Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:48]=[CH:47][CH:46]=[CH:45][C:10]=1[C:11]([NH:13][C:14]1[CH:44]=[CH:43][C:17]([C:18]([N:20]([CH3:42])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])=[O:19])=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:48]=[CH:47][CH:46]=[CH:45][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:20]([CH3:42])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[O:34])=[O:19])=[CH:43][CH:44]=1)=[O:12]
Reactant: CN1CCN(C(=O)CCCCCOc2ccccc2N(C)C(=O)c2ccc(NC(=O)c3ccccc3OCc3ccccc3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C(=O)CCCCCOc2ccccc2N(C)C(=O)c2ccc(NC(=O)c3ccccc3O)cc2)CC1
Yield: 97.8 %

Procedure:
A solution of 4-(2-benzyloxybenzoyl)amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (1.90 g) in methanol (30 ml) was hydrogenated under atmospheric presser in the presence of palladium hydroxide (400 mg) for 6 hours and the catalyst was removed by filtration. The filtrate was evaporated to give 4-(2-hydroxybenzoyl)amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (1.60 g) as a colorless amorphous.
Reaction SMILES: [Na].[CH2:2]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C:19](=[N:24]O)[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[CH2:26])[CH2:7][C@@H:6]1[OH:27])[CH3:3]>C(O)CC.O>[NH2:24][C@@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[CH2:26])[C@H:11]2[C@H:20]1[C@:21]1([CH3:23])[C@@H:8]([CH2:9][CH2:10]2)[CH2:7][C@H:6]([OH:27])[C@@H:5]([O:4][CH2:2][CH3:3])[CH2:22]1
Reactant: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Agent: [Na]
Solvent: O
Solvent: CCCO
Product: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](N)C[C@]12C

Procedure:
Sodium (2.7 g) was added portionwise to a stirred and refluxing solution of 2β-ethoxy-3α-hydroxy-17-methylene-5α-androstan-11-one 11-oxime (1.7 g) in propanol (100 ml) under nitrogen. The cooled reaction mixture was diluted with water and the precipitated solid (1.43 g) was collected by filtration. A portion of this material (300 mg) was purified by partitioning between 2 N-hydrochloric acid and ether when the insoluble hydrochloride which precipitated was collected by filtration and again partitioned between ether and 2 N-sodium hydroxide solution. The organic layer was washed, dried (Na2SO4) and evaporated to give the title compound as a froth (180 mg), [α]D +1.6°.
Reaction SMILES: [CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][C:9]=2[F:17])=[C:5]([O:21]C)[CH:4]=1)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][C:9]=2[F:17])=[C:5]([OH:21])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(OC)c(Oc2ccc(C(N)=O)cc2F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(N)=O)cc2F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 650 %

Procedure:
To 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzamide (13.31 g, 4.59 mmol; which may be prepared as hereinbefore described for D4) in 130 mL of dichloromethane under argon at −78° C. under intense stirring is added over 15-20 min boron tribromide (130 mL at 1M in dichloromethane). The reaction mixture is warmed up at room temperature under stirring and after 3 h is cooled back to −20° C. for quenching with a saturated aqueous solution of ammonium chloride (100 mL). Partial concentration is performed to remove 170 mL of dichloromethane. 100 mL of ethyl acetate are added. Extraction of the aqueous phase (2*25 mL of ethyl acetate), reunification of the organic phases, aqueous sodium hydrogenocarbonate (200 mL at 1N) wash, drying (Na2SO4) and final concentration affords the crude material which is purified on silicagel (gradient dichloromethane/methanol:100/0→95/5) to afford the title compound 8.75 g (68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH3:12]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(F)cc(F)c1
Yield: 62.5 %

