Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH2:6][C:5](=O)[CH2:4][O:3]1.S(=O)(=O)(O)O.[NH3:16]>C(O)C>[NH2:16][C:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: N
Reactant: CC1(C)OCC(=O)CC1=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1(C)OCC(N)=CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 66C (1.5 g, 11 mmol) in ethanol (40 mL) was treated with concentrated sulfuric acid (0.4 mL), refluxed for 4 hours, cooled to ambient temperature, treated with 2M ammonia in ethanol (50 mL), stirred at ambient temperature for 16 hours and concentrated. The residue was purified by chromatography on silica gel eluting with 10% methanol in dichloromethane to provide the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14].[OH-].[Na+]>O>[CH2:13]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:12][CH:11]=1)[CH3:14]
Reactant: CCO
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(N)cc1
Yield: 78 %

Procedure:
32.6 parts of 4-amino-cinnamic acid are heated under reflux for three hours in a mixture comprising 100 parts of absolute ethyl alcohol and 20 parts of 66°Be sulphuric acid. The product is poured on to 200 parts of water and 200 parts of ice, made alkaline to pH 8 by the addition of 38 parts of a 35° Be solution of sodium hydroxide, and the solid is filtered off, washed with water and recrystallised from 150 parts of ethyl alcohol and 150 parts of water. Ethyl-p-amino-cinnamate is thus obtained. Yield 78% M.p. 68°-69° C.
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[Si:20]([NH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](NCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzenemethanamine (21.8 mL, 0.20 mol) and triethylamine (41.2 mL, 0.30 mol) in acetonitrile (400 mL) was added dropwise t-butylchlorodiphenylsilane (52 mL, 0.20 mol). The mixture was stirred at room temperature for 3 hours and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in a 4:1 mixture of ether/hexane and washed sequentially with H2O, saturated NaHCO3 solution and H2O. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave an oil which was distilled under high vacuum. The major fraction consisting of the pure product (45.9 g, 66%) distilled from 140° to 160° C. at about 0.1-0.2 mm Hg and crystallized on standing at room temperature, m.p. 34°-36° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[F:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(F)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 17.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-fluorobenzenesulfonyl chloride (0.0280 mL, 0.195 mmol) to obtain 4-(3-chloro-4-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.00740 g, yield 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[C:25](O)(=[O:27])C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9])[CH:25]=[O:27]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Cl)c(O)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 84 %

Procedure:
A 250 ml three neck round bottom flask fitted with reflux condenser, pot thermometer and mechanical stirrer, was charged with 10 g (0.061 mol) of 2,6-dichlorophenol, 40 ml glacial acetic acid and 3.44 g (0.024 mol) of hexamethylenetetramine. The reaction mass was heated at reflux for 3 hrs (a clear solution was obtained at 70° C.). The progress of reaction was checked by TLC. The mixture was allowed to cool at 100° C.; 30 ml of 10% sulphuric acid were slowly added and stirred at 100° C. for 20-30 min. The reaction mass was poured into 200 g crushed ice. The solid was filtered and washed well with 100 ml water and drying at 70° C. afforded 9.2 g (84%) of 3,5-dichloro-4-hydroxy-benzaldehyde. Melting point: 153-155° C. 1H NMR (400 MHz, CD3OD) δ 9.72 (s, 1H), δ 7.80 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=O)[CH3:2].[Cl:16][C:17]1[S:21][C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27][NH:28][NH2:29])[CH:23]=2)=[CH:19][CH:18]=1>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:28]([CH2:27][C:24]2[CH:23]=[C:22]([C:20]3[S:21][C:17]([Cl:16])=[CH:18][CH:19]=3)[O:26][N:25]=2)[N:29]=1)=[O:15])[CH3:2]
Reactant: NNCc1cc(-c2ccc(Cl)s2)on1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1

