Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][C:12](=[O:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:23].[Cl-].[NH4+]>CCCCCC.CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH3:23])[C:12](=[O:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN1C(=O)CN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Sodium hydride (18 mg, 0.45 mmol, 60% suspension in mineral oil) was washed with hexane (2×2 mL) in, a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (80 mg, 0.30 mmol) in dry DMF (3 mL) at 0° C. The reaction mixture was stirred at this temperature for 1 h. Iodomethane (0.0.19 mL, 0.30 mmol) was added at 0° C. and the reaction mixture was allowed to come to r.t. and stirred overnight. After the completion of the reaction as confirmed by TLC, reaction mixture was cooled to 0° C. and saturated solution of ammonium chloride (2 mL) was added dropwise to the reaction mixture. The crude product was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed in vacuo to afford 1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (75 mg, 89%) as a viscous oil which was used as such without any further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:15](=[O:17])[CH3:16])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of 4-bromo-2-aminopyridine (87 mmol) and pyridine (130 mol) in 200 mL dichloromethane was added dropwise acetyl chloride (117 mmol). The reaction mixture was stirred at room temperature for 4 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was washed with hexane to afford 13.5 g of N-(4-bromopyridin-2-yl)acetamide (72% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1>ClCCl>[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([C:5](=[O:7])[CH3:6])=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Aluminium chloride (1.19 g, 8.9 mmol) was added portionwise to a stirred solution of acetyl chloride (1.21 mL, 17.0 mmol) in dry dichloromethane (20 mL), previously cooled to −10° C., until homogeneous (5 min). The solution was added, via cannula, to a solution of 3,4-dihydro-2H-1-benzopyran (9a) (1.20 g, 8.9 mmol) in dry dichloromethane (17 mL) at −10° C. The mixture was stirred at the same temperature for 30 minutes before being poured into ice/concentrated hydrochloric acid (5:1, v/v, 126 mL). The stirring was maintained at room temperature for 2 hours and the solution was extracted with dichloromethane (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (49a) (1.55 g, 8.8 mmol, 99%) which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:11][C:12](=[O:32])[NH:13][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)[CH2:15]1)([CH3:10])([CH3:9])[CH3:8].CC1(C)C(C)(C)OB([C:41]2[CH:50]=[CH:49][C:48]3[C:47]([CH3:52])([CH3:51])[CH2:46][CH2:45][C:44]([CH3:54])([CH3:53])[C:43]=3[CH:42]=2)O1>CN(C=O)C.COCCOC.CO.O.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:7]([O:11][C:12](=[O:32])[NH:13][CH:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[C:29]([C:50]4[CH:41]=[CH:42][C:43]5[C:44]([CH3:54])([CH3:53])[CH2:45][CH2:46][C:47]([CH3:52])([CH3:51])[C:48]=5[CH:49]=4)[N:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)[CH2:15]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCN(c3ncnc(Cl)n3)CC2)C1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1CCN(C2CCN(c3ncnc(-c4ccc5c(c4)C(C)(C)CCC5(C)C)n3)CC2)C1

Procedure:
23 mg (0.22 mmol) of sodium carbonate are added to 50 mg (0.11 mmol) of {1-[1-(4-chloro-1,3,5-triazin-2-yl)piperidin-4-yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester and 45 mg (0.12 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane in 1.5 ml of DMF/DME/methanol/water (1/1/0.9/0.3). The reaction mixture is degassed a number of times, 8 mg (0.017 mmol) of bis(triphenylphosphine)palladium(II) dichloride are added under nitrogen atmosphere, the mixture is treated in an ultrasound bath for 10 min and subsequently irradiated in the microwave at 100° C. for 20 min. The reaction mixture is diluted with methanol, filtered, and the crude product is purified by means of preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH:10]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:40][OH:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[NH:40][OH:41])[CH:10]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[C:31]([CH3:39])[CH:30]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C(=O)OC(C)(C)C)CCC3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C(=O)OC(C)(C)C)CCC3C(=O)NO)cc2)c2ccccc2n1
Yield: 5.3 %

