Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:11]=[C:10]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[N:9]=2)=[CH:4][CH:3]=1.ClC(Cl)(O[C:39](=[O:45])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:54][C:55]1[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=1>O1CCCC1>[CH:16]12[O:21][CH:19]([CH2:18][CH2:17]1)[CH2:20][N:14]([C:12]1[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:39]([NH:54][C:55]4[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=4)=[O:45])=[CH:3][CH:4]=3)[N:9]=[C:10]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)[N:11]=1)[CH2:15]2
Reactant: Nc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reaction time: 0.08 h

Procedure:
Crude tert-butyl 4-(4-(4-aminophenyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate (approx. 1.4 mmol) was dissolved in tetrahydrofuran (20 mL) and then treated sequentially with triphosgene (0.30 g, 1.0 mmol) and triethylamine (2 mL). After 5 minutes, the mixture was treated with a solution of 4-aminopyridine (0.53 g, 5.6 mmol) in tetrahydrofuran. The mixture was concentrated under reduced pressure to give crude tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-pyridin-4-ylureido)phenyl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate, a sample of which was purified by reversed phase HPLC to give a pure title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS[C:24]1[NH:28][C:27](=[O:29])[CH2:26][N:25]=1.[OH-].[Na+]>C(O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:24]2[NH:28][C:27](=[O:29])[CH2:26][N:25]=2)=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CSC1=NCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(NCc2cccc3cc(S(=O)(=O)c4ccccc4)ccc23)N1

Procedure:
A mixture of C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine, 2-methylsulfanyl-3,5-dihydro-imidazol-4-one (prepared by the method reported by Chen et al., WO9736859) and sodium hydroxide in ethanol is heated to reflux, then concentrated under reduced pressure, diluted with ethyl acetate, and washed with aqueous sodium carbonate. The organic phase is dried (magnesium sulfate) and concentrated under reduced pressure to give 2-[(6-benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-3,5-dihydro-imidazol-4-one.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:13]=[CH:12]C=C[C:7]=1C=O.[CH2:14]1C[O:17][CH2:16][CH2:15]1>>[OH:17][CH:16]([C:2]1[CH:1]=[CH:7][C:6]([Br:5])=[CH:13][CH:12]=1)[CH:15]=[CH2:14]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1Br
Reactant: C=C[Mg]Br
Product: C=CC(O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
81 ml of a 1.6 molar solution of vinylmagnesium bromide in THF are dripped at -10° C. into a solution of 20.0 g of 4 bromobenzaldehyde in 300 ml of absolute THF. After addition the mixture is stirred for 60 minutes at 0° C., poured into ice water and extracted with ethyl acetate. After chromatography on Al2O3 with hexane/ethyl acetate 18.6 g of 4-(1-hydroxy-2-propenyl)-bromobenzene are obtained in the form of colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CC(OC(C)=O)=O.[OH:18][S:19](O)(=[O:21])=[O:20]>CCOC(C)=O>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:19]([OH:21])(=[O:20])=[O:18]
Reactant: Cc1csc2ccccc12
Reactant: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(S(=O)(=O)O)sc2ccccc12
Yield: 13.9 %

Procedure:
A solution of 3-methyl-benzothiophene (900 mg, 6.1 mmol), Ac2O (1.75 mL, 18.5 mmol) and conc. H2SO4 (350 μL, 6.2 mmol) in EtOAc (5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with water and brine and then dried. Upon evaporation of some of the solvent the product precipitated. Et2O was added, and the precipitate was collected giving 193 mg of 3-methylbenzothiophene-2-sulfonic acid (14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3 H) 7.33-7.41 (m, 2 H) 7.69-7.75 (m, 1 H) 7.83-7.88 (m, 1 H).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3N3C=NN=C3CN=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[O:22]>C(O)=O>[C:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1)(=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: c1ccc(C2=NCc3nncn3-c3ccccc32)cc1
Solvent: O=CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 1, 8-chloro-1-[[ (2-propynyl)amino]3-[-6-phenyl-4H-s-triazolo[4,3-a][1,4-]benzodiazepine is heated in formic acid with aqueous formaldehyde to give 5-chloro-2-[3[(2-propynyl)methylamino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.O[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=5)[C:36]([O:38][CH3:39])=[O:37])=[CH:24][CH:25]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Reactant: COC(=O)c1cccc(COCCO)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Reaction time: 0.25 h

