Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH:21]=2)[CH:13]=1)[CH2:9][OH:10].[CH3:33]I.[H-].[Na+].O>CN(C)C=O.C(OCC)C>[CH3:33][O:10][CH2:9][CH:8]([CH2:7]/[CH:6]=[CH:5]/[C:4]#[C:3][C:2]([CH3:32])([CH3:31])[CH3:1])[CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CI
Reactant: CC(C)(C)C#C/C=C/CC(CO)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COCC(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Yield: 80 %

Procedure:
44.4 mg of (E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-3-[3-[3-(3-thienyl)phenylmethoxy]phenyl]propanol obtained in Example 11 is dissolved in 1 ml of dimethylformamide, 17.4 μl of methyl iodide and 8 mg of 60% oily sodium hydride are added under ice cooling and stirring, and the mixture is stirred at room temperature for 4 hours. Water and ethyl ether are added to the reaction solution for dilution, and the organic layer is taken, washed with saturated saline and dried over anhydrous magnesium sulfate. The desiccating agent is filtered, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography [Wako gel C-200, 7 g; hexane/ethyl acetate=19/1] to obtain 39 mg (yield: 80%) of the captioned compound as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9]1([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[N+](C1C=CC=CC=1)([O-])=O>[NH3:1].[C:9]1([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]4[NH:8][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[N:1]=4)=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(OCCCN2CCN(c3ccccc3)CC2)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: N
Product: c1ccc(N2CCN(CCCOc3ccc(-c4nc5ccccc5[nH]4)cc3)CC2)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
A mixture of 1,2-diaminobenzene (0.67 g) and 4-[3-(4-phenylpiperazin-1-yl)propoxy]benzaldehyde (Example A) (2.00 g) in nitrobenzene (65 mL) is stirred for 16 hours at 160° C. The solvent is distilled off under high vacuum and the resulting solid is purified by medium pressure liquid chromatography (MPLC) on silica gel eluting with 200:8:1 dichloromethane: ethanol:0.880 aqueous ammonia to give 0.97 g of the title compound as a tan solid; mp 240°-244° C.
Reaction SMILES: [Na+].[Cl-].[OH-:3].[K+].[CH2:5]([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](Cl)=[O:9])[CH3:6].[OH2:15]>>[CH2:5]([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([O:3][O:15][C:12]([O:15][O:3][C:8](=[O:9])[CH:7]([CH2:5][CH3:6])[CH2:11][CH2:12][CH2:13][CH3:14])([CH2:11][CH:7]([CH3:8])[CH3:5])[CH3:13])=[O:9])[CH3:6]
Reactant: O
Reactant: [OH-]
Reactant: CCCCC(CC)C(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: CCCCC(CC)C(=O)OOC(C)(CC(C)C)OOC(=O)C(CC)CCCC
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
Into a 200 ml beaker were charged 12 g of methylisobutyl ketone peroxide in water (containing 0.0533 mole T4 and 0.0008 mole T3), 25 g of petroleum ether (boiling range 40-60° C.), 12.5 g of NaCl-25%, and 10 g of demi-water. The pH was adjusted with KOH-45% to 13.5 at a temperature of 5-8° C. Then 19.1 g (0.117 mole; 2.2 eq.) of 2-ethylhexanoyl chloride were dosed in 25 minutes simultaneously with the lye, with the pH kept at >13.5. The mixture was stirred for another 90 minutes at 2-4° C. After separation of the water, layer 25 g of isododecane were added, and the organic layer was washed with NaOH-4N and NaHCO3-6%. The product was dried over magnesium sulphate and evaporated. Yield: 42.3 g of product with an active oxygen content of 3.22% (chemical yield:80%). Ratio mono:bis=20:80.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([Cl:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:41][N:40]=[N:39][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([Cl:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(Cl)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][C:4]([N:6]([CH3:23])[C:7]1[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1)=[O:5].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:13][C:11]1[CH:12]=[C:7]([N:6]([CH3:23])[C:4](=[O:5])[CH2:3][N:2]([CH3:24])[CH3:1])[CH:8]=[CH:9][C:10]=1[O:21][CH3:22]
