Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].FF.S(=O)(=O)(O)O.[Br:23]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Br:23][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([S:2]([F:12])([F:13])([F:14])([F:15])[F:1])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Agent: FF
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
150 g (604 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid [lit. e.g.: C. Zarantonello et al., J. Fluorine Chem. 2007, 128 (12), 1449-1453; WO 2005/047240-A1; also available commercially] were initially charged in 300 ml of trifluoroacetic acid, and 90 ml of concentrated sulphuric acid were added. 161.4 g (907 mmol) of N-bromosuccinimide (NBS) were added to the resulting clear solution. The reaction mixture was then stirred at a temperature of 50° C. overnight (about 18 h). After cooling to RT, the mixture was carefully stirred into about 2.25 liters of ice water. The precipitated product was filtered off with suction, washed with water and dried under high vacuum. This gave 193 g (96% of theory, 98% pure) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]3[CH:11]=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]3[CH:11]=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Cl)cc(-n2ncc3c(I)ccnc32)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1cc(F)cc(Cl)c1
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing Intermediate 75A (558.6 mg, 1.46 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (569.2 mg, 2.24 mmol), potassium acetate (584.3 mg, 5.95 mmol), and anhydrous DMSO (11 mL). The reaction mixture was flushed with argon and treated with PdCl2(dppf).CH2Cl2 (59.1 mg, 0.081 mmol). The reaction mixture was heated to 85° C. for 1 h and then at 105° C. for 1.5 h to give conversion to the desired product. LC/MS (Condition B): ret. T=4.29 min, (M+H)+ 291.99, 292.99.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[OH:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
The alcohol (prepared above) (13.4 g, 44.8 mmol) was dissolved in CH2Cl2 (150 ml) and treated with MnO2 (22 g). The reaction mixture was vigorously stirred at RT for 18 h, then treated with a further portion of MnO2 (20 g). More MnO2 (20 g) was added after 10h and the mixture stirred for 18 h, then filtered through Celite® and concentrated in vacuo. The residue was recrystallized from EtOH to afford the title compound (11.27 g; two crops) as a white crystalline solid m.p. 59°-75° C.; δH (CDCl3) 1.5-2.1 (8H,br, m, (CH2)4), 3.88 (3H, s, OMe), 4.80 (1H, br m, OCHCH2), 6.83 (1H, d, J 8.5 Hz, ArH ortho to OMe), and 7.25-7.8 (7H, m, 2×ArH meta to OMe+C6H5); m/z 296 (M+ 11%), 229 (17), 228 (95), 152 (12), 151 (100), 105 (30), 77 (21), and 41 (10).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[C:23]2[OH:31].[H-].[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[C:23]2[O:31][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: COc1ccc2nc(C)cc(O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(C)cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100-mL, round bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.26 g, 1.0 mmol) and 6-methoxy-2-methyl-quinolin-4-ol (0.19 g, 1.0 mmol, Ubichem) in DMF (5 mL), was added NaH (48 mg, 1.2 mmol, 60% in mineral oil, Aldrich) at room temperature The solution was then stirred at room temperature for 24 h. After the solvent was removed in vacuum, EtOAc (30 mL) was added to the residue, and the mixture was washed with brine (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After the product was purified by silica gel chromatography (5:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (10 mL) and MeOH (8 mL). Water (15 mL) was then added dropwise to afford a white precipitate, which was collected by filtration, washed with water (2 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 165–166° C. MS (ESI, pos. ion) m/z: 412; Anal. Calcd for C22H16F3N3O2: C, 64.23; H, 3.92; N, 10.21. Found: C, 64.20; H, 3.85; N, 10.14.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:32]=[CH:31][N:30]=[CH:29][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1.[CH3:33][Mg]Br>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:32]=[CH:31][N:30]=[CH:29][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH:27]=[CH2:33])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: C[Mg]Br
Reactant: CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Product: C=CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1

