Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([OH:18])=O)=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([Cl:21])=[O:18])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1CCCc1ccccc1-2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carboxylic acid (3.4 grams, 0.0142 mole) in thionyl chloride (10 ml) was heated at reflux for 1.5 hours. The excess thionyl chloride was removed by distillation under reduced pressure. Benzene (10 ml) was added and then removed by distillation under reduced pressure to leave 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonyl chloride as a residue.
Reaction SMILES: [CH3:1][Si:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:78]([O:83][CH2:84][CH3:85])(=[O:82])[C@H:79]([CH3:81])O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:44][Si:2]([CH3:43])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:79]([C:78]([O:83][CH2:84][CH3:85])=[O:82])[CH3:81])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Reactant: CCOC(=O)[C@H](C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(=O)OCC[Si](C)(C)C)OC
Yield: 74.1 %

Procedure:
A solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol), PyBOP (234 mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate (53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperature for 1 hour when complete consumption of the starting materials was observed. The reaction was worked up by addition of saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated and washed with 5% aqueous solution of lithium chloride. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (0-20%) to provide 57 mg (74%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz), 3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9 Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61 (m, 2H); 31P (121.4 MHz, CDCl3) δ 28.9, 29.9; MS (m/z) 791.4 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Product: CN1CCN(c2ccc(Cl)nn2)CC1
Temperature: 100 °C
Yield: 59.7 %

Procedure:
A 25-mL single-neck round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 3,6-dichloropyridazine (1.49 g, 10.0 mmol) and N-methylpiperazine (1.17 g, 11.7 mmol), and the flask was placed in an oil bath, which was heated to 100° C. After 1.5 h the flask was cooled to room temperature, and the resulting cake was crushed and triturated with acetonitrile (10 mL). The suspension was filtered, and the filter cake was mixed with 10% aqueous potassium carbonate (15 mL). The resulting mixture was extracted with MtBE (2×35 mL). The organic extracts were combined, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford a 60% yield (1.27 g) of 122e as a white solid: mp 106-107° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (d, 1H, J=9.5 Hz), 6.89 (d, 1H, J=9.6 Hz), 3.65 (t, 4H, J=5.1 Hz), 2.53 (t, 4H, J=5.1 Hz), 2.35 (s, 3H); MS (ESI+) m/z 213.1 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:24][CH:25]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Clc1ccc(Br)nc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ccc(Cl)cn2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-5-chloro-pyridine.
Reaction SMILES: [NH2:1][C:2](=[O:33])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:9]=[C:8]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:7]=1)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2](=[O:33])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:9]=[C:8]([C:26]([OH:28])=[O:27])[CH:7]=1)[CH3:4]
Reactant: C[C@H](Nc1cc(C(=O)OC(C)(C)C)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a suspension of the (S)-tert-butyl 6-((1-amino-1-oxopropan-2-yl)-amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylate (0.426 g, 0.941 mmol) in DCM (10 mL) was added TFA (5 mL, 67 mmol). After stirring overnight, the reaction was evaporated in vacuo and the residue triturated with 3 mL acetonitrile, filtered, rinsed once with 1 mL acetonitrile and dried under vacuum at 40° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid as an off-white powder (0.343 g, 0.865 mmol, 92% yield). 1H NMR (400 MHz, DMSO-d6): 8.40 (2H, d, J=8.8 Hz), 8.05 (1H, d, J=6.6 Hz), 7.56 (1H, s), 7.32-7.24 (2H, m), 7.19-7.14 (2H, m), 7.11 (1H, s), 7.07-7.01 (3H, m), 4.61-4.52 (1H, m), 1.37 (3H, d, J=7.0 Hz). LC/MS: m/z=397.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:10]1[CH:15]=[CH:14][C:13]([O-:16])=[CH:12][CH:11]=1.[Na+]>>[O:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCCCl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: CCCCCCCCOc1ccccc1
Temperature: 140 °C
Yield: 96 %

Procedure:
Into a 100 ml reactor equipped with a reflux condenser and a magnetic stirrer, 17 g 1-chlorooctane, 1.16 g anhydrous sodium phenate and 0.31 g of the product prepared according to Example 1, were introduced. The mixture was heated to 140° C. for 3 hours, 30 minutes. 1-Phenoxyoctane was obtained in a yield of 96%. The mixture was filtered after cooling and the precipitate washed with water and methanol.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:25]([CH2:27][NH2:28])O>CS(C)=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:28]3[CH2:27][CH2:25][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCO
Solvent: CS(C)=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C2(c3ccccc3)OCCN12
Temperature: 100 °C
Yield: 56.6 %