Procedure:
(5R)-5(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-hydroxyphenyl)ethyl]-1,3-oxazolidin-2-one{Example 28 v)} (300 mg), methyl 3-[(2-hydroxyethoxy)methyl]benzoate (340 mg) and triphenylphosphine (642 mg) were dissolved in DCM (10 ml) and stirred for 15 min. To this was added 1,1′-(azodicarbonyl)dipiperidine (612 mg) and the solution was stirred for 16 h. The solution was then diluted in DCM, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 90 g) eluting with CH2Cl2-MeOH (250:1) to give the title compound (450 mg). LCMS RT=3.62 min.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:7][C@@H:6]2[C@@H:8]([OH:11])[CH2:9][O:10][C@@H:5]2[C@@H:4]1[OH:12].[CH3:13]I.[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30](F)=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[F:22]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:12][C@H:4]4[CH2:3][O:7][C@H:6]5[C@H:8]([O:11][CH3:13])[CH2:9][O:10][C@@H:5]45)=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CO[C@@H]2[C@H]1OC[C@@H]2Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 493 mg, 12.32 mmol) was added in portions to a stirring solution of dianhydro-D-glucitol (1.5 g, 10.26 mmol) in DMF (20 mL) at room temperature under N2 (g) atmosphere. After 20 min, methyl iodide (639 μL, 10.26 mmol) was added, the mixture stirred for 30 min, cooled to 0° C., followed by stepwise addition of DMF (20 mL) and NaH (493 mg, 12.32 mmol). N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 1a (500 mg, 1.48 mmol, prepared according to Smaill, J. B., et al., Journal of Medicinal Chemistry, 2000, 43, 1380-1397) was added after 20 min and the reaction was quenched 30 min later at 0° C. by a slow addition of saturated NH4Cl, followed by extraction with EtOAc (100 mL). The organic layer was washed with H2O (2×100 mL), brine (100 mL), dried over MgSO4, and concentrated to a yellow residue 1b. MS m/z (ESI+), 477 [M+1].
Reaction SMILES: [Br:1][CH:2]1[C:7]2([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9][C:4]([CH:17]=[CH:18][O:19][CH3:20])([CH2:5][O:6]2)[CH2:3]1.[Cr](Cl)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[CH3:20][O:19][C:18](=[O:22])[CH2:17][C:4]12[CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)([CH:2]([Br:1])[CH2:3]1)[O:6][CH2:5]2
Reactant: COC=CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a stirred solution of the cis and trans mixtures of 6-bromo-1-(4-chloro-phenyl)-4-(2-methoxy-vinyl)-2-oxa-bicyclo[2.2.2]octane (1.7 g, 4.75 mmol) in dichloromethane (12 ml) and tetrahydrofuran (25 ml) at room temperature, was portionally added pyridinium chlorochromate (3.07 g, 14.26 mmol). The reaction mixture was stirred at room temperature for 2 hours. More pyridinium chlorochromate (2.05 g, 9.51 mmol) was added, and the mixture was stirred for another 60 hours at room temperature. The mixture was filtrated and the filtrate was concentrated, and diluted with ethyl acetate (100 ml). The organic phase was washed with water, brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (heptanes/acetone 2/1) to afford [6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acetic acid methyl ester (1.08 g, 61%) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.79 (m, 1H) 1.87-1.98 (m, 1H) 2.01-2.11 (m, 1H) 2.14 (s, 2H) 2.23-2.30 (m, 1H) 2.52-2.63 (m, 1H) 2.75-2.87 (m, 1H) 3.62 (s, 3H) 3.84 (dd, J=10.11, 2.65 Hz, 2H) 4.19-4.29 (m, 1H) 7.23 (d, J=8.80 Hz, 2H) 7.33 (d, J=8.80 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1.CC(O)=O.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([NH:12][C:9]2[NH:10][N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)n[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
To a solution of 5-phenyl-4H-1,2,4-triazol-3-amine (354 mg, 2 mmol) in dry pyridine (10 mL) was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol). The solution was stirred at room temperature under Argon. After 48 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between CH2Cl2 and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with CH2Cl2. After drying over Na2SO4, the solvent was removed in vacuo to give 0.47 g crude product. The crude product was dissolved in hot HOAc (22 mL), diluted with water (9 mL) and seeded. The product was collected by filtration, washed with water, then EtOH and dried in vacuo to give 361 mg of a granular white solid, mp 245-246° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12]([N:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19](Cl)[CH:18]=[N:17]1)([CH3:15])([CH3:14])[CH3:13].O>CN(C)C=O>[C:12]([N:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=[N:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(F)cc2)cnn(C(C)(C)C)c1=O
Yield: 62.2 %

