Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.Cl[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](CC)([O-])=O>[O:15]=[S:14]1(=[O:16])[C:3]2[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=2[NH:1][C:18](=[O:19])[NH:17]1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC[N+](=O)[O-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of N-(4-amino-phenyl)-methanesulfonamide (Example 3b′, 90.7 g, 0.49 mol) in nitroethane (900 mL) was added dropwise over 1.5 h to a mechanically stirred solution of chlorosulfonylisocyanate (50.6 mL, 0.54 mol) in nitroethane (150 mL) at −20° C. The resulting suspension was stirred at −20° C. for 30 min, then aluminum chloride (77.9 g, 0.58 mol) was added in one portion over 1 min. The resulting brown solution was warmed to 25° C., and then was heated at 110° C. for 1 h (considerable gas evolution was noted during this time). After cooling to −5° C., water (300 mL) was added dropwise via addition funnel over 15 min, followed by the rapid addition of more water (700 mL). The resulting suspension was allowed to warm to 25° C. and vigorously stirred for 30 min, and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with water (1×300 mL) and was air-dried to afford the desired product, N-(1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (115.2 g, 0.40 mmol, 81% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 3.00 (3H, s), 7.22 (1H, d, J=8.5 Hz), 7.46 (1H, dd, J1=8.8 Hz, J2=2.7 Hz), 7.51 (1H, d, J=2.4 Hz), 9.92 (1H, s), 11.20 (1H, s).
Reaction SMILES: C(O)(=O)C.O.[NH2:6]N.C[N:9]([CH:11]=[C:12]1[C:17](=O)[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]1=[O:21])C>C(O)CCC>[CH3:19][C:15]1([CH3:20])[CH2:16][C:17]2[NH:6][N:9]=[CH:11][C:12]=2[C:13](=[O:21])[CH2:14]1
Reactant: NN
Reactant: CN(C)C=C1C(=O)CC(C)(C)CC1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC1(C)CC(=O)c2cn[nH]c2C1
Yield: 38.9 %

Procedure:
According to Scheme 2 Step 2: At 0° C., acetic acid (8.55 mL) followed by hydrazine monohydrate (197 mmol, 11.3 mL), were added slowly to a solution of 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (197 mmol, 38.5 g) in butanol (400 mL). The reaction mixture was stirred under reflux for 16 hours. After evaporation of the filtrate, the crude residue was purified by flash chromatography over silica gel cyclohexane/AcOEt (100:0 to 50:50) and then over C18 gel using water/MeOH (100:0 to 50:50) as eluent to yield 6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (76.7 mmol, 12.6 g, 39%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:43])[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and tert-butyl-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate (18.6 mg, 0.064 mmol) were mixed in 0.3 ml DMF. Triethylamine (25.5 ml, 0.183 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 15.4 mg, yield 44% of the desired product.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([F:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][N:11]([CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20])[CH3:12].[Cl-:27].[NH4+]>CCOCC>[ClH:27].[CH3:12][N:11]([CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)[OH:20])[CH3:10]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: [Cl-]
Reactant: Fc1cccc(Br)c1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)c1cccc(F)c1
Product: Cl
Temperature: 25 °C
Yield: 54.8 %

Procedure:
0.87 g (36.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 4.02 ml (36.0 mmole) of 3-bromofluorobenzene dissolved in 30 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the mixture was stirred for a further hour at RT. 7.0 g (30 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ethers added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 9.27 g of crude base (93.6% of theory) were obtained. 6.04 g of 2-(dimethylaminophenyl-methyl)-1-(3-fluorophenyl)cyclohexanol, hydrochloride (54.8% of theory) were obtained from the crude base according to Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes when heated above 140° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(C)cccc4C)c3O2)cc1
Yield: 18 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.61 mmol) with 2,6-dimethylphenylboronic acid (0.783 g, 5.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.103 g, 0.131 mmol), and potassium carbonate (0.902 g, 6.52 mmol) generally according to the procedure described for Intermediate 37 provided 0.192 g (18%) of (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C24H24O4S: C, 70.56; H, 5.92. Found: C, 68.01; H, 5.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]2[OH:20].[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:20][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][C:8](=[O:13])[C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:22]1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc2oc(=O)c(-c3ccccc3)c(O)c2c1
Product: COc1ccc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c2c1
Yield: 67.5 %