Procedure:
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[4-(1-hydroxyprop-2-en-1-yl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[4-(1-hydroxyethyl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one in Example 11, substituting vinylmagnesium bromide for methylmagnesium bromide.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].C(C1C(N)=C(C)C([N+]([O-])=O)=CC=1)C.[Br:18][C:19]1[C:24]([CH3:25])=[C:23]([N+]([O-])=O)[CH:22]=[CH:21][C:20]=1[CH2:29][CH3:30]>O.Br>[Br:18][C:19]1[C:20]([CH2:29][CH3:30])=[C:21]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: O=N[O-]
Reactant: CCc1ccc([N+](=O)[O-])c(C)c1Br
Agent: Br
Agent: CCc1ccc([N+](=O)[O-])c(C)c1N
Agent: [Na+]
Solvent: O
Product: CCc1c([N+](=O)[O-])ccc(C)c1Br
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
NaNO2 (7.7 g, 110 mmol) in 15 mL of water was added slowly to a stirred solution of the products of Step 1 (19 g, 106 mmol) in 48% aqueous HBr (35 mL) at 0° C. CuBr (1.4 g, 10 mmol) in 48% aqueous HBr (10 mL) was added dropwise. After stirring for 15 mins, the mixture was heated at 90° C. for 2 hrs. After cooling, the mixture was diluted with water and extracted 5 times with EtOAc. The combined organic phases were concentrated and purified by silica gel column chromatography (PE/EtOAc=50:1) to yield a mixture of 2-bromo-1-ethyl-3-methyl-4-nitro-benzene and 2-bromo-3-ethyl-1-methyl-4-nitro-benzene (23 g, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.BrC1C=CC=CC=1[O:18]C.[Mg].[NH2:21][C:22]1[N:26]([C:27]2[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:28]=2[Cl:35])[N:25]=[C:24]([S:36][CH3:37])[C:23]=1[C:38]#N.[Cl-].[NH4+]>CCOCC>[NH2:21][C:22]1[N:26]([C:27]2[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:28]=2[Cl:35])[N:25]=[C:24]([S:36][CH3:37])[C:23]=1[C:38](=[O:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C#N
Reactant: COc1ccccc1Br
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccccc1C(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Yield: 14 %

Procedure:
To a solution of 2-methoxyphenylmagnesium bromide prepared from 18.7 g (0.10 mol) of 2-bromoanisole and 2.43 g (0.10 mol) of magnesium turnings in ether under dry nitrogen was added 1.6 g (5.0 mmol) of 5-amino-4-cyano-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole and the resulting mixture was stirred and refluxed for 16 hours. Upon cooling, the reaction was decomposed with 50 mL of saturated ammonium chloride solution. The organic phase was extracted with aqueous hydrogen chloride and the acidic extract was treated with 10 mL of concentrated hydrogen chloride and heated at 80°-90° C. for 10 minutes after which the mixture was cooled and made alkaline. Extraction with methylene dichloride and chromatography of the extracts with mixtures of hexane and ethyl acetate gave 313 mg (14%) of the title compound, m.p. 200°-202° C. Anal. Calcd. for C18H14O2 N3SCl3 : C, 48.82; H, 3.18; N, 9.49. Found: C, 48.54; H, 3.32; N, 9.09.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>C(O)(C)C>[Cl:12][C:8]1[CH:7]=[CH:6][C:5]([OH:13])=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([NH:24][C:23]1[CH:22]=[CH:21][C:20]([N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)=[CH:26][CH:25]=1)=[N:3]2
Reactant: Oc1ccc(Cl)c2cnc(Cl)nc12
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(C)O
Product: Oc1ccc(Cl)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc12
Temperature: 90 °C

Procedure:
To a solution of isolated 2,5-dichloroquinazolin-8-ol (1 eq) in isopropanol was added 4-morpholinoaniline (1 eq) and the mixture was heated to 90° C. for 1 h. The SNAR went to completion by LC/MS and on concentration yielded 5-chloro-2-(4-morpholinophenylamino) quinazolin-8-ol in quantitative yield. ES/MS m/z 357 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.[IH:20]>>[I:20][C:13]1[CH:18]=[C:17]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:16]=[CH:15][N:14]=1
Reactant: I
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(F)cc1F
Product: Fc1ccc(-c2cc(I)ncn2)c(F)c1