Procedure:
A solution of 550 mg 4-Furan-2-yl-2,4-dioxo-butyric acid ethyl ester and 601 mg [5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-hydrazine in 10 ml acetic acid was heated to 80° C. for 2 h. Then the reaction mixture was diluted with 20 ml water and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over MgSO4. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a n-heptane:ethyl acetate gradient 100%->50%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.CCN(CC)CC.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl.O.P>CN(C=O)C>[C:23]([O:22][C:20]([N:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH2:8][C:9]([OH:11])=[O:10])=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)CNC1CCOCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: P
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)O)C1CCOCC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
2-(tetrahydro-2H-pyran-4-ylamino)acetic acid (0.2 g, 1.256 mmol) F44 was dissolved in DMF (22.5 mL) and Et3N (2.5 mL, 17.94 mmol). After 5 minutes BOC2O (0.583 mL, 2.51 mmol) was added and the reaction solution was heated to 60° C. for 1 h. The reaction was concentrated by reduced pressure providing a light yellow oil to which was added 20 mL HCl H2O which was adjusted to PH3 at 0° C. and stirred for 10 minutes. The reaction mixture was extracted by ethyl acetate 3×20 mL, dried (MgSO4), filtered, and concentrated to dryness. Ether was added and the mixture was sonicated and filtered providing a white solid F45 2-(tert-butoxycarbonyl(tetrahydro-2H-pyran-4-yl)amino)acetic acid (0.14 g, 0.540 mmol, 43.0% yield).
Reaction SMILES: C(OC(=O)C1C=CC(NC(=O)C(N2C3C=C(F)C(F)=CC=3N=C2C2C=CC(Cl)=CC=2)C2CCCCC2)=CC=1)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:51]([CH:52]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[C:53](O)=[O:54])[C:50]3[CH:62]=[C:63]([F:67])[C:64]([F:66])=[CH:65][C:49]=3[N:48]=2)=[CH:43][CH:42]=1.[CH3:68][O:69][C:70](=[O:81])[C:71]1[CH:76]=[C:75]([F:77])[C:74]([NH2:78])=[C:73]([C:79]#[N:80])[CH:72]=1>>[CH3:68][O:69][C:70](=[O:81])[C:71]1[CH:76]=[C:75]([F:77])[C:74]([NH:78][C:53](=[O:54])[CH:52]([N:51]2[C:50]3[CH:62]=[C:63]([F:67])[C:64]([F:66])=[CH:65][C:49]=3[N:48]=[C:47]2[C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=2)[CH:56]2[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]2)=[C:73]([C:79]#[N:80])[CH:72]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1cc(F)c(N)c(C#N)c1
Agent: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)c1cc(F)c(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C#N)c1

Procedure:
The title compound was prepared in analogy to example 22, intermediate d), from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-cyano-5-fluoro-benzoic acid methyl ester (Arzneimittel Forschung, 34(II), Nr. 11a, 1984; 1612-1624) to give the product as a light brown solid (20%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2o1
Yield: 85 %