Procedure:
This compound is obtained according to the method of Example 8 from 12.1 g. (0.045 mol) of 6-methoxy-3-phenyl-4-hydroxy-coumarin and 10.9 g. (0.057 mol) of 2-morpholino-1-chlorethane. After recrystallisation from isopropanol, 11.3 g. of a beige-coloured solid are obtained. M.P. 118° C.; yield 67.5% (theoretical yield 16.7 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH:12]([CH3:14])[CH2:11][C:8]4[C:7]5[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=4)[CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2occ(CC(C)N3CCN(c4cc(Cl)cc5cccnc45)CC3)c2c1

Procedure:
6-chloro-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1. mmol) and 6-chloro-8-piperazino quinoline (247.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil.Yield: 54 mg (12%); (M+H): 436; 1HNMR (400 MHz, CDCl3): δε8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.02˜8.00 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.99˜6.58 (m, 7H); 3.87 (s, 3H); 3.46˜2.62 (m, 11H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>C[Si](C)(C)N[Si](C)(C)C.C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([S:24]([C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)(=[O:26])=[O:25])[CH2:10][CH2:11][C:12]=1[OH:13])=[O:6])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C1CNCCC1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)CCN(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 140 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A suspension of 31.15 g (150 mmol) 3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml hexamethyldisilazane and heated under reflux (140° C.) for 2.5 h. The solution was evaporated complete, the residue dissolved in 400 ml THF and treated with 34 g (150 mmol) of naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was stirred 16 h at room temperature, evaporated, treated with 400 ml aqueous 10% NaCl, stirred for 10 min and extracted with EtOAc (3×400 ml). The organic phase was dried (Na2SO4) and evaporated and crystallized from Et2O at 5° C. to give 53.1 g (90%) of 4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, MS: 362 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CS[C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])SC.[NH2:19][C@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[C:21]1=[O:35]>C(O)C>[C:15]([C:14]([C:17]#[N:18])=[C:11]([NH:19][C@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)=[O:29])[C:21]1=[O:35])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[CH:3]=1)#[N:16]
Reactant: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Reactant: Cc1cccc(N)c1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: Cc1cccc(NC(N[C@H]2CCCCN(CC(=O)N3CCCC3)C2=O)=C(C#N)C#N)c1
Temperature: 80 °C
Yield: 25 %

Procedure:
3-Methylaniline (32.2 mg, 0.250 mmol) and [bis (methylthio)methylene]propanedinitrile (35.5 mg, 0.209 mmol) were dissolved in ethanol(0.3 mL). The reaction mixture was heated at 80° C. for 3 h. To the mixture was added 1-[[(3S) -3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (50.0 mg, 0.209 mmol) and the reaction mixture was heated at 80° C. for another 40 h. Purification by preparative RP HPLC provided the title compound as a pale yellow solid (22 mg, 45%): MS (ESI, pos. ion spectrum) m/z 421; HPLC (method A) tR 3.39 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1([NH2:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:27][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: NN1CCOCC1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid and 4-morpholinamine (CAN 4319-49-7) as starting materials; MS (ESI) 372.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6]S(C)(=O)=O.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14]
Reactant: Oc1ccccc1Br
Reactant: COC(=O)C(C)(C)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)COc1ccccc1Br
Temperature: 100 °C
Yield: 69.5 %

Procedure:
A first intermediate compound 3-(2-Bromo-phenoxy)-2,2-dimethyl-propionic acid, was produced as follows: To a mixture of 3-methanesulfonyloxy-2,2-dimethyl-propionic acid methyl ester (20.00 g, 95.23 mmol) and 2-bromophenol (16.48 g, 95.23 mmol) in acetonitrile (200 mL) was added Cs2CO3 (46.50 g, 142.80 mmol) and the mixture was heated at 100° C. in a sealed flask overnight. The resulting suspension was filtered. The solvent was evaporated and the crude material was partitioned between dichloromethane (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL), dried over Na2SO4 and evaporation of the solvent gave 3-(2-bromo-phenoxy)-2,2-dimethyl-propionic acid methyl ester (19.00 g, 70%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H), 7.26–7.22 (m, 1H), 6.87–6.80 (m, 2H), 4.02 (s, 2H), 3.72 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])=[CH:25][N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cc(C(=O)O)c(F)cn1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncc1F)c1ccc(OCC(F)(F)F)nc1
Yield: 24 %