Procedure:
To a solution of 3,5-difluoro-phenol (10.0 g, 76.87 mmol, 1.0 equiv) and iodo-ethane (28.77 g, 14.91 mL, 184.49 mmol, 2.4 equiv) in acetone (150 mL) was added portionwise potassium carbonate (31.87 g, 230.6 mmol, 3.0 equiv) and the reaction mixture heated to reflux for 6 h. The reaction mixture was filtered, the filtrate poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 7.60 g (63%) of the title compound.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:10]1[C:15]2[O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:14]=2[CH:13]=[CH:12][CH:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Cl-].[Cl-].[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH:1]1([C:22]2[C:17]3[O:16][C:15]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Ic1cccc2c1oc1ccccc12
Reactant: Cl[Mg]C1CCCCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)oc1c(C3CCCCC3)cccc12
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
ZnCl2 (13.6 g, 100.0 mmol) and THF (600 mL) were cooled to 0° C. After that, cyclohexylmagnesium chloride (70.0 mL, 70.0 mmol, 1M in THF) was added at 0° C. The mixture was stirred for 15 min from 0° C. to room temperature. The mixture was bubbled with nitrogen for 15 min, followed by the addition of 4-iododibenzo[b,d]furan (11.8 g, 40.0 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (3.3 g, 8.0 mmol), and Pd2(dba)3 (1.8 g, 2.0 mmol). The resultant mixture was bubbled with nitrogen for 15 min and stirred for 48 h. The reaction mixture was quenched by the addition of saturated K2CO3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 10% DCM/hexane to yield 4-cyclohexyldibenzo[b,d]furan (9.0 g, 90% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1C=NN=C1C1C=CN=CC=1)C.[CH2:14]([N:16]1[C:20]([C:21]2[CH:26]=[CH:25]N=C[CH:22]=2)=[N:19][N:18]=[C:17]1[CH2:27][OH:28])C.C(N1C(C2C=CN=CC=2)=NN=C1C=O)C.CN1C(C2C=NC=CC=2)=NNC1=S>>[CH3:14][N:16]1[C:20]([C:21]2[CH:22]=[N:3][CH:1]=[CH:25][CH:26]=2)=[N:19][N:18]=[C:17]1[CH:27]=[O:28]
Reactant: CCn1cnnc1-c1ccncc1
Reactant: CCn1c(CO)nnc1-c1ccncc1
Agent: CCn1c(C=O)nnc1-c1ccncc1
Agent: Cn1c(-c2cccnc2)n[nH]c1=S
Product: Cn1c(C=O)nnc1-c1cccnc1

Procedure:
The title compound is prepared analogously to the sequence described for 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (example 21), (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (example 22), and 4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (example 23a) by using 4-methyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione as starting material.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:35])([F:34])[C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]2[CH2:31][CH2:30][C:13]3[NH:14][C:15]4[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[O:22])=[CH:19][C:20]=4[C:12]=3[CH2:11]2)=[CH:7][CH:6]=1.Br.Br[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:42]1[CH:43]=[CH:44][C:39]([CH2:38][N:27]2[CH2:28][CH2:29][CH:24]([NH:23][C:21]([C:18]3[CH:17]=[CH:16][C:15]4[NH:14][C:13]5[CH2:30][CH2:31][N:10]([CH2:9][C:8]6[CH:32]=[CH:33][C:5]([C:4]([F:3])([F:34])[F:35])=[CH:6][CH:7]=6)[CH2:11][C:12]=5[C:20]=4[CH:19]=3)=[O:22])[CH2:25][CH2:26]2)=[CH:40][CH:41]=1
Reactant: O=C(NC1CCNCC1)c1ccc2[nH]c3c(c2c1)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Reactant: BrCc1ccncc1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccncc2)CC1)c1ccc2[nH]c3c(c2c1)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of the dihydrochloride salt of step 1, above (65 mg, 0.12 mmol) was dissolved in DMF (2.0 mL) and 4-(bromomethyl)pyridine hydrobromide (2×35 mg, 2×0.14 mmol) and triethylamine (2×80 μL, 2×58 mg, 2×570 μmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (20 mL) to give an off-white solid which was triturated with ethyl ether to provide N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 50, 60%). 1H NMR (DMSO-d6, 300 MHZ) 11.02 (s, 1H), 8.49 (d, J=4.7 Hz, 2H), 7.99 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 1H), 7.31 (d, J=4.7 Hz, 2H), 7.25 (d, J=8.3 Hz, 1H), 3.86 (s, 2H), 3.82-3.70 (m, 1H), 3.63 (s, 2H), 3.50 (s, 2H), 2.90-2.74 (m, 6H), 2.06 (t, J=11.1 Hz, 2H), 1.77 (d, J=10.2 Hz, 2H), 1.60 (q, J=10.9 Hz, 2H) ppm; MS (ES) 548 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[C:15]2[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]1=2)#[CH:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([C:11]#[C:12][C:2]3[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=3)[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(S(N)(=O)=O)s2)CCN(C)C1

