Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Cl[CH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: CN(C)C(=O)c1cccc(CCl)c1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: CN(C)C(=O)c1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
To a flask was added 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) and CH3CN (6 mL) followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.523 ml, 2.59 mmol). The mixture was stirred for 5 minutes, and then 3-(chloromethyl)-N,N-dimethylbenzamide (0.479 g, 2.42 mmol) was added as a CH3CN (4 mL) solution. The reaction was stirred at ambient temperature for 5 hours. The mixture was concentrated and diluted with saturated aqueous NH4Cl (20 mL) and EtOAc (60 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (EtOAc) to provide 0.567 g (72%) of the desired product as an orange foam.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18]C(=O)C3C=CC=C(C#N)C=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:32]([OH:35])(=O)[CH3:33].O.[PH2]([O-])=O.[Na+]>N1C=CC=CC=1.[Ni]>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]([C:32](=[O:35])[C:33]2[CH:5]=[CH:6][CH:7]=[C:8]([C:9]#[N:11])[CH:29]=2)[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Reactant: CC(=O)O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)N(C(=O)c2cccc(C#N)c2)c2ccccc2N)cc1
Temperature: 45 °C
Yield: 6 %

Procedure:
To a mixture of N2-(4-tert-butylbenzoyl)-N1-(3-cyanobenzoyl)-1,2-benzenediamine (1.0 g, 2.5 mmol), water (25 mL), and acetic acid (25 mL) in pyridine (50 mL) was added sodium hypophosphite monohydrate (270 mg, 5.0 mmol) and Raney nickel (400 mg). The reaction mixture was heated at 45° C. for 3 h, cooled to room temperature, and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and chromatographed (silica gel, 5% ethyl acetate/95% methylene chloride) to give 56 mg (6%) of the title compound as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:31])([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:12]([N:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[O:13]>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:13][C:12]([C:11]([F:10])([F:31])[C:24]([F:29])([F:30])[C:25]([F:27])([F:28])[F:26])=[N:14][C:15]([C:20]([F:23])([F:22])[F:21])([C:16]([F:19])([F:18])[F:17])[N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)C(F)(F)C1=NC(C(F)(F)F)(C(F)(F)F)N=C(c2ccc(Br)cc2)O1
Temperature: 60 °C
Yield: 100.4 %

Procedure:
4-Bromobenzonitrile (0.3 g, 1.65 mmol) and 2,2,3,3,4,4,4-heptafluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl)ethylidene}butanamide (1.2 g, 3.3 mmol) were dissolved in diethyl ether (4.0 mL) and heated in a sealed glass tube to 60° C. for 17 hours. The solvent and excess reagent were distilled off to give a colorless liquid (0.9 g, 100 percent yield). EIMS (m/z): 543 (M+), 524 (M-F), 474 (M-CF3).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].CN(C=[O:27])C>CCOC(C)=O>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:18]1[CH2:19][CH2:20][CH:17]([OH:27])[CH2:16]1
Reactant: CN(C)C=O
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(O)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
1-(2-Bromoethoxy)2-methoxy-4-nitrobenzene (0.756 g, 2.7395 mmol) 3-pyrrolidinol (0.477 g, 5.479 mmol) and triethylamine (0.554 g, 5.479 mmol) were combined in DMF (10 mL) and heated to 80° C. The reaction was stirred for 2 h. Cooled to RT and diluted with EtOAc (100 mL) and washed with water (2×100 mL). The organics were dried over MgSO4, filtered and concentrated to afford 0.3967 g (1.407 mmol, 51%) of the desired product as a dark brown oil. 1H NMR (CDCl3) δ 7.90 (d, 1H, J=9.0 Hz), 7.75 (s, 1H), 6.93 (d, 1H, J=9.0 Hz), 4.38 (m, 1H), 4.24 (t, 2H, J=6.2 Hz), 3.95 (s, 3H), 3.2-3.0 (m, 4H), 3.0-2.90 (m, 1H), 2.8-2.70 (m, 1H), 2.60-2.50 (m, 1H), 2.30-2.20 (m, 1H), 1.85-1.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5]P(OCC)(OCC)=O)[CH3:2].[CH3:15][O-:16].[Na+].[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23]O>CO.O1CCCC1>[CH3:15][O:16][C:22](=[O:18])[CH:21]=[CH:20][C:19]1([CH3:23])[CH2:2][CH2:1][O:3][CH2:4][CH2:5]1
Reactant: C[O-]
Reactant: OCC1CCCO1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C=CC1(C)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Into a cooled (0° C.) solution of 1.92 g (8.58 mmol) of diethylphosphonoacetic acid ethyl ester in tetrahydrofuran-methanol (3.5 mL+2.8 mL) was dropped 1.65 mL (8.58 mmol) of 28% sodium methoxide in methanol solution, and stirred for 10 minutes. Into this solution was dropped a solution of 1.0 g (7.80 mmol) of 4-methyltetrahydropyran-4-carbaldeyhde obtained in the above 2) in tetrahydrofuran (1.5 mL), and then stirred for 5 hours at room temperature. After the reaction was completed, the reaction mixture was poured into ice water and extracted with ether. The organic layer was washed with water (three times) and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The obtained residue was purified by medium pressure liquid column chromatography on silica gel (developing solvent; hexane-ethyl acetate) to obtain 0.93 g (yield 64.7%) of 3-(4-methyltetrahydropyran-4-yl)acrylic acid methyl ester as colorless liquid. Its physical property is shown below.
