Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>CN(C)C1C=CN=CC=1>[OH2:29].[OH2:29].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][N:10]=[C:11]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Clc1ccc(-c2n[nH]c(N3CCNCC3)c2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Product: O
Product: O=C(O)CCC(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperzinyl)pyrazole (200 mg; 0.54 mmol; prepared as set forth in Example A-169), succinic anhydride (60 mg, 0.55 mmol) and 4-dimethylaminopyridine (5 mg) was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue treated with methanol and water (1:1). The resultant crystalline solid was filtered and air dried to give 170 mg (58%) of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate, m.p. 281-283° C. (dec.). Anal. Calc'd. for C22H22ClN5O3.2H2O: C, 55.52; H, 5.51; N, 14.72. Found: C, 55.11; H, 5.20; N, 14.44.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:36]=[CH:35][C:22]4[CH2:23][N:24]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:26][O:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)C>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:36]=[CH:35][C:22]4[CH2:23][N:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCN1CCOc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)OCCN(CCC(=O)O)C4)no2)cc1Cl
Product: Cl
Reaction time: 2 h

Procedure:
2M Sodium hydroxide solution (aq) (0.5 ml, 1.000 mmol) was added to a solution of ethyl 3-[8-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]propanoate (Preparation 35) (0.09 g, 0.185 mmol) in ethanol (4 ml) and left at room temperature for 2 hours. The reaction was then evaporated and the resulting crude dissolved in EtOAc/water (30 ml of each) and acidified with acetic acid. The organic layer was dried (magnesium sulphate) and evaporated. The resulting crude was azeotroped with 20 ml of toluene and the residue dissolved in 10 ml of DCM. 1M HCl (1 ml) in ether was added, the reaction mixture evaporated then triturated with ether. The title compound (56 mg) was filtered off as an off-white solid hydrochloride salt. 6H (400 MHz, MeOD) 1.42 (6H, d), 2.92 (2H, t), 3.55 (2H, t), 3.78 (2H, m), 4.40 (2H, m), 4.65 (2H, s), 4.87 (1H, m), 7.31 (1H, d), 7.61 (1H, d), 7.87 (1H, d), 7.96 (1H, dd), 8.11 (1H, dd), 8.21 (1H, d); MS (ES) C23H2435ClN3O6 requires 457; found 458 [M+H]+.
Reaction SMILES: C(=[N+]([O-])[CH:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[C:9]1([F:23])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])C1OC=CC=1.[CH:25](=[N:31]/[OH:32])\[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.CC(C)=O>[F:23][C:9]1([C:16]([O:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[O:17])[CH:8]([O:32]/[N:31]=[CH:25]/[C:26]2[O:30][CH:29]=[CH:28][CH:27]=2)[NH:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1[N+]([O-])=Cc1ccco1
Reactant: O/N=C/c1ccco1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 51 h
Yield: 55.1 %

Procedure:
In 3 ml of pyridine-acetone (pyridine-acetone=2:1) were dissolved 341 mg (1 mmol) of N-(furfurylidene)-(5-fluoro-5-isobutoxycarbonyl-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-6-yl)amine N-oxide and 133 mg (1.2 mmol) of (E)-furfuraldoxime, and the solution was stirred at room temperature for 51 hours. The reaction solution was treated in the same manner as described in Example 9 to give 188 mg of isobutyl 5-fluoro-6-[(E)-furfurylideneaminooxy]-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][NH:23]C.[CH3:25]OCCOC>>[O-:15][N+:4]1[C:5]2[CH:14]=[C:13]3[C:9](=[CH:8][C:6]=2[N:7]=[C:2]([NH:23][CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH3:25])[N:3]=1)[CH2:10][CH2:11][CH2:12]3
Reactant: COCCOC
Reactant: CNCCNCCOC
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Product: COCCN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 20 °C
Yield: 66 %

Procedure:
A solution of the chloride 21 (2.0 g, 9.03 mmol) and N′-(2-methoxyethyl)-N1-methyl-1,2-ethanediamine (268) (2.38 g, 18.1 mmol) in DME (140 mL) was heated at reflux temperature for 22 h. The solution was cooled to 20° C., the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-16%) of MeOH/DCM, to give 1-oxide 30 (1.89 g, 66%) as a yellow solid: mp 107-110° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.89 (br s, 1H, NH), 3.48-3.56 (m, 4H, CH2O, CH2N), 3.36 (s, 3H, OCH3), 3.00 (q, J=7.6 Hz, 4H, H-6, H-8), 2.63-2.71 (m, 4H, 2×CH2N), 2.33 (s, 3H, NCH3), 2.14 (p, J=7.4 Hz, 2H, H-7); 13C NMR δ 158.8, 154.4, 148.8, 143.1, 129.8, 120.5, 114.7, 71.0, 58.8, 56.7, 56.0, 42.4, 38.8, 33.1, 32.3, 25.7; HRMS (FAB+) calcd for C16H24N5O2 (MH+) m/z 318.1930, found 318.1930.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.[CH:10]1([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:17]([CH:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]3[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1ccnc(CCl)n1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Product: Nc1ccnc(CN2CCC(C(=O)NC3CCCCC3)CC2)n1