Procedure:
The compound was prepared according to Example 1 using 2,4-difluorophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2([C:19]([OH:21])=[O:20])[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[CH2:12]2)=[CH:2]1>N.[Rh]>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:19]([OH:21])=[O:20])[CH2:12][C@H:13]([NH2:14])[C:16]([OH:18])=[O:17])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(O)C1=NOC(Cc2c[nH]c3ccccc23)(C(=O)O)C1
Agent: [Rh]
Agent: N
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Yield: 92.4 %

Procedure:
404 mg (1.40 mmols) of 5-(RS)-(3-indolylmethyl)-4,5-dihydroisoxazole-3,5-dicarboxylic acid was dissolved in 8 ml of 14% aqueous ammonia solution, 250 mg of a 5% rhodium-active carbon catalyst was added thereto, and catalytic hydrogenation was conducted under a hydrogen pressure of 1 MPa for 7 hours. The catalyst was removed by filtration, and the filtrate was freeze-dried to obtain 378 mg of monatin and a small amount of DL-alanine as a by-product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])=[CH:16][CH:15]=1
Reactant: CCN=C=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
500 mg (1.63 mmol) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine were introduced into 20 ml of toluene, and a solution of 284 mg (4.0 mmol) of ethyl isocyanate in a little toluene is added dropwise. After one hour at 80° C., a further 180 mg of ethyl isocyanate are added, and the mixture was stirred at 80° C. for one hour. For workup, the solvent was removed and the residue was triturated with H2O and ethyl acetate, filtered off with suction and dried, resulting in the title compound as a pale yellowish solid (m.p.: 218-220° C.). The ethylurea obtained in this way was converted into the corresponding hydrochloride in a manner known to the skilled worker.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH3:19])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.00 g, 3.28 mmol) in anhydrous N,N-dimethylformamide (5 mL), potassium carbonate (1.359 g, 9.83 mmol) and iodomethane (0.246 mL, 3.93 mmol) to give a brown suspension. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted into dichloromethane (3×15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown oil. The residue was purified via Biotage chromatography (silica 50 g column, cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give a pale yellow solid (780 mg, 74.6% yield). 1H NMR (500 MHz, CDCl3): 7.51-7.44 (5H, m), 7.20 (1H, s), 4.91 (2H, s), 3.36 (3H, s).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][C:7]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>S(=O)(=O)(O)O>[F:6][C:7]1[CH:14]=[C:13]([F:15])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: N#Cc1ccc(F)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of potassium nitrate (73.2 g, 0.718 mmol, 2 eq) and concentrated sulfuric acid (350 mL) was cooled to 0° C. and 2,4-difluorobenzonitrile was added in portions over 10 to 15 minutes. The mixture was stirred for 30 minutes and then poured onto ice to give a precipitate. The precipitate was isolated by filtration, washed with water and lyophilized to provide 2,4-difluoro-5-nitrobenzonitrile (50 g, 0.28 mol) as an off-white solid; PB-CI/MS: 185=(MH+); 1H-NMR (300 Mhz, DMSO-d6): 8.093(t, 1H), 8.982(t, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[CH:19]=[CH:18]3)=[O:14])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C>CCCCCC.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]([OH:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[CH:19]=[CH:18]3)=[O:14])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1)c1ccc([N+](=O)[O-])cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3C(=O)O)cc2)c1)c1ccc([N+](=O)[O-])cc1
Yield: 50 %

Procedure:
A solution of (S)-tert-butyl 4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (23 mg, 0.04 mmol, 1 equiv) in DCM/TFA 1/1 was stirred for 30 min at room temperature. The reaction mixture was neutralized by addition of DIEA, concentrated and purified by preparative HPLC to afford a beige powder (9 mg, 0.02 mmol, 43%). ESI-MS (m/z): 520 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[C:21]2[CH:22]=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[NH:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: N=C(NO)c1cccc2[nH]ccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Temperature: 25 °C
Yield: 33.7 %