Procedure:
The title compound is prepared in 24% yield (102 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.17 mmol, Amine-1, single enantiomer) and 2-amino-5-fluoroisonicotinic acid (182 mg, 1.17 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: C(O)C.Cl.[NH2:5][OH:6].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:22]3)[CH2:17][C:16]2=[O:33])=[CH:11][CH:10]=1)#[N:8]>C(N(CC)CC)C>[OH:6][NH:5][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:26]3)[CH2:17][C:16]2=[O:33])=[CH:11][CH:10]=1)=[NH:8]
Reactant: NO
Reactant: CCOC(=O)CN1CCC(N2CCN(c3ccc(C#N)cc3)C(=O)C2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(N2CCN(c3ccc(C(=N)NO)cc3)C(=O)C2)CC1
Yield: 69.5 %

Procedure:
Ethanol (38 ml), 0.90 g of Hydroxylamine hydrochloride, and 1.64 g of triethylamine were added to 3.0 g of ethyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate, and the mixture was heated under reflux for 3 hours. The crystals formed were collected by filtration at the temperature of about 30° C, and recrystallized from chloroform-ethanol to give 2.27 g of ethyl 4-[4-(4-hydroxyamidinophenyl)-3-oxo-1-piperazinyl]-1-piperidineacetate
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.CN([CH:28]=[O:29])C>CCOC(C)=O>[C:20]([O:19][C:18]([NH:17][CH:14]1[CH2:13][CH2:12][N:11]([C:28]([O:10][CH2:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:29])[CH2:16][CH2:15]1)=[O:24])([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc(C)cc(CO)c1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(COC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (3,5-dimethylphenyl)methanol (1.020 g, 7.49 mmol) in DMF (5 mL) at RT was added CU (1.214 g, 7.49 mmol). The reaction mixture was heated at 50° C. for 20 hrs. Tert-butyl piperidin-4-ylcarbamate (1.5 g, 7.49 mmol) was added and the reaction mixture stirred at 50° C. for 4 hrs. The mixture was diluted with EtOAc and washed with a saturated solution of sodium bicarbonate, brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-100% EtOAc in hexanes as eluent to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)ccc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Cl)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
5-Chloro-2-fluoroaniline (25 g, 172 mmol) was added to conc. hydrochloric acid (150 mL, 37%). The mixture was cooled (−10° C.) and a solution of sodium nitrite (11.9 g, 172 mmol) in water (193 mL) was added slowly (<−5° C.). This done, a solution of tin(II)chloride (118 g, 618 mmol) in conc. hydrochloric acid (116 mL) was added slowly (−6° C.). The mixture was stirred for 1 h, filtered through Celite® and the filter cake washed extensively with water. The filtrate was adjusted to pH 14 with conc. sodium hydroxide solution and the suspension extracted with diethylether. Organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was removed in vacuo to yield the title compound as yellow solid (22.9 g, 83%), EI-MS: m/e=160.0 (M+).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O>CCOCC.CN(C=O)C>[C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][C:15]([Cl:21])=[O:17])[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCC1(c2ccccc2)OCCO1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)CCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Step AAH (2): To a solution of 4-(2-phenyl-1,3-dioxolan-2-yl)butanoic acid (490 mg, 2.07 mmol) in anhydrous Et2O (10 mL) was added oxalyl dichloride (526 mg, 4.15 mmol). Anhydrous DMF (2 drops) was added and the resulting mixture stirred at rt for 1 h. The crude reaction was concentrated in vacuo. The residue was diluted with toluene (10 mL) and reconcentrated to afford 4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl chloride (2.07 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:50])[C@H:47](O)[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][C@H:47]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:50])[CH3:48])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@@H](O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (R)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Br:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Br:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O

Procedure:
216 mg of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) from Example D-1 e) were reacted with glycine and sodium methylate analogously to Example D-1 g). 192 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.15 (t, 1H), 8.22 (d, 1H), 7.52 to 7.74 (m, 7H), 4.01 (d, 2H).