 mmol) in two portions. The mixture was stirred at rt for 15 minutes and a solution of 7-bromo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.22 g, 0.87 mmol) in 10 mL of THF was added dropwwase. The mixture was then heated at 60° C. for 12 h. The reaction was cooled and quenched. It was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4, concentrated, and chromatographed with 20-100% EtOAc in hexane to give 0.07 g of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzazepine. MS (AP+): 267, 269, M+H.