Procedure:
According to the procedure of Example 24, Step 3, 0.55 g (0.99 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester and hydroxylamine afforded 4-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-yl methoxy)-benzenesulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester as an amorphous white solid (0.030 g, 5.3%) after purification using reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column, eluting an acetonitrile:water gradient. MS: 571 (M+H)+
Reaction SMILES: C(N1CCN(C2C=CC([B:16]([OH:18])[OH:17])=CC=2)CC1)(C)C.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]2)=[CH:22][CH:21]=1>>[CH3:33][C@H:28]1[NH:29][C@@H:30]([CH3:32])[CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([B:16]([OH:18])[OH:17])=[CH:21][CH:22]=2)[CH2:27]1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Reactant: CC(C)N1CCN(c2ccc(B(O)O)cc2)CC1
Product: C[C@@H]1CN(c2ccc(B(O)O)cc2)C[C@H](C)N1

Procedure:
The title compound was synthesized according to the synthesis of 4-(4-isopropylpiperazin-1-yl)phenylboronic acid, except substituting 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine (300 mg, 1.11 mmol). The reaction was quenched with sat. NH4Cl solution, extracted with EtOAc, dried over MgSO4, filtered, and concentrated to dryness. The title compound was isolated by silica gel chromatography (MeOH/CH2Cl2, 6:94 to 1:4) as a yellow solid (59 mg, 23%). 1H NMR (400 MHz, MeOD) δ 7.59 (d, J=6.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 3.67-3.63 (m, 2H), 3.09-3.01 (m, 2H), 2.32 (t, J=11.6 Hz, 2H), 1.18 (d, J=6.4 Hz, 6H); MS ESI 235.1 [M+H]+, calcd for [C12H19BN2O2+H]+ 235.15.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]1.[CH3:25][Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl.C[Mg]Br.Cl>CCOCC.N1C=CC=CC=1>[OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCCCCC(=O)CCC1CCC(CCCCCCCC(=O)O)O1
Agent: C[Mg]Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(C)(O)CCC1CCC(CCCCCCCC(=O)O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
IX (6.30 g, 0.0185 mole), hexamethyldisilazane (HMDS) (12 ml), trimethylchlorosilane (TMCS) (6 ml), and pyridine (40 ml) were mixed and kept overnight at room temperature. The resulting white suspension was evaporated to dryness (50° C, 10 mm Hg). Ether (100 ml) was added, and the suspension was filtered. The resulting clear, yellow solution of X was cooled to 0° C, and methylmagnesium bromide in ether (3.8N, 8.0 ml, 0.030 mole) was added dropwise during 20 minutes. After stirring for 2 hours at room temperature, the white suspension being formed was poured into a mixture of cold hydrochloric acid (0.25N, 140 ml) and ether (50 ml). The ethereal phase was separated, and the aqueous layer was extracted with ether (50 + 25 ml). The combined ethereal extracts were washed with water 50 ml) and dried over sodium sulfate. The solvent was removed from a water bath (60° C, 10 mm Hg), and the residual light yellowish oil (7.40 g) was distilled under reduced pressure to give 5.40 g (82%) of XI as a light yellowish oil, b0.08 203°-210° C, nD25 1.4710.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH3:11].CCCCCC.C([Li])CCC.[CH:23]1([CH:29]=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl-].[NH4+]>O1CCCC1>[CH:23]1([CH:29]([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4][C:3]=2[CH3:11])[OH:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=CC1CCCCC1
Reactant: Cc1sc2ccccc2c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1sc2ccccc2c1C(O)C1CCCCC1
Reaction time: 0.17 h
Yield: 85 %