Procedure:
A mixture of 5-bromo-thiophene-2-sulfonic acid amide (200 mg, 0.8 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (222 mg, 0.9 mmol), TBAF.3H2O (756 mg, 2.4 mmol) and dichloro bis(triphenyl phosphine) palladium (II) (28 mg, 0.04 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by column chromatography using neutral alumina and 5% MeOH-DCM, followed by reverse phase HPLC to yield 5-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylethynyl)-thiophene-2-sulfonic acid amide. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.57 (d, 1H), 7.46 (d, 1H), 7.36 (m, 2H), 7.21 (d, 1H), 4.42 (s, 2H), 3.71 (s, 2H), 3.3 (m, 2H), 3.1 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.[OH:9][C:10]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:11]=1C#N.Cl>O.C1COCC1>[OH:9][C:10]1[C:17]([CH:18]([CH3:19])[CH3:20])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:11]=1[C:7](=[O:6])[CH3:8]
Reactant: CCOCC
Reactant: CC(C)c1cc(C#N)c(O)c(C(C)C)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)C)cc(C(C)C)c1O
Yield: 12.6 %

Procedure:
To dry THF (10 mL) there was added 3.0 M solution of methylmagnesium bromide in diethylether (Aldrich) (10.9 mL; 32.8 mmole) and then a previously prepared solution of 2-hydroxy-3,5-diisopropyl benzonitrile (2.78 g, 13.7 mmole) and dry THF (70 mL) was added. After 7 hours under the reflux the reaction mixture was mixed with water (100 mL), acidified with concentrated hydrochloric acid (50 mL) and refluxed for one more hour. After cooling and extraction with ethyl acetate an oily product was obtained, which was purified on a silica gel column, whereat there were obtained 380 mg (12.5%) of 2′-hydroxy-3′5′-diisopropylacetophenone:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]Br.Cl>N1C=CC=CC=1>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrBr
Agent: Cl
Solvent: c1ccncc1
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 0 °C
Yield: 92.2 %

Procedure:
A 250 ml, three-necked, round bottom flask was fitted with mechanical stirrer, addition funnel and reflux condenser (with drying tube). To the flask was added 16.7 g (0.10 mole) of carbazole and 100 ml of pyridine. The resulting mixture was stirred at 0° C. and 17.7 g (0.12 mole) of bromine was added dropwise over a period of 35 min. After stirring at 0° C. for an additional 1 hr, the resulting red mixture was poured into 600 ml of 3 N--HCl solution. The resulting precipitate was collected by filtration, washed with 200 ml of water, twice with 100 ml portions of 5% NaOH solution, and three times with 250 ml portions of water. The crude product was dissolved in 1500 ml of ether and dried over magnesium sulfate. Concentration of the ethereal solution gave 22.7 g (85% yield) of powder, m.p. 179°-183° C. Recrystallization three times from methanol gave 8.7 g of the desired product, m.p. 200°-201° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][N:11]([S:45]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:44][CH:43]=1)(=[O:47])=[O:46])[O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (200 mg, 0.474 mmol), 4-benzyloxybenzenesulphonyl chloride (134 mg, 0.474 mmol), diisoproylethylamine (0.083 mL, 0.474 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction mixture was warmed to 55° C. and an additional quantity of dimethylaminopyridine (˜2 mg) was added. After stirring for 2 hours, the reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydrogen sulfate (1N). After separating the phases, the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (235 mg, 74%) as a foam. H1-NMR (chloroform-D3): 0.94 (m, 6H), 1.62 (m, 7H), 3.05 (m, 5H), 3.74 (m, 2H), 3.98 (m, 4H), 4.18 (m, 1H), 4.88 (d, 1H), 5.08 (m, 1H), 5.19 (s, 2H), 5.70 (d, 1H), 7.13 (d, 2H), 7.34 (m, 10H), 7.80 (d, 2H). MS(ESI): 691(M+Na).
Reaction SMILES: [C:1]1([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][O:23]C1C=CC(NN)=CC=1>>[CH3:22][O:23][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:19](=[O:20])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:6][CH:5]=1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, but using 4-methoxyphenyl hydrazine hydrochloride instead of phenyl hydrazine hydrochloride. 1H NMR (DMSO-d6) δ (ppm): 3.76 (3H, s), 6.98 (1H, q, J=5.50 Hz), 7.01 (1H, d, J=9.33 Hz), 7.55 (1H, m), 7.70 (2H, m), 8.05 (1H, q, J=5.09 Hz), 8.08 (1H, d, J=9.33 Hz), 8.19 (1H, d, J=7.96 Hz), 8.70 (1H, d, J=6.31 Hz). m/z 292.4 (MH+).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.[OH-].[K+].O>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:12]=[C:11]2[C:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)CCc1ccc2c(ccn2Cc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc2c(c1)c(C1=CCN(C)CC1)cn2Cc1ccccc1
Temperature: 62.5 °C
Reaction time: 0.25 h