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=2)=[O:15])[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (1.23 g, 5.25 mmol, Intermediate 15, step b) in THF (12 mL) at 4° C. was added 0.5 M (3-chlorophenyl)magnesium bromide in THF (12.7 mL, 6.35 mmol). The mixture was stirred at 4° C. to room temperature overnight, and quenched with NH4Cl (aqueous). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (40 g silica gel column, 0-70% EtOAc in heptanes) to give the title compound as an oil, which solidified upon standing.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH3:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])[C:12]2=[CH:11][C:10]1[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc2c(c1)C(=Cc1[nH]cc(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (496 mg) suspended in ethylene glycol (2 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (157 mg) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 128 mg (29%) of 3-[2-(5-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[Br:11][C:12]1[NH:16][CH:15]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=1.O>C(#N)C>[Br:11][C:12]1[NH:16][C:15]([CH:9]=[O:10])=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1c[nH]c(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Br)[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
POCl3 (Aldrich; 0.531 mL, 5.70 mmol) was added (dropwise, over 1 min) to DMF (1.32 mL, 17.10 mmol) under argon at 0° C., and the resulting solution was stirred at 0° C. for 15 min. This solution was then added (dropwise, over 1 min) to a dark-brown solution of methyl 5-bromo-1H-pyrrole-3-carboxylate (581 mg, 2.85 mmol) in ACN (6.0 mL) at 23° C., and the resulting solution was stirred under argon at 50° C. for 3 h. The reaction mixture was then poured into 10:1 water/sat. aq. NaHCO3 (50 mL) and extracted with DCM (3×50 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-30% EtOAc/hexanes) furnished methyl 5-bromo-2-formyl-1H-pyrrole-3-carboxylate (245 mg, 1.05 mmol, 37% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.09 (1H, s), 9.56 (1H, br. s.), 6.72 (1H, d, J=2.7 Hz), 3.90 (3H, s). m/z (ESI, +ve) 231.9/234.1 (M+H)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:39]=[C:40]([CH3:42])[CH:41]=1)[O:9][C:10]1[N:15]([CH2:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:20]=[C:19]([F:33])[CH:18]=2)[C:14](=[O:34])[NH:13][C:12](=[O:35])[C:11]=1[CH:36]([CH3:38])[CH3:37].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O.CC(C)=O>[F:33][C:19]1[CH:18]=[C:17]([CH2:16][N:15]2[C:10]([O:9][C:8]3[CH:7]=[C:6]([CH:41]=[C:40]([CH3:42])[CH:39]=3)[CH:2]=[O:1])=[C:11]([CH:36]([CH3:37])[CH3:38])[C:12](=[O:35])[NH:13][C:14]2=[O:34])[CH:22]=[C:21]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:20]=1
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C5OCCO5)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-1-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-1H-pyrimidine-2,4-dione (714 mg, 1.24 mmol), PPTS (62 mg, 0.25 mmol), and water (5 drops) in acetone (10 ml) was heated under reflux for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:1 to 2:3)) to afford 548 mg (83%) of a white solid. 1H NMR (200 MHz, CD3OD/CDCl3) δ 1.00 (6H, d, J=7.4 Hz), 2.30 (3H, s), 2.58 (1H, m), 3.71 (3H, s), 4.19 (2H, s), 4.65 (2H, s), 5.78 (1H, s), 5.86 (1H, s), 6.76-6.80 (3H, m), 7.02 (1H, s), 7.11-7.16 (2H, s), 7.32 (1H, s), 9.78 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CO>[CH3:12][N:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CNCCc1ccccn1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccccn1)Cc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