Reactant: COc1ccc(N(C)C(=O)CN(C)C)cc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N(C)C(=O)CN(C)C)cc1N
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of 1,1-dimethylethyl [5-[(N,N-dimethylglycyl)(methyl)amino]-2-(methyloxy)phenyl]carbamate (2.01 g, 5.96 mmol) in 1,4-dioxane (40 ml) was treated with 4.0M HCl in dioxanes (7.45 ml, 29.8 mmol) and stirred for 3 hours. Additional 4.0M HCl in dioxanes (7.45 ml, 29.8 mmol) was added and the reaction was stirred for 16 hours. The solution was poured into ethyl acetate, diluted with water, and neutralized by careful addition of solid potassium carbonate. The aqueous layer was washed with chloroform and the organic layers were combined, dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford N1-[3-amino-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (1.19 g, 5.01 mmol, 84% yield) as a tan oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.78 (d, J=8.2 Hz, 1 H), 6.48 (d, J=2.4 Hz, 1 H), 6.41 (d, J=8.2 Hz, 1 H), 4.91 (br. s., 2 H), 3.77 (s, 3 H), 3.05 (s, 3 H), 2.82 (s, 2 H), 2.12 (s, 6 H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:29]1[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)c1cc2ncnn2nc1Cl
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
160 mg of 60% sodium hydride in oil was suspended in 20 ml of tetrahydrofuran; 1.20 g of 4-(diphenylmethyl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine was added, followed by heating and refluxing for 1 hour. After cooling, 610 mg of 6-chloro-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 1 hour. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 790 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[CH2:17][CH2:16][CH:15]2[CH:7]([NH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6]1)[CH3:4].[C:18](O)(=O)[CH3:19]>>[CH2:3]([N:5]1[CH2:17][CH2:16][CH:15]2[CH:7]([N:8]([CH2:18][CH3:19])[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6]1)[CH3:4]
Reactant: CCN1CCC2c3ccccc3NC2C1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCC2c3ccccc3N(CC)C2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NaBH4 (1.08 g) was added under ice-cooling to a solution of 2-ethyl-1,2,3,4,4a,9a-hexahydro-pyrido[3,4-b]indole (1.16 g) in 40 ml of acetic acid. After stirring the solution at room temperature for 4 hrs, additional NaBH4 (0.54 g) was added and the mixture was stirred for 3 hrs. After removal of acetic acid by evaporation, the residue was neutralized with ammonia, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was evaporated off, thereby affording 1.26 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH2:12]([O:14][P:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:13]>C(OCC)(=O)C>[Cl-:1].[CH2:12]([O:14][P+:15]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:8]=[O:9])[CH:10]=1)[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: O=Cc1cc(CCl)ccc1O
Solvent: CCOC(C)=O
Product: CCO[P+](Cc1ccc(O)c(C=O)c1)(OCC)OCC
Product: [Cl-]
Temperature: 80 °C

Procedure:
A 100-mL round-bottom flask was charged with 5-chloromethyl-2-hydroxybenzaldehyde (10.3327 g, 60.4 mmol) and dissolved in ethyl acetate (40 mL) and triethylphosphite (11.5 mL, 67 mmol) was added. The mixture was heated at reflux (80° C.) for 3 hours. The mixture was cooled to room temperature and the solvent removed under reduced pressure to give triethoxy(3-formyl-4-hydroxybenzyl)phosphonium chloride as a viscous oil which was used without further purification. The viscous oil (10.003 g, 30 mmol) was dissolved in ethanol (40 mL) and ethylenediamine (1.2 mL, 18 mmol) was added slowly. The mixture was heated at reflux (80° C.) for 3 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to give a thick, yellow, oily substance. The oil was washed with ether (3×10 mL). The ether was evaporated slowly over 24 hours to produce a thick, yellow, viscous oil (10.2215 g, 98%) in ˜85% purity based on 1H NMR spectroscopy.