Procedure:
To a solution of 7.75 g of 2-trichloroacetamido-5-nitrobenzophenone in 50 ml. of dimethylsulfoxide was added 1.47 g of monoethanolamine, and the mixture was heated at 100°C for 2 hours. After cooling, the reaction mixture was poured into 500 ml. of water and the resulting precipitate was collected by filtration, washed successively with water and ether to give 3.52 g of 9-nitro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 275°-276°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:14])[CH2:12][CH3:13])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:15][CH:12]([CH3:13])[C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)=[O:14]
Reactant: CCC(=O)c1cc2c(Cl)cccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1cc2c(Cl)cccc2s1
Reaction time: 18.5 h
Yield: 236.8 %

Procedure:
A mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (1.65 g), phenyltrimethylammonium tribromide (2.76 g) and tetrahydrofuran (20 ml) was stirred under nitrogen for 18.5 hours, then it was filtered and diluted with water (200 ml). The product was extracted into dichloromethane (3×40 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (3.06 g) as a pale yellow solid, m.p. 104-106° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].CCN(C(C)C)C(C)C.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([NH:11][CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:13][CH:12]=1)=[O:23]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-nitrophenethylamine hydrochloride (50 g, 0.247 mole), DIEA (128 mL, 0.74 mole, 3 eq.) and CH2Cl2 (500 mL) in a 1 L round bottom flask equipped with a magnetic stirrer was added (CF3CO)2O (52.5 mL, 0.37 mole, 1.5 eq) dropwise at 5-10° C. (with ice/water bath). After stirring for another 1 h after the addition at RT, the reaction was quenched with water (200 mL) and transferred into a separatory funnel. The organic layer was separated, washed with water and sat. NH4Cl, dried over Na2SO4, filtered, concentrated to give a brown oil. The crude was triturated with water (300 mL), filtered and dried on vacuum overnight to give the desired 2,2,2-trifluoro-N-[2-(4-nitro-phenyl)-ethyl]-acetamide as a yellow solid. This can be used for next step without further purification. An analytical sample was obtained through recrystallization from CH3OH/H2O as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].CS(C)=O.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][N:12]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2c[nH]cn2)cc1Cl
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCn1cnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 45 °C
Yield: 43.3 %

Procedure:
Charge a round bottom flask with 4-(3-chloro-4-fluoro-phenyl)-1H-imidazole (1.85 g; 1.00 equiv; 9.41 mmol), KOH (3.00 equiv; 28.23 mmol; 1.58 g, crushed to a fine powder), in DMSO (281.56 mmol; 20.00 mL). Add 2-dimethylaminoethyl chloride hydrochloride (1.20 equiv; 11.29 mmol; 1.63 g) in one portion and the solution becomes yellow. Heat at 45° C. for 2 days. Dilute the reaction with EA and wash with water, brine and dry the organics over MgSO4; filter, and concentrate to an orange oil. Purify the crude with ISCO chromatography over a Biotage 40M column eluting with a gradient of 5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min to give the title compound (1.09 g; 4.07 mmol; 43.27%) as a light orange oil. MS(ES): (m/z)=268.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:25]4[CH2:26][CH2:27][N:22]([C:28]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[NH:30][N:29]=5)[CH2:23][CH2:24]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3ccccc23)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 3-piperazin-1-yl-1H-indazole (Table No.1, SM 3) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=488.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([OH:27])=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(OCc3ccccc3)cc12
Reaction time: 24 h
Yield: 51.2 %

Procedure:
A solution of benzyl bromide (230 μl, 1.9 mMol) in acetone (6 ml) is added at room temperature, over 15 minutes, to a mixture containing 1-chloro-9-hydroxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 10) (490 mg, 1.73 mMol), acetone (7 ml), DMF (2 ml) and K2CO3 (400 mg). The assembly is left stirring for 24 h, then the solvents are subsequently evaporated under vacuum. Water is then added (30 ml). The assembly is again left stirring for 24 h. The solid form is recovered by filtration, washed with water, then dried at room temperature for 18 h. An inter-mediate, 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole (330 mg, 51% yield) is obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99%/1% to 95%/5%) as eluent. The product obtained is identical to that obtained according to the method described in J. Chem. Soc. Perkin Trans. 1, 1979, 1706. The mixture of 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole obtained above (320 mg, 0.86 mMol), DMF (7 ml) and sodium methoxide (30% solution in methanol, 10 ml) is heated under reflux for 20 h. The reaction mixture is poured into 60 ml of water, then left stirring for 2 h. The solid formed, recovered by filtration, is washed with water then dried. 280 mg (88% yield) of the expected compound 9-benzyloxy-1-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 7) are then obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99.5%/0.5% to 99%/1%) as eluent. The proton NMR spectrum of Compound 7 is the following:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:27][CH:28]([CH3:32])[CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:31][CH2:30][CH2:29][CH:28]([CH3:32])[CH3:27])#[N:24]
Reactant: CC(C)CCN
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)CCN=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.3 %

