Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[CH2:12]1[O:15][CH:13]1[CH3:14]>>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][N:5]([CH2:12][CH:13]([OH:15])[CH3:14])[CH2:4][CH2:3][N:2]([CH3:11])[CH3:1]
Reactant: CN(C)CCNCCN(C)C
Reactant: CC1CO1
Product: CC(O)CN(CCN(C)C)CCN(C)C
Temperature: 120 °C
Reaction time: 22 h

Procedure:
N,N,N",N"-Tetramethyldiethylenetriamine (TMDETA, 24.96 g, 157.2 mmole) and propylene oxide (PO, 9.1 g, 157.0 mmole) were charged to a 50 mL autoclave. The reactor was sealed, the contained air was replaced with nitrogen, the reactor was pressured to 100 psi (689 kPa) with nitrogen, and the contents were heated to 120° C. Analysis of samples withdrawn after 6 and 22 hours showed that little change in composition had occurred after the first 6 hours. After 22 hours, the reaction mixture was cooled to ambient temperature and the product was removed. GC analysis of the crude product showed that it contained 4.8% unreacted TMDETA and 82.3% TMHPDETA.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:23]C(=O)C)=[N:10][C:11]2[CH:12]=[CH:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[NH2:23][C:9]1[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17][C:16]2[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(=O)Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Solvent: CO
Product: Nc1nc2ccc3cc(O)ccc3c2nc1Cc1ccccc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A solution of the obtained crude product of N-(2-benzyl-8-hydroxybenzo[f]quinoxalin-3-yl)acetamide (13) in methanol (20 mL) was heated to 65° C. and stirred overnight (14 hours). After cooling to room temperature, the solution was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=1/1→1/10) to give 3-amino-2-benzylbenzo[f]quinoxalin-8-ol (14, ν-coelenteramine) (51.3 mg, 170 mmol, quant., two steps) as an ocherous solid. TLC Rf=0.34 (n-hexane/ethyl acetate=1/1); 1H NMR (500 MHz, CD3OD) δ 4.33 (s, 2H), 7.16-7.20 (m, 2H), 7.21-7.26 (m, 1H), 7.30-7.38 (m, 5H), 7.50 (d, 1H, J=9.0 Hz), 7.76 (d, 1H, J=9.0 Hz), 8.77 (d, 1H, J=9.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: O=C(c1ccc([N+](=O)[O-])c(F)c1)N1CCCC1
Solvent: CO
Product: Nc1ccc(C(=O)N2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
515.0 mg (2.16 mmol) (3-Fluoro-4-nitro-phenyl)-pyrrolidin-1-yl-methanone were dissolved in 20 mL MeOH. The solution was evacuated and rinsed with argon several times. 150 mg palladium on charcoal (10%) were added and again the mixture was evacuated and rinsed with argon several times. Finally argon was exchanged by hydrogen (balloon filled with hydrogen) and the mixture was stirred for 2 h at room temperature. The reaction mixture was filtered over “Celite” and the filter residue was washed with 30 mL MeOH. The filtrate was concentrated under vacuo to give pure (4-Amino-3-fluoro-phenyl)-pyrrolidin-1-yl-methanone as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[OH:12].CN(C)C=[O:16]>C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[CH3:1][O:2][C:3]1[C:4](=[O:12])[CH:5]=[C:6]([CH3:11])[C:7](=[O:16])[C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1cc(C)cc(O)c1OC
Agent: [Co+2]
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(C)=CC1=O

Procedure:
To a dimethylformamide solution (30 ml) of 2,3-dimethoxy-5-methylphenol (3 g) is added bis(salicylidene)ethylenediiminocobalt(II) (35 mg) and the mixture is reacted and worked up in the same manner as Example 7. The resultant crude crystals are recrystallized from hexane. The above procedure yields 2,3-dimethoxy-5-methyl-1,4-benzoquinone (2.13 g) as orange-yellow needles melting at 59° C.-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:26])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:12]=1)[C:5]#[N:6].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[Cl:26][C:8]1[CH:7]=[C:4]([C:5]2[NH:29][N:28]=[N:27][N:6]=2)[CH:3]=[C:2]([Cl:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:12]=1
Reactant: N#Cc1cc(Cl)c(Oc2ccc(O)c(C(=O)N3CCCCC3)c2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=C(c1cc(Oc2c(Cl)cc(-c3nnn[nH]3)cc2Cl)ccc1O)N1CCCCC1