6.8 g of 3-nitrobenzyl chloride in 25 ml of methanol are slowly added dropwise to a solution of 5.4 g of 2-(2-methylaminoethyl)pyridine in 20 ml of methanol at 40° C. 15 ml of triethylamine in 15 ml of methanol are subsequently added, and the mixture is stirred for 15 hours at 40° C. After removal of the solvent by evaporation in vacuo, the residue is taken up in 300 ml of water and extracted three times with dichloromethane. After drying over sodium sulphate, the dichloromethane is evaporated in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol 100:5).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([Br:20])=[CH:7][CH:8]=2)[C:3]1=[O:21].[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[C:9]4[C:4](=[CH:5][C:6]([Br:20])=[CH:7][CH:8]=4)[C:3]3=[O:21])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(-c2nn(N)c(=O)c3cc(Br)ccc23)cc1
Product: COc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3cc(Br)ccc23)cc1

Procedure:
The product from Example 174A and 2-(adamant-1-yl)acetyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.28 (s, 1H), 8.50 (d, J=2.1 Hz, 1H), 8.14 (dd, J=8.6, 2.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.51-7.55 (m, 2H), 7.11-7.15 (m, 2H), 3.85 (s, 3H), 2.05 (s, 2H), 1.92-1.98 (bs, 3H), 1.58-1.70 (m, 12H); MS (ESI+) M/Z, 524 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](Cl)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:16]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]=1
Reactant: NCCCO
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(NCCCO)nc21
Yield: 82 %

Procedure:
2-Chloroderivative (2) (0.5 mmol) and 3 ml of 3-aminopropanol were heated for 3 hours to 160° C. (sealed ampoule). Excess of the amine was evaporated at a temperature below 70° C. and the residue was purified by column chromatography (stepwise 0; 1; 2% MEOH in CHCl3) and crystallized from diethyl ether afforded the product in 82% yield; m.p. 98-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:55]1[C:64]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59][C:58]=2[N:57]=[CH:56]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:61]3[CH2:62][CH2:63][C:64]4[S:55][CH:56]=[N:57][C:58]=4[CH2:59][CH2:60]3)=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: c1nc2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCc2ncsc2CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 1.5 mL DMF. 32 mg HATU and 15 μL triethylamine were added to this solution and the mixture was stirred for 5 min. at RT. Then, 15 mg 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine and 15 μL triethylamine in 0.5 mL DMF were added. The mixture was stirred over night at RT. The reaction solution was purified by HPLC to yield 23 mg of the desired compound.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=2)[N:56]=1)(=O)=O.N1CCC1>O.CS(C)=O>[F:42][C:34]1[CH:33]=[C:32]([C:27]2[C:26]([CH:24]3[CH2:23][N:22]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=5)[N:56]=4)[CH2:25]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:41]=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37]
Reactant: O=S(=O)(Oc1ccc2ccc(F)cc2n1)C(F)(F)F
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CNC2)cc1F
Agent: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(c3ccc4ccc(F)cc4n3)C2)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of 4-(3-(azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.953 g, 1.517 mmol), potassium carbonate (0.839 g, 6.070 mmol), 7-fluoroquinolin-2-yl trifluoromethanesulfonate (0.537 g, 1.821 mmol, prepared according to Step 3 of Example 2), and DMSO (10 mL) was stirred at 50° C. for 1 h. LCMS showed the product and no more azetidine starting material. The mixture was diluted with water and extracted with CH2Cl2 three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g, 5-100% EtOAc-hexane. The impurity 2-hydroxyquinoline was further removed by trituration with CH2Cl2 and hexane twice. The product was obtained as a white solid (510 mg, 78%). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.50 Hz, 3 H) 4.33-4.50 (m, 5 H) 6.56 (d, J=9.00 Hz, 1 H) 6.81 (d, J=7.04 Hz, 1 H) 6.98 (td, J=8.61, 2.54 Hz, 1 H) 7.31-7.45 (m, 3 H) 7.56 (dd, J=8.71, 6.36 Hz, 1 H) 7.84 (d, J=9.00 Hz, 1 H) 8.28 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.15 Hz, 1 H) 8.64 (d, J=2.35 Hz, 1 H). m/z=432 (M+1 ).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].[OH-].[Na+].O>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Oc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-methoxyphenoxy)benzaldehyde (5.0 g, 21.9 mmol) in methanol (35 mL) was added a solution of sodium borohydride (0.86 g, 22.8 mmol) in an aqueous solution of 2N sodium hydroxide (2.5 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was neutralized with acetic acid, then, extracted with ethyl acetate, washed with brine, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain (3-(4-methoxy-phenoxy)-phenyl)-metanol (5.3 g, quantitatively) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([C@@H:30]2[CH2:32][C@H:31]2[C:33](Cl)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:33]([CH:31]5[CH2:32][CH:30]5[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:34])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4c4ccccc4)nc3cc21

Procedure:
2-Phenyl-cyclopropanecarboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and trans-2-phenyl cyclopropan-1-carbonyl chloride (137 μl, 0.89 mmol). The title compound was obtained as yellow powder (216 mg, 59%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][C@@H:15]1[N:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C@@H:34]([NH:36][C:37](=[O:49])[C@@H:38]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH:39]([CH3:41])[CH3:40])[CH3:35])=[CH:28][CH:27]=2)=[O:23])[C:20]2[CH:51]=[C:52]([OH:57])[C:53]([O:55][CH3:56])=[CH:54][C:19]=2[C:18](=[O:58])[N:17]2[CH:59]=[C:60](/[CH:62]=[CH:63]/[CH3:64])[CH2:61][C@@H:16]12)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Si:65]([O:72][C@@H:73]1[N:79]([C:80]([O:82][CH2:83][CH:84]=[CH2:85])=[O:81])[C:78]2[CH:86]=[C:87]([O:92][CH2:93][CH2:94][CH2:95]I)[C:88]([O:90][CH3:91])=[CH:89][C:77]=2[C:76](=[O:97])[N:75]2[CH:98]=[C:99](/[CH:101]=[CH:102]/[CH3:103])[CH2:100][C@@H:74]12)([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66]>CC(C)=O>[CH2:46]([O:45][C:43]([NH:42][C@H:38]([CH:39]([CH3:41])[CH3:40])[C:37]([NH:36][C@H:34]([CH3:35])[C:33]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([N:21]2[C:20]3[CH:51]=[C:52]([O:57][CH2:95][CH2:94][CH2:93][O:92][C:87]4[C:88]([O:90][CH3:91])=[CH:89][C:77]5[C:76](=[O:97])[N:75]6[CH:98]=[C:99](/[CH:101]=[CH:102]/[CH3:103])[CH2:100][C@H:74]6[C@H:73]([O:72][Si:65]([C:68]([CH3:71])([CH3:69])[CH3:70])([CH3:67])[CH3:66])[N:79]([C:80]([O:82][CH2:83][CH:84]=[CH2:85])=[O:81])[C:78]=5[CH:86]=4)[C:53]([O:55][CH3:56])=[CH:54][C:19]=3[C:18](=[O:58])[N:17]3[CH:59]=[C:60](/[CH:62]=[CH:63]/[CH3:64])[CH2:61][C@H:16]3[C@@H:15]2[O:14][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9])=[O:23])=[CH:31][CH:30]=1)=[O:50])=[O:49])=[O:44])[CH:47]=[CH2:48]
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O[Si](C)(C)C(C)(C)C)cc1)C(C)C
Reactant: C=CCOC(=O)N1c2cc(OCCCI)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)N[C@@H](C(=O)N[C@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/C)C[C@H]4[C@H](O[Si](C)(C)C(C)(C)C)N5C(=O)OCC=C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O[Si](C)(C)C(C)(C)C)cc1)C(C)C
Temperature: 75 °C
Yield: 35 %

Procedure:
Potassium carbonate (0.030 g, 0.21 mmol, 1.0 eq) was added to a solution of the phenol 18 (0.175 g, 0.21 mmol, 1.0 eq) and the iodo linker 49 (0.214 g, 0.32 mmol, 1.5 eq) in acetone (10 mL). The reaction mixture was heated under a nitrogen atmosphere at 75° C. in a sealed flask for 17 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by flash chromatography (silica gel, 2/98 v/v methanol/DCM to 5/95 v/v methanol/DCM) to afford the product as a pale yellow solid (0.100 g, 35%). LC/MS (4.293 min (ES+)), m/z: 1359.13 [M]+.