Procedure:
2-(1-benzyl-1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in methanol (1000 ml) and N-methyl-4-piperidone (100 ml) was added thereto at 25° C. The reaction mass was stirred for 15 minutes and potassium hydroxide (200 g) was added at 25° C. The reaction mass was heated to 60-65° C. for 8 hours and cooled gradually to 25° C. Water (2500 ml) was added slowly and stirred the mixture till solid is obtained. The solid was filtered and dried at 50-55° C. under vacuum to obtain the title compound (Yield: 98 g, HPLC Purity: 99%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].C(C(C1N=CC(B(O)O)=CC=1)(C)C)#N.FC(F)(F)C(O)=O.Br[C:43]1[S:47][C:46]([N+:48]([O-:50])=[O:49])=[C:45]([C:51]([NH2:53])=[O:52])[CH:44]=1>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[C:3]([C:2]([C:6]1[N:7]=[CH:8][C:9]([C:43]2[S:47][C:46]([N+:48]([O-:50])=[O:49])=[C:45]([C:51]([NH2:53])=[O:52])[CH:44]=2)=[CH:10][CH:11]=1)([CH3:1])[CH3:5])#[N:4]
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC(C)(C#N)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 2-methyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanenitrile and [6-(1-cyano-1-methylethyl)pyridin-3-yl]boronic acid as trifluoroacetic acid salts (260 mg, approx. 0.673 mmol combined), 5-bromo-2-nitrothiophene-3-carboxamide (169 mg, 0.673 mmol) (Intermediate 10 Step 4), and tetrakis(triphenylphosphine)palladium(0) (38.9 mg, 0.034 mmol) were dissolved in fully degassed tetrahydrofuran (2.7 ml) and fully degassed 2 M aqueous sodium carbonate (0.7 ml). The reaction was stirred at 70° C. for 4 hours. It was then allowed to cool to room temperature, taken up in ethyl acetate, and washed with water (2×) and brine (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via reverse phase HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH:12]=[CH:13][C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[H][H]>[Ni].CO>[CH3:19][C:17]1([CH3:20])[CH2:16][O:15][C:14]([CH2:13][CH2:12][C:4]2[CH:5]=[C:6]([NH2:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:18]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C=CC1=NC(C)(C)CO1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)cc1CCC1=NC(C)(C)CO1

Procedure:
Raney nickel, 3 g, is added to a solution of 4,5-dihydro-2-[2-(2-methoxy-5-nitrophenyl)ethenyl]-4,4-dimethyloxazole, 10.9 g, in methanol, 500 ml. The mixture is exposed to hydrogen gas until the appropriate quantity of hydrogen is taken up, filtered and the solvent evaporated to give 10.2 g of 3-[2-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)ethyl]-4-methoxybenzenamine as a gum. To an ice cold solution of the previous crude gum and 7 ml of triethylamine in chloroform is added 10.5 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, chromatographed over silica gel and eluted with diethylether to give 10.5 g of N-[3-[2-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)ethyl]-4-methoxyphenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide as a gum; thin layer chromatography on silica gel: Rf =0.57 (ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: N#Cc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (82 mg, 0.873 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(4-cyanophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 24; 145 mg, 0.44 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-Hydroxybenzotriazole (70.8 mg, 0.52 mmol) in DMF (15 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 100 mg.
Reaction SMILES: [I-:1].[I-].[I-].[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]3[C:30]([CH:31]=2)=[S+:29][C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:35]([N:42]1[CH2:48][CH2:47][CH2:46][N:45](C2C=C(CC)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)[CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N1CCCN(C2C=C(CC)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)CC1)(OC(C)(C)C)=O.C(N1CCCNCC1)(OC(C)(C)C)=O>CO>[I-:1].[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]3[C:30]([CH:31]=2)=[S+:29][C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([N:45]4[CH2:46][CH2:47][CH2:48][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:43][CH2:44]4)[CH:27]=2)[N:22]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cccc(C)c3nc12
Agent: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [I-]
Solvent: CO
Product: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCCN(C(=O)OC(C)(C)C)CC4)cc(C)c3nc12

Procedure:
A solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-ethyl-9-methyl-phenothiazin-5-ium triiodide (100 mg, 0.12 mmol) in methanol (10 mL) and 4-Boc-1,4-diazepane (100 mg, 0.5 mmol) was stirred for 4 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.