Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1c2n(c3c(-c4cccc(C#N)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (63 mg, 77%), MS (ISP) m/z=325.6 [(M+H)+], mp 266° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[ClH:39].O1CCOCC1>C(OCC)(=O)C.CCOCC>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([CH:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:34]1.[ClH:39]
Reactant: CC1Cc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
tert-Butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidine-1-carboxylate (0.26 g, 0.50 mmol) in ethyl acetate (1 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.00 mL, 4.00 mmol) at r.t. for 1 h. The mixture was diluted with ether (3 mL), and centrifugalized. The solvents were decanted. The residue was dried in-vacuo to afford the desired product as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=422.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][S:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][S:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(SC#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C#CSc3ccc(C(=O)O)cc3)ccc21

Procedure:
In a manner similar to that of Example 2, by reaction of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethynylsulphanyl)benzoate in THF, and after crystallization from heptane, theexpected derivative is obtained in the form of a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][C@H:25]2[C@:20]([CH3:61])([CH2:21][CH2:22][C@H:23]([O:27][CH2:28][CH2:29][N:30]([C:32]3[CH:37]=[CH:36][C:35]([C@H:38]4[CH2:55][C@@:53]5([CH3:54])[C@@H:49]([CH2:50][CH2:51][C@:52]5([OH:59])[C:56]#[C:57][CH3:58])[C@H:48]5[C:39]4=[C:40]4[C:45]([CH2:46][CH2:47]5)=[CH:44][C:43](=[O:60])[CH2:42][CH2:41]4)=[CH:34][CH:33]=3)[CH3:31])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:63])([C@@H:17]([OH:62])[CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:6][CH2:5]1.[CH3:64][S:65][CH2:66]Cl.N1C=CC=C[CH:69]=1>>[CH3:69][CH:10]([CH2:9][C@H:8]([C@@H:7]1[C@:16]2([CH3:63])[C@H:4]([C@H:3]3[C@H:19]([CH2:18][C@@H:17]2[OH:62])[C@:20]2([CH3:61])[C@@H:25]([CH2:24][C@@H:23]([O:27][CH2:28][CH2:29][N:30]([C:32]4[CH:33]=[CH:34][C:35]([C@H:38]5[CH2:55][C@@:53]6([CH3:54])[C@@H:49]([CH2:50][CH2:51][C@:52]6([OH:59])[C:56]#[C:57][CH3:58])[C@H:48]6[C:39]5=[C:40]5[C:45]([CH2:46][CH2:47]6)=[CH:44][C:43](=[O:60])[CH2:42][CH2:41]5)=[CH:36][CH:37]=4)[CH3:31])[CH2:22][CH2:21]2)[CH2:26][C@H:2]3[O:1][CH2:64][S:65][CH3:66])[CH2:5][CH2:6]1)[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: c1ccncc1
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]45)cc3)C[C@@]21C
Reactant: CSCCl
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCSC)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 25 °C