Procedure:
A solution of 6-fluoro-2(3H)-benzoxazolone (1.0 g) in 80% aqueous sulfuric acid (6.5 g) was cooled to 0° to 5° C., and 60% nitric acid (0.8 g) was gradually added thereto at 0° to 5° C. The resultant mixture was stirred at the same temperature for 30 minutes and poured onto ice water. The precipitated crystals were collected by filtration, washed with water and dried to give 6-fluoro-5-nitro-2(3H)-benzoxazolone (1.1 g). m.p., 175.4° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O.O>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:3][CH2:2]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCBr
Reactant: Oc1cccc(C2CCNCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(c2cccc(O)c2)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 3-(4-piperidinyl)phenol (Preparation 47, 376 mg, 2.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydrogen carbonate (267 mg, 3.18 mmol) and 1-bromohexane (0.36 ml, 2.55 mmol). The reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then diluted with water (20 ml) and extracted with diethyl ether (3×10 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil which was not purified further (500 mg, 89%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].ClC1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.NC[CH2:72][N:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH2:72][N:73]4[CH2:78][CH2:77][O:76][CH2:75][CH2:74]4)=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Reactant: NCCN1CCOCC1
Agent: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(NCCN3CCOCC3)nc2s1
Yield: 34 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.061 mmol, 30 mg) and 4-(2-aminoethyl)morpholine (1.531 mmol, 201 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(2-morpholinoethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96e (12 mg, 34%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.24 (s, 3H), 2.46 (br s, 4H), 2.56 (br s, 2H), 3.50 (br s, 2H), 3.60 (br s, 4H), 7.28 (d, J=8.6 Hz, 1H), 7.61 (m, 2H), 7.75 (m, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.18 (s, 1H), 8.25 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=584 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1
Reactant: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCNCC3)c2)ccn1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCN(C)CC3)c2)ccn1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid piperidin-4-ylamide (36 mg, 0.085 mmol, Example 181) was dissolved in tetrahydrofuran (2.0 ml) and methanol (1.0 ml); and a 37% aqueous formaldehyde solution (0.036 ml, 0.43 mmol) and acetic acid (0.0098 ml, 0.17 mmol) were added thereto. While stirring at room temperature, sodium triacetoxyborohydride (27 mg, 0.13 mmol) was added; and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (25 mg, 0.057 mmol, 67%) as colorless crystals.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:12])(=[O:11])[CH3:10]>>[C:3]1([CH:2]2[O:12][C:9](=[O:11])[CH2:10][CH2:1]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: C=Cc1ccccc1
Product: O=C1CCC(c2ccccc2)O1
Temperature: 110 °C
Yield: 70 %

Procedure:
Styrene in the amount of 20 grams was dissolved in 100 milliliters of acetic acid containing 10% potassium acetate. Ceric acetate in the amount of 0.005 mole was added and the reaction mixture was heated in a sealed tube at 110° C. overnight. The lactone, gamma-phenyl butyrolactone, was obtained in 70% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([CH3:38])[CH:36]=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:34][CH:35]([CH3:38])[CH3:36])[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 409.2858, C26H37N2O2 requires 409.2855; LC-MS: (M+H)+ 409.2, tr 5.97 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15](=[NH:18])OC)[CH:6]=1)[CH3:3].[Cl-:19].[NH4+:20]>C(O)C>[ClH:19].[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15]([NH2:18])=[NH:20])[CH:6]=1)[CH3:3]
Reactant: [Cl-]
Reactant: COC(=N)CCSCc1cc(CN(C)C)ccn1
Reactant: [NH4+]
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCC(=N)N)c1
Product: Cl
Yield: 24.5 %

Procedure:
Methyl 3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate (8.68 g), ammonium chloride (1.74 g) and ethanol (60 ml) were stirred at room temperature for 4 hours. Ethanol was evaporated at reduced pressure and the residue chromatographed using silica gel and a chloroform-methanol gradient elution. Fractions containing the required product (as shown by TLC) were combined and solvent evaporated at reduced pressure to give 3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionamidine hydrochloride (2.30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:14]=1)[CH:12]=[O:13].P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:14]=1)[C:12]([OH:34])=[O:13]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Yield: 89.8 %