Procedure:
{5-[2,6-Dichloro-4-(1H-tetrazol-5-yl)-phenoxy]-2-hydroxy-phenyl}-piperidin-1-yl-methanone was prepared from 3,5-dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-benzonitrile according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (2.0 equiv) and ammonium chloride (2.0 equiv) were used initially, and the reaction mixture was heated to reflux for 2 hours, after which additional sodium azide (2.0 equiv) was added, and the reaction was heated to reflux for 20 hours. After the reaction had been acidified and the crude product collected by filtration, then purified by preparative TLC (methanol:water:dichloromethane 20:3:77) to afford the title product of Example 3. MS (APCI+) Calc.: 433.0, Found: 434.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][C:19]4[N:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.Cl.[O:30]([NH2:32])[CH3:31]>C(O)C.O>[CH3:31][O:30][N:32]=[CH:25][C:22]1[CH:23]=[N:24][C:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][C:9]3[C:10]4[C:2]([Cl:1])=[CH:3][S:4][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:28][CH:27]=2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)nc1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCO
Product: CON=Cc1ccc(Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)nc1
Yield: 77 %

Procedure:
A solution of 6-{4-[2-(5-Chlorothieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenoxy}pyridine-3-carbaldehyde (0.2 g, 0.5 mmol) and methoxylamine hydrochloride (0.2 g, 2.5 mmol) in ethanol (10 mL) was heated at reflux for 1 hour. After cooling, the reaction was diluted with water and the solid collected by filtration and air dried affording product, 0.17 g, 0.4 mmol, 77 percent yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>O1CCCC1>[CH:22]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]3[N:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:13]=[C:14]([CH3:15])[C:3]=23)[CH2:24][CH2:23]1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(NC3CC3)c12
Temperature: 100 °C

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.7 g, 2.37 mmol) and cyclopropylamine (0.7 g, 73.6 mmol) in tetrahydrofuran (20 mL) was heated under reflux at 100° C. overnight in a sealed stainless tube. The solution was cooled to room temperature, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=93:7) to give N-cyclopropyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine. To a solution of the compound above in ethanol (10 mL), a saturated hydrochloric acid/ethanol solution (10 mL) was added and the solvent was evaporated under reduced pressure. The residue thus obtained was recrystallized from methanol/ethyl acetate to give the title compound (0.52 g, 56% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:41])[N:18]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]3=[O:35])[CH2:25]4)[C:17](=[O:40])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1>CO.[Pd]>[F:8][C:6]1[CH:5]=[C:4]([C@@:9]2([CH3:41])[N:18]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[C:24]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C@:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]3=[O:35])[CH2:25]4)[C:17](=[O:40])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1C/C=C/c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1CCCc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21

Procedure:
5-{(1E)-3-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]prop-1-en-1-yl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (the first eluting peak of Example 1) (32 mg, 0.058 mmol) was dissolved in 1 mL of methanol and hydrogenated using an H-Cube apparatus and 10% Palladium on carbon cartridge while eluting with 10% acetic acid in methanol. The reaction was concentrated in vacuo and partitioned between ethyl acetate and 10% sodium bicarbonate. The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and conc in vacuo to yield the title compound MS: m/z=557 (M+1), HRMS: m/z=557.2713 (M+1); calculated m/z=557.2723 (M+1) for C33H35F2N4O2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[F:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:49]4[CH:48]=[N:47][N:46]([CH2:45][C:44]5[CH:60]=[CH:61][CH:62]=[C:42]([F:41])[CH:43]=5)[CH:50]=4)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 93.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(2-fluoro-4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67) (250 mg, 0.370 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (168 mg, 0.555 mmol) using Pd(DPPF)Cl2 (14 mg, 0.018 mol) and sodium carbonate (118 mg, 1.110 mmol) in toluene/ethanol/water (5/5/1 ml) to afford 250 mg (93.2% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=724.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2ccc([N+](=O)[O-])cc2C)c1
Reaction time: 18 h
Yield: 90.1 %

Procedure:
A solution of 2-bromo-5-nitrotoluene (40.0 gm, 185 mmol) in 1,2-dimethoxyethane (600 mL) was added to tetrakis(triphenylphosphine)palladium(0) (9.77 gm, 9.25 mmol) under nitrogen at room temperature. A solution of 3-methoxyphenylboronic acid (31.5 gm, 207 mmol) in ethanol (150 mL) was added. Finally, 2M aqueous sodium carbonate (800 mL) was added and the mixture was heated under reflux with rapid mechanical stirring for 18 h. After being cooled, the mixture was partitioned between ethyl acetate and water and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel eluting with hexane:ethyl acetate=98:2 then 95:5 gave 1-(3-methoxyphenyl)-2-methyl-4-nitrobenzene (40.55 gm, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@H:27]([S:38][CH3:39])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41].[OH:42]OS([O-])=O.[K+].C(O)(C(F)(F)F)=O.C(Cl)Cl>C1COCC1.O.CCOC(C)=O>[NH2:30][C@H:28]1[C@H:27]([S@:38]([CH3:39])=[O:42])[C@@H:26]([CH3:40])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:41])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29]1
Reactant: CS[C@@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@@H]1[S@](C)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a solution of tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylthio)cyclohexylcarbamate (1.0 equiv.) in THF (0.05 M) in a 0° C. bath was added the oxone (1.0 equiv.) as a solution in H2O. The solution was left stirring at 0° C. for 5 mins. The solution was diluted with EtOAc, washed with H2O, NaCl(sat.), dried over MgSO4, filtered, concentrated to yield Boc protected product. The material was treated with 25% TFA/CH2Cl2 for 30 minutes, at which time the volatiles were removed in vacuo, the residue was dissolved in DMSO and purified by reverse phase HPLC. The product fractions were lyophilized directly to yield N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-((S)-methylsulfinyl)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 33% yield, LC/MS=503.2 (MH+), Rt=0.58 min; and N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-((R)-methylsulfinyl)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 37% yield. LC/MS (m/z)=503.2 (MH+), Rt=0.60 min.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoic acid, 0.05 g of 5% palladium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : % C, 70.6; % H, 7.6; % N, 3.9; Found: % C, 71.0; % H, 7.6; % N, 4.1.
Reaction SMILES: [C:1]1(/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:1]1(/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:8]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:28])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C(=C/c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1
Yield: 84.2 %