Procedure:
The title compound is prepared according to the reactions described above starting from 2-chloromethyl-pyrimidin-4-ylamine and piperidine-4-carboxylic acid cyclohexylamide; LC-MS A: tR=0.47 min; [M+H]+=318.12.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:34])=[O:33])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
N-(2-(2-Aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (555 mg, 2.22 mmol) and triethylamine (0.40 ml, 2.66 mmol) were dissolved in dichloromethane (12 ml) and cooled to -78° C. A solution of benzenesulfonyl chloride (0.28 ml, 2.22 mmol) in dichloromethane (3 ml) was added dropwise. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (40 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (20 ml). The aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using ethyl acetate/heptane 1:3 as eluent, to give 557 mg of N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38](=[O:52])[CH2:39][NH:40][C:41](=[O:51])[CH:42]([NH2:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[CH3:36][O:37][C:38](=[O:52])[CH2:39][NH:40][C:41](=[O:51])[CH:42]([NH:50][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)CNC(=O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)CNC(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 5.0 mmol of 5-chloro-1H-indole-2-carboxylic acid (50 mL of a 0.1 M solution in acetonitrile) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol), 1-hydroxybenzotriazole (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol), followed by (2-amino-3-phenyl-propionylamino)-acetic acid methyl ester (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol). The reaction was agitated overnight at 80° C. and then concentated to dryness to give the title compound. HPLC RT 8.15 (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C(C)=CC=CC=1C.O([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of 3,5-dichloro-phenol (5.9 g, 36 mmol) in methylene chloride (50 mL) was added 2,6-lutidine (8.38 mL, 72.4 mmol) and triisopropylsilyl triflate (9.7 mL, 36 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 4 h. The reaction was quenched with 0.1 N HCl and diluted with ethyl acetate. The organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with flash chromatography (5% ethyl acetate/hexanes) to give the desired product as a colorless oil (10.5 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.95 (t, J=1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 2H), 1.26 (m, 3H), 1.09 (d, J=7.0 Hz, 18H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:35].F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[CH3:33][N:34]([CH3:35])[C:6]([CH:4]1[CH2:3][C:2]([OH:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:5]1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.050 g, 0.098 mmol) in dry DMF (1 mL) was added HATU (0.056 g, 0.147 mmol), HOBt (0.014 g, 0.107 mmol), DIPEA (0.025 g, 0.196 mmol) and saturated solution of dimethyl amine in THF (2 mL) at 0° C. Resulting reaction mixture was stirred 0° C. for 1 hour and at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was quenched with water (5 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (2×20 mL), brine (20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.2% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford white solid (0.029 g, 55%). 1H-NMR (400 MHz, CDCl3) δ: 2.53-2.57 (m, 2H), 2.79-2.88 (m, 2H), 3.02 (s, 6H), 3.27-3.31 (m, 1H), 3.67 (d, 1H, J=17.2 Hz), 4.08 (d, 1H, J=17.16 Hz), 5.04 (s, 1H), 7.57 (d, 2H, J=8.4 Hz), 7.64-7.65 (m, 4H); LC-MS (m/z): [M+H] 534.8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10](=[N:13][N+:14]([O-:16])=[O:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10]([NH:19][CH3:18])=[N:13][N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CSC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reactant: CN
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A mixture of 0.82 g of 1-(6-chloro-3-pyridylmethyl)-1,2-dimethyl-3-nitroisothiourea, 0.464 g of 40% methylamine aqueous solution and 10 ml of acetonitrile was stirred for 2 hours at 70° C., and concentrated. The residue was purified by a column chromatography [developing solution: dichloromethane-methanol [10:1]) to afford 0.56 g of 1-(6-chloro-3-pyridylmethyl)-1,3 -dimethyl-2-nitroguanidine (Compound No. 8).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[N:5]=1>C(Cl)Cl.C(O)C.[Pd]>[F:15][CH:2]([F:1])[O:3][C:4]1[N:5]=[C:6]([CH3:14])[C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)c(C)nc1OC(F)F
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (33.4 g, 153 mmol) in methylene chloride (100 mL) and ethanol (600 mL) was added 10% palladium on charcoal (3.3 g). The resulting suspension was hydrogenated on a Parr device at 40 psi 12 for 1 h. TLC was used to monitor the reaction. Additional 3.3 g of palladium on charcoal were added hourly until no starting material remained. A total of 13.2 g of Pd/C was added. The reaction mixture was kept under an H2 atmosphere for 2 h after the last addition of catalyst. The reaction mixture was filtered through Celite and sand and the collected solids were washed with ethyl acetate (2×100 mL). The filtrate was concentrated in vacuo to give a grey oil, which was purified by column chromatography on silica gel (35%→50% ethyl acetate in hexanes) to furnish 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (25.7 g, 89% yield) as a pale yellow oil which solidified upon cooling in a refrigerator. The product was recrystallized from hexanes below 0° C. to afford white needles: mp 40-42° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=74.0 Hz, 1H), 6.84 (s, 1H), 2.27 (s, 3H), 2.15 (s, 3H); LRMS (ESI) m/e 189.2 [(M+H)+, calcd for C8H11N2OF2 189.1]. Anal calcd. for C8H10N2OF2: C, 51.12, H, 5.38, N, 14.86. Found: C, 51.17, H, 5.29, N, 14.87.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CO>[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH2:1][C:3]2[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1ccc(CNc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of (E)-3-(4-formylphenyl)acrylic acid 229 (1 g, 5.67 mmol) and 3-chlorobenzenamine 230 (596 L, 5.67 mmol) in THF (8 ml), dibutyltin dichloride (173 mg, 0.57 mmol) was added followed by dropwise addition of phenylsilane (697 uL, 5.67 mmol). The resulting mixture was stirred at room temperature in the nitrogen atmosphere overnight, diluted with MeOH and concentrated under reduced pressure. The solid residue was triturated with DCM to yield the title compound 231 (1.24 g, 76% yield). 1H NMR: (DMSO) δ (ppm): 7.61 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.00 (t, J=8.0 Hz, 1H), 6.53 (t, J=2.0 Hz, 1H), 6.49-6.48 (m, 2H), 6.46 (d, J=16.0 Hz, 1H), 4.28 (bs, 2H). MS: (calc.) 287.7; (obt.) 288.1 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([C:20]#[N:21])=[C:16](Cl)[N:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25]>CC(O)C.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]3[NH:24][N:25]=[C:20]([NH2:21])[C:17]3=[N:18][CH:19]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(C#N)c(Cl)n2)cc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc3c(N)n[nH]c3n2)cc1
Temperature: 120 °C

