Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([OH:12])=[CH:14][CH:15]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(O)cc1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(O)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-hydroxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.98 (m, 5H), 2.14 (s, 1H), 2.27-2.34 (m, 2H), 2.36-2.43 (m, 1H), 3.50 (s, 2H), 3.60 (s, 3 H), 4.36 (s, 1H), 6.70-6.98 (m, 2H), 7.56-7.82 (m, 2H); MS (APCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([C:19]([O:21]CC)=[O:20])[C:6]=1[C:24]([O:26]CC)=[O:25])[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([C:19]([OH:21])=[O:20])[C:6]=1[C:24]([OH:26])=[O:25])[CH2:2][CH3:3]
Reactant: CCCOc1c(C(=O)OCC)c(C(=O)OCC)c(OCCC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1c(C(=O)O)c(C(=O)O)c(OCCC)c2ccccc12
Temperature: 60 °C
Yield: 90.8 %

Procedure:
Diethyl 1,4-bis(propyloxy)-2,3-naphthalenedicarboxylate (11.45 g, 29.5 mmol) was dissolved in ethanol (70 ml) and treated with sodium hydroxide (3.54 g, 88.5 mmol) dissolved in water (15 ml). This was heated at 60° C. under argon for 4 hours. The reaction was confirmed to be complete by LC/MS and thin layer chromatography. The reaction mixture was cooled to room temperature and evaporated to a third of the volume. This was acidified to pH2 with hydrochloric acid (2N) and extracted with ethyl acetate (3×100 ml). Combined organics washed with water, brine and dried over magnesium sulphate. Solvent was evaporated to give the title compound as a yellow solid (8.91 g, 26.8 mmol).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C:11]([CH3:33])([CH3:32])[CH2:12][N:13]1[C:25]2[C:24]3[N:23]=[CH:22][C:21]([Br:26])=[CH:20][C:19]=3[N:18]=[C:17]([NH2:27])[C:16]=2[N:15]=[C:14]1[CH2:28][O:29][CH2:30][CH3:31].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[NH2:27][C:17]1[C:16]2[N:15]=[C:14]([CH2:28][O:29][CH2:30][CH3:31])[N:13]([CH2:12][C:11]([NH:10][S:35]([CH3:34])(=[O:37])=[O:36])([CH3:32])[CH3:33])[C:25]=2[C:24]2[N:23]=[CH:22][C:21]([Br:26])=[CH:20][C:19]=2[N:18]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 4 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
Triethylamine (13.02 g, 128.7 mmol) was added to a suspension of 1-(2-amino-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine dihydrochloride (6.00 g, 12.9 mmol) in dichloromethane (500 mL), and the reaction was cooled to 4° C. A solution of methanesulfonyl chloride (1.62 g, 14.2 mmol) in dichloromethane (10 mL) was then added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 24 hours, diluted with dichloromethane (200 mL), washed sequentially with water (200 mL), 4% aqueous sodium carbonate (2×200 mL), water (200 mL), and brine (200 mL), and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 0 to 25% CMA in chloroform) followed by recrystallization from acetonitrile to provide 5.21 g of N-{2-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, 211-212° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:16])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(C2Cc3ccccc3O2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3Cc4ccccc4O3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of 4-(2,3-dihydrobenzofuran-2-yl)benzoic acid (0.02 g, 0.08 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.04 g, 0.2 mmol) and N-hydroxybenzotriazole (0.02 g, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (0.10 g, 1.0 mmol). The reaction mixture was stirred for 15 minutes at room temperature, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.03 g, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water. The organic phase was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product as a white solid 4-(2,3-dihydrobenzofuran-2-yl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (Compound I-51) (0.02 g, 66%). LRMS (M+H+) m/z: calcd 374.16. found 374. 1H NMR (300 MHz, CD3OD): δ 7.80-7.77 (m, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.18-7.12 (m, 2H), 6.87-7.80 (m, 2H), 6.09 (s, 1H), 5.79 (t, J=9.0 Hz, 1H), 4.49 (s, 2H), 3.73-3.64 (m, 1H), 3.14-3.06 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.CN.C[CH2:21][N:22]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O1CCCC1.C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:22][CH3:21])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of 4-(4-hydroxyphenyl)benzoic acid (1 g, 4.7 mmol, 1 equiv) in tetrahydrofuran (20 mL), methylamine hydrochloride, (0.409 g 6 mmol, 1.3 equiv), EDCl (1.18 g, 6.2 mmol, 1.3 equiv), HOBt (0.74 g, 5.5 mmol, 1.2 equiv), and triethylamine (2 mL). The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 15:2 ethyl acetate/petroleum ether) to give 4-(4-hydroxyphenyl)-N-methylbenzamide as a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.CN1CCOCC1>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCN(CCO)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
4-Nitrophenyl chloroformate (9.85 g, 49 mmol) was dissolved in DCM (200 mL), and cooled to 0° C. 2-(4-methylpiperazin-1-yl)ethanol (7.2 g, 50 mmol) and NMM (6 mL) were added, and the reaction mixture was allowed to warm gradually to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution until the yellow colour extracted into the aqueous layer had disappeared. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (10.7 g, 71%) as a yellow oil which solidified on standing.
Reaction SMILES: N[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.N([O-])=[O:28].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][OH:28])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CO)o2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in acetic acid/water (1:1 v/v, 3 ml) was cooled to 0° C. Sodium nitrite (68 mg) was added and the solution stirred 24 hours at room temperature. Concentrated sodium hydroxide solution was added to the reaction and the mixture extracted with ether (3×20 ml). The combined organic phases were treated with potassium hydroxide in methanol (5%, 3 ml) for 2 hours, washed with water, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90 minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate/chloroform (1:1)/water and the organic phase dried and reduced to dryness under vacuum. This material was purified by HPLC, to give, after evaporation of the solvent, N-cyclopropyl-4′-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[CH3:17][S:18]([O:9][CH:6]1[CH2:7][CH2:8][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1)(=[O:20])=[O:19]
Reactant: CC(C)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C