Procedure:
To a solution of 3,4-diethoxybenzoic acid (0.11 g; 0.52 mmol), and the product of Step A (0.09 g; 0.51 mmol) in anhydrous THF (2 ml), PyBroP (0.25 g; 0.54 mmol) was added followed by DIPEA (0.21 ml; 1.22 mmol), with stirring, at room temperature under N2. After 2 h of stirring, the mixture was diluted to 15 ml with EtOAc, washed with saturated NH4Cl (2×5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was suspended in anhydrous toluene (10 ml). To it 1M TBAF in THF (0.5 ml) was added and the reaction mixture was refluxed for 3 h under N2, cooled to room temperature and solvents were removed under reduced pressure. The residue was washed with H2O (5 ml) and the solid was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.06 g; 34%) as colourless solid. 1H-NMR (CDCl3) 1.5 (m, 6H); 4.16-4.26 (m, 4H); 6.98 (d, 1H, J=8.5 Hz), 7.31-7.37 (m, 3H); 7.54 (d, 1H, J=8.1 Hz); 7.74 (d, 1H, J=2 Hz); 7.83 (d, 1H, J=8.4 Hz); 8.06 (dd, 1H, J=2, 8.4 Hz); 8.42 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=O)=[O:4].CC(O)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(C=O)c2c1
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]nc(CN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 3-formyl-1H-indazole-5-carboxylic acid methyl ester (600 mg, 2.94 mmol) in DCM was added HOAc (0.25 mL, 4.41 mmol) followed by morpholine (0.31 mL, 3.53 mmol) and NaHB(OAc)3 (809.6 mg, 3.62 mmol) at rt. The reaction was stirred at rt overnight, and was quenched with brine. The reaction mixture was extracted with EtOAc, washed with brine, dried, and concentrated in vacuo. Purification by flash column afforded 3-(4-morpholinylmethyl)-1H-indazole-5-carboxylic acid methyl ester (800 mg, 95.7%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[O:25][C:24]2[C:17](=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)[O:16]1.CO.[BH4-].[Na+]>C(O)=O>[O:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:18]([CH2:19][NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[O:16][CH2:15]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
A mixture of 2-phenoxy-phenylamine (410 mg, 2.22 mmol) and 2,3-(methylenedioxy)-benzaldehyde (500 mg, 3.33 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (253 mg, 6.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5% B, 80 g, 4.0 CV, 60 mL/min) to afford 360 mg (51%) of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl) amine as a white solid.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)CCCNC(=O)COc1ccc(CCCCN)cc1
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (292 mg, 0.75 mmol) 5 was added to a solution of compound 4 (200 mg, 0.65 mmol), DIPEA (0.39 mL, 2.25 mmol), and ethanol (5 mL). The reaction mixture was stirred at 65° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (80:18:2 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 6 (190 mg, 56%) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.65 (m, 6H), 2.15 (s, 6H), 2.32 (m, 2H), 2.64 (m, 2H), 3.27 (m, 8H), 4.49 (s, 2H), 6.89 (d, 2H), 7.15 (d, 2H). m/z (ESI) 520.
Reaction SMILES: [I-:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N+](C)(C)C)=[N:3]1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)C>CN(C=O)C>[I-:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:3]1
Reactant: C[N+](C)(C)Cc1n[nH]c2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
(1H-indazol-3-ylmethyl)trimethylammonium iodide (45.0 g, 142 mmol) obtained in Step 3 was dissolved in DMF (220 mL), and the solution was mixed with triphenylphosphine (44.7 g, 170 mmol), followed by heating under reflux for 2.5 hours. After cooling to room temperature, the reaction mixture was added with diethyl ether and was stirred overnight. The resulting precipitates were collected by filtration to obtain (1H-indazol-3-ylmethyl)triphenylphosphonium iodide (68.3 g, 92%).