Reaction SMILES: C(O)(=O)C.C([O:7][C:8]([CH:10]1[CH2:29][C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][C:20]=3[C:12]=2[CH2:11]1)=[O:9])C>O>[C:23]1([CH2:22][O:21][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:29][CH:10]([C:8]([OH:9])=[O:7])[CH2:11][C:12]=4[C:20]=3[CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 100 ml of 80% acetic acid in water, was added 1,2,3,4-tetrahydro-7-phenylmethoxycyclopent[b]indole-2-carboxylic acid ethyl ester (10 g, 0.03 mole). After stirring at 100° C. for four hours, the mixture was cooled, poured into 500 ml of water, stirred for five minutes, and extracted with ethyl acetate (3×). The organic layer was washed successively with water and saturated sodium chloride solution, and thereafter dried over anhydrous MgSO4. After filtering, the solution was concentrated to a dark oil (~10 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to a tan solid, 1.3 g, m.p. 160°-162° C. This material was recrystallized from ether to give the product as a tan solid, 1.0 g, m.p. 161°-163° C.
Reaction SMILES: [CH3:1][C:2]([S:32][C:33]([C:46]1C=CC=C[CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:31])[C@H:3]([NH:13][C:14](=[O:30])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4](=[O:12])[NH:5][CH2:6][CH2:7]CCC=O.C(Cl)Cl.C(O)(C(F)(F)F)=O>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[S:32][C@H:33]2[CH2:46][CH2:47][CH2:7][CH2:6][N:5]2[C:4](=[O:12])[C@H:3]1[NH:13][C:14](=[O:30])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCC=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)S[C@H]2CCCCN2C(=O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a round bottom flask was added (R)-(9H-fluoren-9-yl)methyl 3-methyl-1-oxo-1-(5-oxopentylamino)-3-(tritylthio)butan-2-ylcarbamate (35 mg, 0.050 mmol), DCM (1 mL) and TFA (0.077 mL, 1.0 mmol). The reaction mixture was stirred at rt for 15 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (9H-fluoren-9-yl)methyl (3R,9aS)-2,2-dimethyl-4-oxooctahydropyrido[2,1-b][1,3]thiazin-3-ylcarbamate (12 mg, 0.027 mmol, 55% yield) as a white solid. Anal. Calcd. for C25H28N2O3S m/z 436.3. found: 437.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.78 (d, J=7.15 Hz, 2H), 7.63 (t, J=6.60 Hz, 2H), 7.41 (td, J=7.42, 3.30 Hz, 2H), 7.33 (t, J=7.42 Hz, 2H), 5.84 (d, J=8.80 Hz, 1H), 4.90 (dd, J=8.80, 3.85 Hz, 1H), 4.63 (d, J=8.80 Hz, 1H), 4.54-4.35 (m, 2H), 4.26 (t, J=7.15 Hz, 1H), 4.16-3.99 (m, 1H), 3.22 (ddd, J=13.06, 8.39, 4.40 Hz, 1H), 2.00 (dt, J=8.80, 4.40 Hz, 1H), 1.93-1.81 (m, 1H), 1.80-1.67 (m, 3H), 1.62-1.52 (m, 1H), 1.39-1.24 (m, 3H), 1.19 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: CC(C)N1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C(C)C)CC5)c34)cc2Cl)cn1
Yield: 71 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-isopropylpiperazine to give the title compound in 71% yield; NMR Spectrum: 0.91 (d, 6H), 2.39 (br s, 4H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.55 (m, 1H), 2.78 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.25 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[OH:43][C:44]1[CH:56]=[CH:55][C:47]2[O:48][C:49]([C:52](O)=[O:53])=[CH:50][O:51][C:46]=2[CH:45]=1>CN(C)C=O>[OH:43][C:44]1[CH:56]=[CH:55][C:47]2[O:48][C:49]([C:52]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:53])=[CH:50][O:51][C:46]=2[CH:45]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C1=COc2cc(O)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, add 5.5 mmol of 1-[bis(4-fluorophenyl)methyl]piperazine, 5.5 mmol of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and 5.5 mmol of HOBt (hydroxybenzotriazole) in succession to a solution at 0° C. of 5 mmol of 6-hydroxy-1,4-benzodioxin-2-carboxylic acid in 25 cm3 of N,N-dimethylformamide. Stir for 2 hours at 0° C. and then for 12 hours at room temperature, and concentrate the reaction mixture under reduced pressure. Extract the resulting amide with diethyl ether and then, after concentration to dryness, purify the crude product by chromatography on a silica column (eluant: petroleum ether then an increasing gradient of ethyl acetate in petroleum ether). 6-Hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 85%. The product obtained is precipitated from 10 ml of pentane and is then filtered and recrystallised from cyclohexane. Melting point: 163° C. ##STR58##