Procedure:
A solution of 1-isopropylpyrrolidin-3-ol (2.0 ml) and triethylamine (2.5 ml) in toluene (25 ml) was cooled to 0° C. and methanesulphonyl chloride (1.4 ml) was added dropwise with stirring. The mixture was allowed to warm to ambient temperature and is stirred for a further 2 h. The reaction was filtered and the filtrate evaporated to an oil which was used immediately.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:30])[CH:18]([CH3:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:23]3[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH:18]([CH3:29])[C:17]([OH:30])=[O:16])=[CH:25][C:24]=3[F:26])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Product: CC(Cc1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1)C(=O)O
Yield: 31.5 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.045 g, 0.21 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (49 mg, 0.21 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]2[C:6]([O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[H][H]>[Pd].C(O)C>[ClH:1].[NH2:18][C:17]1[C:2]([Cl:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:16]=1
Reactant: [H][H]
Reactant: COC(=O)C(C)Oc1noc2cc(Cl)c([N+](=O)[O-])cc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)Oc1noc2cc(Cl)c(N)cc12

Procedure:
A suspension of methyl 2-[(6-chloro-5-nitro-1,2-benzisoxazol-3-yl)oxy]propionate (2.0 g, 6.7 mmol), 5% palladium on activated carbon (0.1 g) and concentrated hydrochloric acid (0.6 mL) in ethanol is hydrogenated until 430 mL of hydrogen is taken up. The reaction mixture is then filtered through diatomaceous earth and concentrated in vacuo to give the title product as a brown gum which is identified by NMR spectral analyses.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:40]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclopentanecarboxylic acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(cyclopentanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (113 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Yield: 89.9 %

Procedure:
The crude 5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 1.04 mmol) from above was dissolved in CH2Cl2 (25 mL) and BBr3 (1 M solution in DCM, 5 mL, 5.0 mmol) was added and stirred over night. CH2Cl2 and water were added and the phases separated. The aqueous phase was again extracted with EtOAc/CH2Cl2 (1:1). The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (217 mg, 76%), which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](O)([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[NH:20]=[N+:21]=[N-:22]>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:20]=[N+:21]=[N-:22])([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1c(F)cccc1F
Reactant: [N-]=[N+]=N
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1c(F)cccc1F
Reaction time: 24 h

Procedure:
20.6 g (120 millimoles) of 2-(2,6-difluorophenyl)propan-2-ol are dissolved in 300 ml of hydrazoic acid solution (1N, in benzene) and 22.8 g (200 millimoles) of trifluoroacetic acid are added to this solution. After 24 hours at room temperature, the reaction solution is diluted with 500 ml of hexane, washed with water and then with sodium bicarbonate until free of acid and dried over sodium sulfate. The solvent is removed by evaporation and the residue is distilled, affording 2-(2,6-difluorophenyl)-2-azidopropane of bp15 =85°-87° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CC(C)=O>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([N:17]=[N+:18]=[N-:19])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 209.7 %