Procedure:
The compound of Example 1I is dissolved in pyridine and cooled in an ice bath; methylthiomethyl chloride (1.2 eq) is added, and the mixture is warmed to ambient temperature, then heated to 90° C. overnight. The solvents are removed in vacuo; the residue is partitioned between aqueous phosphoric acid (1N) and ethyl acetate. The organic extract is washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is purified by column chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+]([O-])=O)[C:5]=1Cl)([O-:3])=[O:2].CN(C)[C:20](=[S:22])[SH:21].[Na].[OH2:25].C(Cl)(Cl)Cl>CS(C)=O>[N+:1]([C:4]1[C:5]2[S:22][C:20](=[O:25])[S:21][C:6]=2[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CN(C)C(=S)S
Agent: [Na]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=c1sc2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The compound of Example I is prepared in the following manner: To a magnetically stirred solution of 16.2 g (60 mmoles) 2,6-dinitro-4-trifluoromethylchlorobenzene in 60 ml dimethylsulfoxide was added dropwise a solution of 10.74 g (60 mmoles) sodium dimethyldithiocarbamic acid. The reaction is mildly exothermic and accompanied by evolution of oxides of nitrogen. After allowing the reaction mixture to stir for 3 hours, 450 ml water and 225 ml chloroform are added and, after shaking well in an extraction funnel, the chloroform extract was withdrawn and the aqueous phase similarly extracted with two more 220 ml portions of chloroform. The combined chloroform extract was washed thrice with 750 ml portions of water, and dried over anhy. Na2SO4. After removing the solvent on a rotary evaporator, the residue was chromatographed over 180 g Silica-Gel. Elution with hexane-benzene (1:1) yielded 7.3 g (43.3%) 4-nitro-6-trifluoromethyl-1,3-benzodithiole-2-one, m.p. 103°-107° C. One recrystallization from ethanol yielded product, m.p. 111°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:46])[C:43](Cl)=[O:44]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:41][N:42]([CH3:46])[C:43]([N:24]1[CH2:23][CH2:22][C:21]2[CH:27]=[CH:28][C:18]([NH:17][C:15]3[N:16]=[C:9]4[C:8]([C:6]5[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:13][CH:12]=[CH:11][N:10]4[N:14]=3)=[CH:19][C:20]=2[CH2:26][CH2:25]1)=[O:44]
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To {8-[5-chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.054 g, 0.110 mmol) in dichloromethane (4 mL) under an atmosphere of nitrogen was added triethylamine (0.0349 g, 0.345 mmol), N,N-dimethylcarbamoyl chloride (0.0159 mL, 0.172 mmol), followed by 4-dimethylaminopyridine (0.0014 g, 0.012 mmol) and was stirred at r.t. for 3 h and concentrated. The reaction was partitioned between dichloromethane/water, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using Prep TLC plates (5% methanol in dichloromethane) and concentrated to give 7-{8-[5-chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid dimethylamide (0.030 g, 48%). MP=98-99° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.58 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.48 (m, 3H), 7.30 (d, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.38 (m, 2H), 3.28 (m, 4H), 2.84 (m, 4H), 2.74 (s, 6H). MS=541 (MH)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]4[C@:20]([C:22]([C:24]5[N:25]=[CH:26][S:27][CH:28]=5)=[O:23])([CH2:21][C:12]=3[CH:11]=[N:10]2)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]4)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[Cl:52]>CCOCC.ClCCl>[Cl:45][C:46]1[CH:47]=[C:48]([S:53]([N:18]2[CH2:17][CH2:16][C:15]3[C@:20]([C:22]([C:24]4[N:25]=[CH:26][S:27][CH:28]=4)=[O:23])([CH2:21][C:12]4[CH:11]=[N:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=5)[C:13]=4[CH:14]=3)[CH2:19]2)(=[O:54])=[O:55])[CH:49]=[CH:50][C:51]=1[Cl:52]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cscn2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cscn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To HCl 2M in ether (2809 μl, 5.62 mmol) was added (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (135 mg, 0.281 mmol) as a solution in ether (1 mL). The resulting suspension was stirred at room temperature for 1 h. The solvent was removed to give a white solid. This was dissolved in dichloromethane (1.4 mL) and Hunig's base (245 μl, 1.405 mmol), and 3,4-dichlorobenzene-1-sulfonyl chloride (76 mg, 0.309 mmol) was added to the solution. The resulting solution was stirred at room temperature for 18 h. The crude product was purified by chromatography on silica gel (gradient: 5-95% ethyl acetate in isohexane to afford (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone (111 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.76 min, m+H=588.8; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d, J=2.2 Hz), 8.22 (1H, d, J=2.2 Hz), 7.77 (1H, t, J=1.2 Hz), 7.52 (2H, d, J=1.2 Hz), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.20-7.13 (2H, m), 6.52 (1H, d, J=2.2 Hz), 5.44 (1H, dd, J=12.6, 2.2 Hz), 4.13 (1H, d, J=16.8 Hz), 3.90-3.87 (1H, m), 2.92-2.81 (2H, m), 2.78 (1H, d, J=12.6 Hz), 2.62-2.50 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)C=C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:24]1[CH:25]=[C:18]([CH3:17])[CH:19]=[CH:20][CH:23]=1)[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)C(=O)[O-]
Reactant: C=Cc1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1cccc(C2CC(C(=O)O)Nc3cc(Cl)cc(Cl)c32)c1