Procedure:
3-Bromo-2-methyl-1-benzothiophene (2.00 g) synthesized above was dissolved in tetrahydrofuran (40 mL), 1.6M n-butyllithium hexane solution (6.63 mL) was added dropwise at −78° C. The mixture was stirred under a nitrogen atmosphere for 10 min, cyclohexanecarbaldehyde (2.50 mL) was added, and the mixture was stirred −78° C. for 30 min and at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (1.95 g, 85%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[C:30]=4[CH3:31])=[CH:24][C:6]2=3)=[CH:22][CH:21]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc3c(c2)N(c2ccc(Cl)cc2)C[C@@H](C)c2nnc(C)n2-3)cnn1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (41 mg, 0.1 mmol), 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg) and cesium carbonate (65 mg, 0.2 mmol) in toluene, ethanol and water (5 mL, 4:2:1) was stirred at 100° C. for 0.5 hour under microwave (pressure: 3.2 bar, equipment power: 150 W). The reaction mixture was evaporated, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1), to give (R)-6-(4-chlorophenyl)-8-(1,5-dimethyl-1H-pyrazol-4-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a yellow solid (10 mg, 23%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16](=[O:33])[N:17]([CH3:32])[CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:32][N:17]([CH2:18][C:19]#[C:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=1)[C:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=1)=[O:33]
Reactant: CCOC(=O)Cn1ccc2ccc(CC(=O)N(C)CC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)Cc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 e], [6-({methyl-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-carbamoyl}-methyl)-indol-1-yl]-acetic acid ethyl ester was treated with LiOH to obtain the title compound as yellow crystals.
Reaction SMILES: O=S(Cl)Cl.[N:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[O:18]1[C:14]2([CH2:19][CH2:20][C:11]([C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)=[CH:12][CH2:13]2)[O:15][CH2:16][CH2:17]1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2ccncc2)CCC2(C1)OCCO2
Reaction time: 0.25 h
Yield: 63 %

Procedure:
SOCl2(10.5 ml) was added dropwise at −10° C. to a solution of 8-(pyridin-4-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (6.0 g, 25.5 mmol, 1 eq) in pyridine (50 ml), and stirring was carried out for 15 min. After monitoring by thin-layer chromatography, the reaction mixture was poured carefully onto ice (100 g), neutralized with sat. sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (2×150 ml). The combined organic phases were washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH in dichloromethane). Yield: 63% (3.5 g, 16.1 mmol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(=O)O[CH2:10][CH2:9][O:8]1>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:9][OH:8])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C1OCCO1
Solvent: CN(C)C=O
Product: OCCn1cc(I)cn1
Yield: 53.2 %

Procedure:
A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83 g, 77.6 mmol) in DMF (50 mL) was stirred at 125° C. for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC, using 30-70% EtOAc in DCM, to give the title compound (9.36 g, 53%). LCMS (Method 1): Rt 2.24 min, m/z 239 [MH+].
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:3][CH:2]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCOc1ccc(-c2ccccc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccc(-c2ccccc2)cc1

Procedure:
A solution of 1-(4-biphenyloxy)-6-chlorohexane (10.0 g) and potassium phthalimide (9.0 g) in dimethylformamide (100 ml) was heated at 140° C. for 4 hours. The cooled solution was poured into water (900 ml) and filtered to yield N-[6-(4-biphenyloxy) hexyl]phthalimide. (b) In a similar manner, but using the appropriate corresponding optionally substituted 1-(3- or 4-biphenyloxy)-ω-chloroalkane, obtained as described in Preparation 4, the following compounds of Formula C were prepared:
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[O:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1N1CCOCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2N2CCOCC2)cc1
Temperature: 120 °C