Procedure:
To a solution of (2E)-2,3-diphenylacrylic acid (0.32 g, 1.4 mmol) (prepared according to procedure given in example 1) in DMF (5 mL) was added Methyl-7-aminoheptanoate (0.25 g, 1.3 mmol), EDCI (0.55 g, 2.8 mmol) and HOBt (0.19 g, 1.4 mmol). TEA (0.6 mL, 4.3 mmol) was added dropwise with constant stirring to the above reaction mixture and it was stirred for 2 hours at room temperature. Reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×100 mL). The organic layer was washed successively with water (3×50 mL), and brine solution (1×50 mL). The organic layer was dried over Na2SO4 and concentrated to afford the title compound (0.4 g, 61% yield).
Reaction SMILES: ClC1C=C(C2C=C(C(O)=O)OC=2C2C=CC=C(C#N)C=2)C=C(F)C=1.[Br:25][C:26]1[O:30][C:29]([C:31]([O:33]CC)=[O:32])=[CH:28][C:27]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1>>[Br:25][C:26]1[O:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][C:27]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Agent: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 20A starting with the compound from Example 18A. The crude product obtained after extraction is dried under high vacuum and reacted further without chromatographic purification. 47.0 mg (86% of theory) of the title compound are obtained.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]2[NH:30][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[N:27]=4)[N:22]=[CH:21][C:20]=3[O:19][CH2:18]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[CH3:32][O:31][C:26]1[N:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([C@H:14]3[CH2:15][CH2:16][C@H:11]([NH2:10])[CH2:12][CH2:13]3)[NH:30][C:29]2=1
Reactant: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](N)CC1)CO3
Temperature: 40 °C
Reaction time: 16 h

Procedure:
10% Palladium on activated carbon (285 mg, 2.68 mmol, 1.0 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester (1.20 g, 2.68 mmol, 1.0 eq) in methanol (80 mL) and tetrahydrofuran (8 mL). The resulting mixture is stirred under hydrogen flow (1 bar) at 40° C. for 16 hours. The catalyst is then removed by filtration and the solution is concentrated to afford trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexylamine as a yellow solid (620 mg, 74% yield) which is directly engaged in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[NH2:16][CH2:17][CH2:18][C:19]1C=C[C:23]([OH:24])=[C:21](O)[CH:20]=1.[ClH:27].O1C=CC=C1CCN>>[ClH:27].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:16][CH2:17][CH2:18][C:19]1[O:24][CH:23]=[CH:21][CH:20]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: NCCc1ccco1
Product: CC(=O)Nc1cccc2c1CCC(NCCc1ccco1)C2

Procedure:
Starting from 0.61 g (0.0031 mol) of 5-acetylamino-2-tetralone and 0.9 g (0.006 mol) of 2 (2-furyl)ethylamine-hydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 0.8 g (77.1% of theory) and with a melting point of 256° C., which increases to 257° C. after recrystallisation from methanol/ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO[CH:16](OC)[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]=[CH:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:9]2=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(F)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Fluoro-3-nitrophenyl isocyanate (0.45 ml) was added to a solution of (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (750 mg) in chloroform (10 ml). The reaction was shaken at 70° C. for 2 hours. A second portion of 4-fluoro-3-nitrophenyl isocyanate (0.45 ml) was added. After 16 hours at 70° C., volatiles were removed and TFA.(10 ml) was added. After shaking for 16 hours, volatiles were removed and the residue was purified by chromatography on silica gel (eluent: dichloromethane/hexane 8:1). The product with the molecular weight of 391.36 (C21 H14FN3O4); MS (ESI): 392 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C#N)cc1Cl
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 3-chloro-4-methoxybenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3-chloro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.