Procedure:
To a solution of 0.63 g (0.005 mol) of p-fluorobenzyl alcohol dissolved in 20 ml of N,N-dimethylformamide was added 0.24 g of 55% sodium hydride at room temperature under stirring. After addition, the resulting mixture was further stirred at room temperature for fifteen minutes. The reaction liquid was added dropwise with 1.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone, and was stirred at room temperature for eight hours. The reaction mixture was poured into 200 ml of water and then extracted with 50 ml of benzene. The resulting benzene layer was washed successively with 50 ml of 10% sodium hydroxide, 50 ml of 1N-hydrochloric acid, and 100 ml of water, dried over anhydrous sodium sulfate, and freed of solvent by distillation to give 1.5 g of crude product. The crude product was recrystallized from 20 ml of hexane to obtain 0.9 g of 2-t-butyl-5-(p-fluorobenzyloxy)-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:11]1[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:29](=[O:40])[NH:30][C@@H:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH3:32])[CH:17]=2)[C:12]1=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>O.CO.C1COCC1>[CH2:4]([N:11]1[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:29](=[O:40])[NH:30][C@@H:31]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH3:32])[CH:17]=2)[C:12]1=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CCCCc1cc2cc(C(=O)N[C@H](C)c3ccc(F)cc3)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(CCCCC(=O)O)cc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide monohydrate (4.0 equiv.) in water (0.66 M) was added to a stirred mixture of (R)-methyl 5-(2-benzyl-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (1 eq) in MeOH/THF (v/v=1/4) and the mixture was stirred at room temperature. After 2 h, the mixture was neutralized with 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to dryness. To the residue was added Et2O and sonicated, upon which some solid precipitated. The solids were filtered, triturated with Et2O and dried to yield (R)-5-(2-benzyl-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid. LCMS [M+H]+=501. 1H NMR (CDCl3, 500 MHz) δ ppm: 8.44 (d, 1H, J=8.5 Hz), 7.92 (br s, 1H), 7.71 (d, 1H, J=8.0 Hz), 7.40 (dd, 2H, J=5.0 Hz, J=8.5 Hz), 7.32-7.23 (m, 3H), 7.12 (d, 2H, J=7.5 Hz), 7.06 (t, 2H, J=9.0 Hz), 6.42 (s, 1H), 5.43 (br s, 2H), 5.39-5.35 (m, 1H), 2.63 (t, 2H, J=7.5 Hz), 2.37 (t, 2H, J=6.5 Hz), 1.70-1.64 (m, 4H), 1.63 (d, 3H, J=7.0 Hz).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[C:34](Cl)(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: CCCCCCCCCC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and n-decanoyl chloride by using the same techniques as in Example 41.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:14]([O:21][C:22]([N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1,2,3,6-tetrahydropyridine (5.0 g) in dichloromethane (200 mL) was cooled to 0° C. and treated with triethylamine (10.1 mL) followed by benzylchloroformate (10.3 mL). The reaction mixture was stirred for 1 hour at 0° C., diluted with dichloromethane, washed (dilute hydrochloric acid, sodium bicarbonate solution), dried and evaporated. The crude product was distilled to give the N-protected derivative (11.01 g); bp 160°-165° C. (26.7 Pa); NMR (CDCl3): 2.15 (broad, 2), 3.5 (t,2, J=6), 3.96 (m, 2), 5.15 (s, 2), 5.8 (2 broad peaks, 2), 7.4(m, 5); MS: m/z=218(M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14]O)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.O.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][F:41])=[O:6])[CH2:3][CH2:2]1
Reactant: [F-]
Reactant: O=C(NC1CC1)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CC1)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCF)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.3 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(cyclopropylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (240 mg, 0.65 mmol) obtained in Example 351a) and triethylamine (140 μl, 1.00 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride (60 μl, 0.78 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (10 ml), tetrabutylammonium fluoride monohydrate (425 mg, 1.63 mmol) was added, and the mixture was stirred at 80° C. for 16 hr. After the reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (90 mg, 37%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:16][CH:17]=3)=[O:22])=[CH:9][CH:8]=2)=[CH:3][N:2]=1
Reactant: NCc1ccc(-c2ccnnc2)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(-c2ccnnc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-(pyridazin-4-yl)phenyl)methanamine 1-3 (19 mg, 0.1 mmol), biphenyl-4-carboxylic acid 1-4 (20 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (38 mg, 0.1 mmol) in DMF (0.5 mL) was added DIEA (0.052 mL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-(4-(pyridazin-4-yl)benzyl)biphenyl-4-carboxamide 1 as a white solid. MS m/z 366.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ9.59 (m, 1H), 9.21 (dd, 1H), 9.16 (t, 1H), 7.96 (m, 3H), 7.87 (d, 2H), 7.74 (d, 2H), 7.69 (m, 2H), 7.47-7.41 (m, 4H), 7.37 (m, 1H), 4.52 (d, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:27][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Temperature: 50 °C

Procedure:
Crude trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (65.0 g, approx. 148 mmol) was suspended in ethanol (1000 mL, IMS grade) and water (300 mL). Ammonium chloride (47.5 g, 888 mmol) was added, and the mixture was stirred at 50° C. Powdered iron (33.0 g, 592 mmol) was added slowly and the resulting mixture was stirred at reflux for 2 h, then cooled to room temperature. The mixture was filtered and the filter cake washed with further ethanol, then the combined filtrate was concentrated under vacuum. The residue was suspended in water and extracted with dichloromethane (×2) and the combined organic extracts were dried (Na2SO4) and concentrated under vacuum. The residue was triturated with methanol then water to give 19.0 g (33%) of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. The methanol mother liquor was concentrated and the resulting residue triturated with acetonitrile to give a further 11.0 g (19%) of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. NMR (400 MHz, DMSO) δ: 8.04 (m, 2H), 7.68 (m, 2H), 7.59 (m, 3H), 6.76 (d, 1H), 5.68 (br s, 1H), 3.71 (br s, 1H), 1.91 (m, 2H), 1.84 (m, 2H), 1.34 (m, 4H), further signals partially obscured residual water peak.