Procedure:
A solution of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg), 3-methylbutylamine (1.15 mmol,100 mg) and triethylamine (1.5 mmol, 150 mg) in acetonitrile (2 ml) was stirred for 24 h at 60° C. After concentration the residue was purified by column chromatography (heptane:ethyl acetate 1:1) to give the title compound (100 mg, 27%).
Reaction SMILES: [P:1]([O:19][C@@:20]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])([C@H:27]([C:29]1[C:34]([F:35])=[CH:33][N:32]=[CH:31][N:30]=1)[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.[OH-].[OH-].[Pd+2]>[P:1]([OH:11])([OH:3])([O:19][C@@:20]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])([C@H:27]([C:29]1[C:34]([F:35])=[CH:33][N:32]=[CH:31][N:30]=1)[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[O:2]
Reactant: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OP(=O)(O)O)c1ccc(F)cc1F
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A solution of the compound of step (a) (5.0 g, 8.83 mmol) in methanol (100 ml) was hydrogenated over Pearlman's catalyst (1.0 g) at room temperature and at 414 kPa (60 p.s.i.) for 16 hours. The solution was filtered through a pad of celite (trade mark) and concentrated. The crude product was redissolved in hot methanol (20 ml) and granulated at 0° C. for 1 hour. After filtering and washing with methanol (5 ml) the product was dried under vacuum at 50° C. to give the title compound (1.72 g, 49%). m.p. 145-146° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+].CO>C(OCC)(=O)C>[CH3:13][O:14][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccc2ccc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(O)cc2n1
Yield: 79 %

Procedure:
2-Chloro-quinolin-7-ol (4.2 g, 23.4 mmol, 1.0 eq) is added at room temperature to a stirred solution of sodium methoxide in methanol (15% weight, 200 mL, 561.6 mmol, 24.0 eq) and the resulting mixture is heated under reflux for 20 hours. Solvent is removed, the residue is dissolved in water (50 mL) and neutralized with acetic acid, followed by extraction with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford 2-methoxy-quinolin-7-ol as a yellow solid (3.3 g, 79% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:23]#[N:24])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.N[OH:28].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:23]([NH2:24])=[O:28])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C(N)=O
Reaction time: 4 h

Procedure:
1 ml dry MeOH was added to 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (Example 1, 4.5 mg, 0.01 mmol) under nitrogen followed by 10 eq hydroxylamine hydrochloride. 10 eq NaOMe was added and the mixture was stirred for 4 h. The solvent was concentrated and the crude product was purified on silica using CH2Cl2/MeOH (97:3 to 96:4) as eluents. 2.10 mg 2-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (E2) ES/MS m/z: 363.5 (M+H), 361.6 (M−H); 1H NMR (MeOD, 500 MHz): 7.65 (m 1H), 7.60 (m, 1H), 7.29 (m, 1H), 7.18 (m, 1H), 7.12 (m, 2H), 6.79 (m, 2H), 2.12 (s, 3H), 1.99 (s, 3H) and 1.90 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carboxamide (E3) ES/MS m/z: 348.2 (M+H), 346.3 (M−H); 1H NMR (MeOD, 500 MHz): 7.93 (m 1H), 7.61 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.08 (m, 2H), 6.81 (m, 2H), 2.07 (s, 3H), 2.03 (s, 3H) were obtained as white solids. For Example 2, the title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[C:18]([O-])(=[O:20])C.[Na+]>CN(C)C=O>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:20])=[CH:10][CH:9]=1
Reactant: COc1cccc2ccccc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c2ccccc12

Procedure:
Phosphorus oxychloride (315 g, 1.6 mole) was added dropwise over 4 hours to a stirred solution of 1-methoxynaphthalene (250 g) (2) in dried dimethylformamide (150 g). the reaction mixture was heated on a water bath for a further 4 hours, cooled, and poured onto ice (1 k) and 2M aqueous sodium acetate (1.5 l). The organic layer was extracted with dichloromethane (1 l) and washed with dilute hydrochloric acid and then with water. The organic layer was dried (MgSO4), filtered, and the solvent removed. 4-Methoxy-1-naphthaldehyde (3) was obtained as a pale yellow oil.