Procedure:
To a 25 mL round-bottomed flask were added 4-(2-fluoropyridin-3-yl)morpholine (0.523 g, 2.87 mmol), 4-aminophenol (0.451 g, 2.88 mmol), cesium carbonate (1.18 g, 3.45 mmol) and DMSO (5 mL). The reaction mixture was heated at 120° C. for 8 h. After cooling to room temperature, the reaction mixture was filtered through SCX cartridges, and rinsed with DCM, MeOH, and 2.0 ammonia in MeOH. The ammonia rinses were combined and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in CH2Cl2, to provide 4-(3-morpholinopyridin-2-yloxy)benzenamine. MS: [M+1]=272.1
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[N:36]1([CH2:42][CH2:43][CH2:44][NH2:45])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:45][CH2:44][CH2:43][CH2:42][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: NCCCN1CCCCC1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCCCN4CCCCC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 39.8 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (j), starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.145 g of 3-piperidino-propylamine instead of the cyclopropylamine used in example 34 stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol/aqueous ammonia (28%) 40/5/0.5 by volume as eluents), 0.05 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(3-piperidin-1-ylpropyl)amine is obtained with the following characteristics:
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>C(O)C.O=[Pt]=O>[NH2:1][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])C1CNCCN1Cc1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Product: NC1CNCCN1Cc1ccccc1
Reaction time: 0.75 h
Yield: 183.7 %

Procedure:
Reaction of Intermediate 2 with 4-nitrobenzaldehyde under standard reductive amination conditions gave 1-(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)-4-(4-(nitro)benzyl)piperazine in 46% yield. PtO2 (60 mg) was suspended in ethanol (40 ml) and stirred under an atmosphere of hydrogen for 0.75 h. The preceding nitrobenzyl piperazine (0.33 g, 0.74 mmol) was then added and the mixture stirred for 2 h. The catalyst was removed by filtration through celite, the solvent removed under vacuum and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (70:8:1) to give the title-amino-benzyl piperazine (0.26 g, 85%). The 4.1 hydrogen oxalate salt was prepared: mp 150°-153° C. (Found: C, 49.04; H, 4.80; N, 12.76. C24H29N7.4.1(C2H2O4) requires C, 49.28; H, 4.77; N, 12.49%); m/e 416 (M+1)+ ; δ (250 MHz, d6 -DMSO; free base) 1.72-1.86 (2H, m, CH2); 2.16-2.44 (10H, m, 5 of CH2); 2.70 (2H, t, J=7.4Hz, CH2); 3.23 (2H, s, CH2); 4.93 (2H, s, NH2); 6.48 (2H, d, J=8.4Hz, Ar-H); 6.89 (2H, d, J=8.4Hz, Ar-H); 7.27 (1H, s, Ar-H); 7.29 (1H, dd, J=2.1 and 8.6Hz, Ar-H); 7.47 (1H, d, J=8.6Hz, Ar-H); 7.78 (1H, d, J=2.1Hz, Ar-H); 9.02 (2H, s, Triazole-H); 11.07 (1H, s, NH).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:25]=[CH:24][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15](=[O:23])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH2:31]([O:30][C:28]([CH2:27][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:25][CH:24]=2)[CH2:13][CH2:14][C:15]1=[O:23])=[O:29])[CH3:32]
Reactant: O=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2N1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a suspension of sodium hydride (60% oil suspension, 154 mg) in tetrahydrofuran (4 ml) was added a solution of 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (800 mg) in tetrahydrofuran (6 ml) at 0° C. and the mixture was stirred at 0° C. for 5 minutes. To the mixture was added ethyl bromoacetate (472 mg) and then the mixture was stirred at ambient temperature overnight. The reaction was quenched with saturated ammonium chloride aqueous solution and the resultant mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, and then it was dried over magnesium sulfate. Filtration and evaporation afforded 1-ethoxycarbonylmethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (691 mg) as a slightly yellow amorphous.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: CSc1cccc2c(Cl)cc(C)nc12
Reactant: NCc1ccc(Cl)cc1
Product: CSc1cccc2c(NCc3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylsulfanylquinoline and 4-chlorobenzylamine.