Procedure:
[4-(6-Chloro-5-cyano-pyrazin-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.0 g) was suspended in a mixture of 10 ml iPrOH and 10 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 70 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, and the precipitate was filtered off and washed with water to afford [4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acid tert-butyl ester as a yellow solid after drying under vacuum. Yield: 815 mg (83%).
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30].O>O1CCCC1>[CH2:1]([C:8]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of diethyl 2-(6-heptenyl)malonate (3.83 g, 14.92 mmol) in anhydrous tetrahydrofuran (50 ml) was slowly added dropwise to a suspension of 60% sodium hydride (0.52 g, 12.94 mmol) in anhydrous tetrahydrofuran (150 ml) at 0° C., and the resulting mixture was stirred for 1 hour. The 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane prepared in Example 2 (4.0 g, 9.95 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) and then slowly added dropwise to the mixture, followed by stirring for 2 days at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(6-heptenyl)-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)malonate (4.7 g, Yield 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1[C:28](=[O:43])[C:29]2[C:34]([C:35]=1[C:36]1C=CC=CC=1)=[CH:33][CH:32]=C(O)C=2.O1CCC(CCO)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:32][CH2:33][CH:34]4[CH2:29][CH2:28][O:43][CH2:36][CH2:35]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCC1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCOCC3)cc21
Reaction time: 17 h
Yield: 33 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(tetrahydro-2H-pyran-4-yl)ethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 17 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (33%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH2:13]([O:31][C:32](Cl)=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C.O>CC(N(C)C)=O>[CH2:13]([O:31][C:32]([N:6]([C:4](=[O:5])[C:3]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=1[OH:1])[NH2:7])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NNC(=O)c1cc(O)ccc1O
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCOC(=O)N(N)C(=O)c1cc(O)ccc1O
Temperature: 40 °C

Procedure:
33.6 g of 2,5-dihydroxybenzoic acid hydrazide are dissolved in 150 ml of dimethylacetamide and 66.5 g of chloroformic acid octadecyl ester in 150 ml of dimethylacetamide, and 21 g of triethylamine, are added simultaneously over the course of 30 minutes. Thereafter the reaction mixture is warmed to 40° C for 3 hours whilst stirring, cooled and poured into 2 litres of water. The N-(2,5-dihydroxybenzoyl)-hydrazinecarboxylic acid octadecyl ester obtained (Stabiliser No. 8) forms a pulverulent precipitate which is isolated, washed with water, dried at 80° C and recrystallised from isopropanol. Melting point 163° C.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[C:20](Cl)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[CH2:21]([C:20]1[O:27][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCCCCCC(=O)Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCCc1ocnc1C(=O)OCC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Ethyl 2-isocyanoacetate (1.0 g, 8.84 mmol) was dissolved in DMF (5 mL) in a 25 mL 1 neck pear shaped flask that was equipped with a magnetic stirrer and an Ar inlet. DBU (1.999 mL, 13.26 mmol) and heptanoyl chloride (1.770 mL, 11.49 mmol) were added and the reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×30 mL). The phases were separated and the organic phase was dried over MgSO4 and concentrated in vacuo to a dark oil. The desired product was isolated by distillation at 90-95° C. at 0.3 mmHg as a clear oil (0.89 g, 45%). LCMS Anal. Calc'd for C12H19NO3 225.1, found [M+H] 226.1. 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 1.35-1.26 (m, 6H), 0.86 (t, J=6.3 Hz, 3H).