Procedure:
An acetone solution of 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride (e6) (2.0 g) was added to a stirred aqueous solution of sodium azide (2.0 g) and the suspension stirred at room temperature for 30 minutes. Extraction with ethyl acetate gave 4-acetylamino-5-chloro-2-methoxy-benzoyl azide (e7) (4.3 g) as a white crystalline solid on trituration under petrol, m.p. 135°-140°. [I.R.ν(N3)=2140 cm-1 and ν(C=O)=1645, 1705 cm-1 ]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH:20]1([C:23]([NH2:25])=[NH:24])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:24][C:23]([CH:20]4[CH2:22][CH2:21]4)=[N:25][C:7]=3[C:6]=2[CH:18]=1
Reactant: N=C(N)C1CC1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Agent: Cl
Product: O=C1Cc2cnc(C3CC3)nc2-c2cc(Cl)ccc2N1
Yield: 83 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropancarboxamidine hydrochloride. Yield: 83%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:36]=[CH:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=5)[CH:3]=4)[N:8]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Temperature: 150 °C

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [Intermediate B] (0.20 g, 0.43 mmole) in CH3CN (4 mL) in a Personal Chemistry microwave reaction vial was added 4-formylphenylboronic acid (64 mg, 0.43 mmol), bis(triphenylphosphine)-palladium(II) dichloride (40 mg, 0.057 mmol), and 1 M Na2CO3 (2 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and partitioned between EtOAc and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate AJ. HPLC retention time: 3.01 minutes. MS ESI (m/z): 492.4 (M+H)+, calc. 491.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27](=[O:39])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:19][C:18]=1[F:40])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[F:40][C:18]1[CH:19]=[C:20]([NH:23][C:24]([C:26]2[C:27](=[O:39])[N:28]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:21]=[CH:22][C:17]=1[O:16][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)c1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To tert-Butyl 3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-ylcarbamate (119 mg, 0.176 mmol) in THF (2 mL) at rt was added tetrabutylammonium flouride (260 μL, 0.264 mmol, 1 M in THF). After stirring at rt for 30 min, the reaction was diluted with ethyl acetate (20 mL), washed with water followed by brine (10 mL each), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5% MeOH/EtOAc) to give the title compound (66 mg, 66%) as a yellow oil. 1H NMR (CD3OD) δ 8.62 (dd, 1H, J=7.2, 2 Hz), 8.04 (d, 1H, J=6 Hz), 7.94-7.90 (m, 2H), 7.50-7.46 (m, 2H), 7.33-7.25 (m, 3H), 7.20 (t, 1H, J=8.8 Hz), 6.67 (t, 1H, J=6.8 Hz), 6.40 (d, 1H, J=5.2 Hz), 4.78 (s, 2H), 1.49 (s, 9H); MS(ESI+) m/z 565.17 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.BrCC1CCCCO1.[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]2[C:29]3([CH2:39][O:40][C:23]=2[CH:22]=1)[C:37]1[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[NH:31][C:30]3=[O:38]>>[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]2[C:29]3([CH2:39][O:40][C:23]=2[CH:22]=1)[C:37]1[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:31]([CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1)[C:30]3=[O:38]
Reactant: COc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)OCC21C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 6-fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: mp 132-134° C.; 1H NMR (300 MHz, CDCl3) δ7.58 (d, J=9.4 Hz, 1H), 7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.06-7.01 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 6.71-6.67 (m, 2H), 6.62 (d, J=12.1 Hz, 1H), 6.34 (d, J=3.4 Hz, 1H), 6.10 (d, J=3.4 Hz, 1H), 4.90 (d, J=16.3 Hz, 1H), 4.57 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.7 Hz, 1H), 4.41 (d, J=16.2 Hz, 1H), 3.91 (s, 3H); MS (ES+) m/z 433.9 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][CH:21]=[C:20]2O>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][CH:21]=[C:20]2[Cl:3]
Reactant: COc1ccc2nncc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1ccc2nncc(Cl)c2c1
Yield: 59 %

Procedure:
Phosphorous oxychloride (5 ml) was added to a mix of dimethylaniline (157 mg, 1.3 mmol) and 6-methoxy-4-hydroxycinnoline (208 mg, 1.2 mmol). The reaction was heated at reflux for 15 min, then cooled and concentrated under vacuum. The residue was partitioned between chloroform (100 ml) and water (30 ml), then the organic layer was washed with brine and dried (Na2SO4). Chromatography of the residue adsorbed onto silica gel (3 g) on silica gel (15 g) eluent CH2Cl2 to 10% Ethylacetate/CH2Cl2 gave 6-methoxy-4-chlorocinnoline (135 mg, 0.7 mmol) in 59% yield as white yellow solid. δH (CDCl3)=4.03 (s, 3H); 7.28 (d, 1H); 7.51 (dd, 1H); 8.41 (d, 1H) and 9.22 (br s, 1H). MS (ESI) (M+H)+195.