Procedure:
To a solution of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (5.60 g, 0.0128 mol) in acetonitrile (30.0 ml) were added an aqueous solution (10.0 ml) of sodium dihydrogen phosphate (12.0 g, 0.100 mol), an aqueous solution (30.0 ml) of sodium hypochlorite (5.19 g, 0.0577 mol) and an aqueous hydrogen peroxide (1.701 ml, 30%) and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (5.20 g, 0.0115 mol, 90%).
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:20]([OH:24])(=[O:23])(=[O:22])=[O:21]>C(O)C>[Cl:20]([O-:24])(=[O:23])(=[O:22])=[O:21].[CH3:12][C:11]1([CH3:16])[C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=[CH:18][C:9]=2[N+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:10]1[CH3:9]
Reactant: NN(c1ccccc1)c1ccc2ccccc2c1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: Cl
Solvent: CCO
Product: CC1=[N+](c2ccccc2)c2ccc3ccccc3c2C1(C)C
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
N-Phenyl-N-(2-naphthyl)hydrazine (2.3 g) (or hydrochloride (2.7 g)) was dissolved in 50 ml of ethanol and 10 g of 3-methyl-butanone-2 was added. To this mixture 10 ml 70% perchloric acid was added slowly with stirring at room temperature. Stirring was continued for one hour at 80-90° C. and after cooling down, the resultant precipitate was filtered off and washed with ethanol to provide 0.6 g (16%) 1,1,2-trimethyl-3-phenyl-1H-benzo[e]indolium perchlorate as a yellow solid, which was sufficiently pure for the next synthetic step. 1H NMR (400 MHz, TFA) δ 8.05 (d, 1H, J=8.5), 7.86 (t, 2H, J=7.6), 7.62 (dd, 4H, J=6.8, 13.4), 7.52 (t, 1H, J=7.6), 7.37 (d, 2H, J=7.3), 7.00 (d, 1H, J=8.9), 2.58 (s, 3H), 1.81 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]\[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]\[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:37]=[CH:38][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:40][CH:41]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(C(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2csc(C(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.11 g), tetrahydrofuran (2 mL) and ethanol (0.64 mL) was added 1N aqueous sodium hydroxide solution (0.60 mL), and the mixture was stirred at 50° C. for 3 hrs. To the reaction mixture were added 1N hydrochloric acid (0.60 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.10 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 156-157° C.
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[CH3:58])[CH:53]([NH:59][C:60](=[O:74])[CH2:61][C:62]2[N:63]=[C:64]([C:67]4[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][N:68]=4)[S:65][CH:66]=2)[C:52]3=[O:75])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:73][C:72]1[C:67]([C:64]2[S:65][CH:66]=[C:62]([CH2:61][C:60]([NH:59][CH:53]3[C:52](=[O:75])[N:51]4[CH:54]3[S:55][CH2:56][C:57]([CH3:58])=[C:50]4[C:48]([OH:49])=[O:47])=[O:74])[N:63]=2)=[N:68][CH:69]=[CH:70][CH:71]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(-c4ncccc4O)n3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ncccc4O)n3)C2SC1
Yield: 92.8 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8l (167 mg, 0.279 mmol), Et3SiH (0.446 mL, 2.79 mmol), and trifluoroacetic acid (0.860 mL, 11.2 mmol) in dry ClCH2CH2Cl (6 mL) am 0° C. under nitrogen to give 9l (112 mg, 93%) as a yellowish solid after crystallization from THF/CH2Cl2 /hexane. mp 180° C. (dec); IR (KBr) 3540-2540 (br), 3280, 1774, 1725, 1661 cm-1 ; 1H NMR (DMSO-d6) δ1.97 (3H, s, CH3),3.30 (1H, d, J=18.0Hz), 3.51 (1H, d J=18.0 Hz), 3.79 (2H, s, CH2), 4.99 (1H, d, J=4.6 Hz), 5.56 (1H, dd, J=8.1 and 4.6 Hz), 7.37 (1H, dd, J=8.4 and 4.3 Hz), 7.44 (1H, dd, J=8.4 and 1.0 Hz), 7.58 (1H, s), 8.14 (1H, dd, J=4.3 and 1.0 Hz), 9.11 (1H, d, J=8.1 Hz, NH), 11.64 (1H, s, OH), 13.12 (1H, br s, CO2H); FDMS m/z 432 (M+), 433 (M+ +1); Anal. Calcd for C18H16N4O5S2 : C, 49.99; H, 3.73; N, 12.95. Found: C, 50.24; H, 3.58; N, 12.68.