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:8][C:9]([NH:21][C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[CH:19][N:18]=2)=[O:11])[CH:7]=1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: Cc1ccnc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccnc(NC(=O)Cn2cc(C)c(=O)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (75 mg, 0.4 mmol), 4-methylpyridin-2-amine (44 mg, 0.4 mmol), HBTU (151 mg, 0.4 mmol) and 0.1 mL of Et3N in DMF (5 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 10.97 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.58 (s, 2H), 2.33 (s, 3H), 1.77 (s, 3H). [M+H] calc'd for C13H14N4O2, 275; found, 275.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].[CH3:13][NH:14][NH2:15].Cl.C(Cl)Cl>CCO.O>[CH3:13][N:14]1[C:6]([NH2:7])=[CH:5][C:4]([C:3]([CH3:10])([CH3:9])[C:2]([F:1])([F:11])[F:12])=[N:15]1
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: CNN
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (1 g, 5.58 mmol) in EtOH (10 mL) was added methylhydrazine (3.33 g, 28.9 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (40% EA: 60% PE, 12 g silica column). All fractions found to contain product by TLC (EA:PE=1:2, Rf=0.2) were combined and concentrated to yield a white solid of 1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.293 mmol, 41.1% yield): 1H NMR (400 MHz, CD3OD): δ 5.48 (s, 1H), 3.56 (s, 3H), 1.42 (s, 6H). ES-LCMS m/z 208 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[C:46](Cl)=[O:47]>>[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[C:46]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:47]
Reactant: O=C(Cl)c1cnccn1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cnccn3)CN2C1=O
Yield: 52.5 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and pyrazinecarbonyl chloride (75 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 62 mg (52%) of 18-(pyrazinecarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.8% pure (HPLC), MS m/z 673 (M−H)−, HRMS: calcd. 675.2812 and found 675.2792 (M+H)+, mp 150-152° C.
Reaction SMILES: [N+:1]([C:4]1C=CC=CC=1)([O-])=O.[CH3:10][NH2+:11](=S)[CH3:12].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C]=[O:21]>>[CH3:10][N:11]([CH3:12])[C:4]([NH:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: [C]=O
Reactant: c1ccccc1
Product: CN(C)C(=O)Nc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A 1/2-liter autoclave was charged with nitrobenzene (30.0 g.), dimethylammonium sulphide (40 g.) benzene (60 g.) and carbon monoxide to a pressure of 50 atmospheres. The temperature of the autoclave was raised to 110° C and its contents were maintained at this temperature with stirring for 21/2 hours. The pressure was renewed to 50 atmospheres at intervals as required by passing in more carbon monoxide. The contents of the autoclave were then allowed to cool below 70° C before being removed and distilled to separate the volatiles, which included unreacted nitrobenzene. The residue, weighing 16 g., was recrystallised from a mixture of benzene and 60-80 petroleum ether to give 1,1-dimethyl-3-phenylurea (12.3 g.).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2)C1C=CC=CC=1>CO.C(O)C.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cc2c(O)cc(C)cc2[nH]1

Procedure:
11.0 g of the thus obtained 4-benzyloxy-2-ethoxycarbonyl-6-methyl indole are suspended in 150 ml methanol and, after addition of a suspension of 1.0 g, 10% Pd/C in 20 ml ethanol hydrogenated at normal pressure in a duck-shaped shaking vessel. The catalyst is aspirated and the filtrate is evaporated. There is obtained pure 4-hydroxy-2-ethoxycarbonyl-6-methylindole in virtually quantitative yield.