Procedure:
Compound 18 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-methylstyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: [OH-].[Na+].C(OC(N[C@@H](C)C([O:17][C@H:18]1[C:23]2[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:22]=2[O:21][C:20]([CH3:31])([CH3:30])[C@@H:19]1Br)=O)=O)C1C=CC=CC=1>O.O1CCOCC1>[O:17]1[C@@H:18]2[C@H:19]1[C:20]([CH3:30])([CH3:31])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=12
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of sodium hydroxide (0.672 g) in water (16 ml) was added dropwise to a stirred solution of (3R,4S)-4-{(2S)-2-benzyloxycarbonylaminopropionyloxy}-3-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (3.896 g) in 1,4-dioxane (24 ml). After being stirred at ambient temperature for 1 hour, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with isopropyl ether and dried to give (3S,4S)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.401 g).
Reaction SMILES: NN1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[CH:25]([N:28](CC)C(C)C)(C)C.O>CN1CCCC1=O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:25]([NH:28][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
4-Amino-1-tert-butoxycarbonylpiperazine (3.00 g), 4-fluoronitrobenzene (2.54 g) and N,N-diisopropylethylamine (8.82 g) were dissolved in N-methyl-2-pyrrolidone (30 mL), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-tert-butoxycarbonyl-4-(4-nitrophenyl)aminopiperidine (2.55 g) as a white solid.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1[CH:30]=[CH:31]C2N(O)N=[N:35][C:33]=2[CH:34]=1.CCN=C=NCCCN(C)C.Cl.Cl.[N+:52]([C:55]1[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=1[O:57]N1CCCCC1)([O-:54])=[O:53]>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:35]2[CH2:31][CH2:30][CH:29]([O:57][C:56]3[CH:64]=[CH:65][CH:66]=[CH:67][C:55]=3[N+:52]([O-:54])=[O:53])[CH2:34][CH2:33]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: On1nnc2ccccc21
Reactant: O=[N+]([O-])c1ccccc1ON1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.1 g, 0.00039 mole) in DMF (3 mL) was added DIPEA (0.176 g, 0.0014 mole), HOBt (0.078 g, 0.00058 mole) and EDCI.HCl (0.11 g, 0.00058 mole). After 2 minutes (2-nitro-phenoxy)-piperidine hydrochloride (0.12 g, 0.00046 mole) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using neutral aluminium oxide (5% methanol in chloroform) to afford 0.130 g (72%) of N-biphenyl-4-yl-3-[4-(2-nitro-phenoxy)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 460.18 (M+1)+, 95%, 1H NMR (DMSO-d6): δ 7.9 (m, 1H), 7.7 (m, 7H), 7.5 (m, 3H), 7.3 (m, 1H), 7.1 (m, 1H), 5.0 (m, 1H), 3.6 (m, 6H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:31])[NH:18][C@@H:19]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:17](=[O:31])[NH:18][C@@H:19]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)NCc1ccc(N)nc1
Reaction time: 1 h

Procedure:
The urea 148 (210 mg) was dissolved in 2 ml of DCM and 2 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture was concentrated and purified by precipitation using AcOEt/Hexane to afford the urea deprotected 149 as yellow solid (204 mg, 89%). HPLC method B tr=17.99 nm (95.8%). ESI-MS m/z: 329.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.[CH2:16]([O:23]/[N:24]=[C:25]1\[CH2:26][CH2:27][C:28]2[C:33]\1=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:16]([O:23]/[N:24]=[C:25]1\[CH2:26][CH2:27][C:28]2[C:33]\1=[CH:32][CH:31]=[C:30]([C:2]1[C:3]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1)[CH:29]=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Reactant: OCCn1cc(Br)c(-c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCCn1cc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c(-c2ccncc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To 2-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol (100 mg; Example 4, step 3) in 7 mL acetonitrile and 3 mL water, was added 136 mg (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (product of Example 2, Step 4), and 155 mg potassium carbonate. The mixture was purged with nitrogen and about 43 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The mixture was heated at 80° C. After 1 hour, the reaction mixture was filtered through celite, the filter cake washed with ethyl acetate, and filtrate evaporated under vacuum. The residue was purified by chromatography, eluting with a mixture of 8:1 ethyl acetate-methanol to afford 110 mg (69% yield) product as a white solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 425.2 by positive ESI.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([C:48]1[CH:63]=[C:62]([C:64](=[NH:67])[NH:65]O)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]>CN(C=O)C.O1CCOCC1>[CH2:46]([C:48]1[CH:63]=[C:62]([C:64]2[N:67]=[C:11]([C:9]3[CH:8]=[C:7]([CH3:14])[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=3)[O:13][N:65]=2)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]
Reactant: Cc1cc(CC(C)C)nc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1cc(-c2noc(-c3cc(C)cc(CC(C)C)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reaction time: 1 h
Yield: 10 %

Procedure:
To a solution of 6-isobutyl-4-methyl-pyridine-2-carboxylic acid (100 mg, 0.435 mmol) and DIPEA (169 mg, 1.31 mmol) in DMF (5 mL), TBTU (210 mg, 0.653 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acet-amide (170 mg, 0.522 mmol) is added. Stirring is continued at 0° C. for 1 h. The reaction is quenched by adding water. The mixture is diluted with sat. aq. NaHCO3-solution and extracted with EA and two times with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate. This material is dissolved in dioxane (5 mL) and the mixture is stirred at 80° C. for 24 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol followed by prep. HPLC to give the title compound (21 mg) as a pale yellow oil; LC-MS: tR=1.00 min, [M+H]+=483.26; 1H NMR (CDCl3): δ 0.99 (d, J=6.8 Hz, 6H), 1.29 (t, J=7.5 Hz, 3H), 2.21 (hept, J=6.8 Hz, 1H), 2.36 (s, 3H), 2.48 (s, 3H), 2.72 (q, J=7.5 Hz, 2H), 2.79 (d, J=7.3 Hz, 2H), 3.47-3.55 (m, 1H), 3.74-3.92 (m, 3H), 4.16-4.24 (m, 3H), 7.18 (s, 1H), 7.23 (t br, J=5.8 Hz, 1H), 7.88 (s, 1H), 7.90 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].NCCCCCC(N)=[O:17]>>[C:7]1(=[O:9])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:17]
Reactant: NCCCCCC(=O)O
Reactant: NCCCCCC(N)=O
Product: O=C1CCCCCN1
Product: O=CCCCCC(=O)O

Procedure:
Process according to claim 1, wherein the starting mixture is an aqueous mixture containing 6-aminocaproic acid, 6-aminocaproamide, oligomers thereof and ε-caprolactam which aqueous mixture is obtained through reductive amination of 5-formylvaleric acid or its ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[N:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[C:14]([O:16]C)=[O:15])[N:4]=1.CS(C)=O.[OH-].[Na+]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[N:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)ccnc1Oc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(Oc2nccc(-c3ccccc3)c2C(=O)O)n1
Yield: 44.5 %

Procedure:
2.6 g (0.007 mol) of methyl 2-(4,6-dimethoxypyrimidin-2-yloxy)-4-phenylnicotinate and 50 ml of dimethylsulfoxide were weighed, and 4.6 ml (0.009 mol) of 2N sodium hydroxide aqueous solution was added dropwise thereto at 60° C. After the dropwise addition, the resultant mixture was further stirred for 30 minutes at 60° C. The resultant mixture was poured into water, and was washed twice with ethyl acetate. The aqueous layer was then adjusted to pH 2 with 10% hydrochloric acid aqueous solution, and the precipitated crystal was filtrated out. The crystal thus obtained was washed with water, and was then dried. The dried crystal was recrystallized with ethyl acetate to obtain 1.1 g of a white crystal.