Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (343 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (307 mg, 94%) as a pale-yellow solid.
Reaction SMILES: [Fe-4:1]([C:12]#[N:13])([C:10]#[N:11])([C:8]#[N:9])([C:6]#[N:7])([C:4]#[N:5])[C:2]#[N:3].[Ni:14]>>[Fe-4:1]([C:10]#[N:11])([C:6]#[N:7])([C:2]#[N:3])([C:4]#[N:5])([C:8]#[N:9])[C:12]#[N:13].[Ni+4:14]
Reactant: [Ni]
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Product: [Ni+4]

Procedure:
300 mg/l of ferrocyanide ions and 100 mg/l of nickel ions,
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@H:2]2[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CN1C(=O)[C@@H](N)CCC[C@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CCC[C@@H](c2ccccc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of (3S,7S)-3-amino-1-methyl-7-phenylazepan-2-one (2e) (57 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (95 mg), HOBt-hydrate (88 mg), EDAC.HCl (75 mg) and N-methyl morpholine (42 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (80 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 1.40 (d, 3H), 1.51 (m, 1H), 1.90-2.01 (m, 3H), 2.12-2.15 (m, 2H), 2.52 (s, 3H), 3.55 (s, 2H), 4.47-4.56 (m, 1H), 4.92-5.00 (m, 2H), 6.29 (bd, 1H), 6.69-6.76 (m, 1H), 6.84 (bd, 2H), 7.27-7.41 (m, 6H). MS APCI, m/z=444 (M+1)/466 (M+Na). LC/MS 2.54 min., Method A.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1
Yield: 89 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were tert-butyl amine (4.72 g, 0.065 mole) and 4-methylbenzoyl chloride (5.02 g, 0.0325 mole), the reaction was carried out in benzene and the reaction produced 5.54 g of crystals of the desired product (89% yield), mp 114°-116° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.615 ppm (d, 8 Hz, 2H; 2,6-aryl H); 7.193 ppm (d, 8 Hz, 2H; 3.5-aryl H); 5.970 ppm (bs, 1H; N-H); 2.377 ppm (s, 3H; 4-CH3); 1.461 ppm (s, 9H; tert-butyl H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([O:10][C:11]([CH:13]([CH3:23])[CH2:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[CH3:9].[OH-].[Na+]>C(O)C>[CH2:6]([O:5][C:3]([CH2:2][N:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:14][CH:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH3:23])=[O:4])[CH3:7]
Reactant: CCOC(=O)C(C)CNCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN(Cc1ccccc1)CC(C)C(=O)OCC
Temperature: 0 °C
Yield: 61.4 %

Procedure:
88.4 g (0.53 mole) of ethyl bromoacetate were added to a solution of 98.0 g (0.44 mole) of N-(2-ethoxycarbonylpropyl)benzylamine [prepared as described in Step (1) above] dissolved in 200 ml of ethanol, and the mixture was heated under reflux for 2 hours. The reaction mixture was then poured into 500 ml of ice-water and made alkaline by the addition of a 50% w/v aqueous solution of sodium hydroxide. It was then extracted with ethyl acetate. The ethyl acetate extract was washed, in turn, with a 1N aqueous solution of sodium hydroxide and with water and dried. It was then freed from the solvent by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 1:9 by volume mixture of ethyl acetate and toluene, to give 83.0 g of N-ethoxycarbonylmethyl-N-(2-ethoxycarbonylpropyl)benzylamine as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Cl-].[NH4+]>[Fe].O1CCCC1.O>[CH3:1][C:2]1([CH3:21])[C:6]2[C:7]([O:11][C:12]3[N:13]=[CH:14][C:15]([NH2:18])=[CH:16][N:17]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COc2cccc(Oc3ncc(N)cn3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.2 %

Procedure:
To a solution of 2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-nitropyrimidine (Intermediate 64, 1.257 g) in a mixture tetrahydrofuran/water (30 ml/15.00 ml) iron (1.222 g, 21.88 mmol) and ammonium chloride (1.170 g, 21.88 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours. The catalyst was filtered off, and the filtrate was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was recrystallized from ethyl acetate to afford the title compound (768 mg) as a white solid.
Reaction SMILES: [CH2:1]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]1[O:12][CH2:11][CH:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:13][O:14]1
Reactant: CCCCCCCCCC(CO)CO
Reactant: O=Cc1cccc(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC1COC(c2cccc(F)c2F)OC1

Procedure:
Quantities: compound from Example 10 (31.4 g, 0.155 mol), 2,3-difluorobenzaldehyde (21.5 g, 0.15 mol) and 4-toluenesulphonic acid (100 mg). The experimental procedure was as described in Example 114.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH2:23][CH2:22][CH2:21][C:18]=3[CH:19]=2)[NH:14][C@@H:13]([CH3:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[CH2:36]([O:35][C:33]([N:14]1[C:15]2[C:20](=[CH:19][C:18]3[CH2:21][CH2:22][CH2:23][C:17]=3[CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:12][C@@H:13]1[CH3:24])=[O:34])[CH3:37]
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc3c(cc2N1)CCC3
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-(2-methyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinolin-4-yl)-carbamic acid benzyl ester (Example 1A) (2.0 g, 5.9 mmol) in anhydrous dichloromethane (50 mL) was added pyridine (1.0 mL). The mixture was cooled to 0° C., and ethyl chloroformate (1.0 mL) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 4 h. The reaction mixture was washed twice with 25 mL of 2N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 15% ethyl acetate/hexanes as eluent afforded the title compound (500 mg). 1H NMR (CDCl3) δ1.1 (d, 3H), 1.2 (t, 3H), 4.2 (m, 2H), 5.2 (s, 2H), 7.0 (s, 1 H), 7.3 (s, 1 H), 7.4 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([O:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[CH:74]1([NH:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[C:80]=2[CH3:87])[CH2:76][CH2:75]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([O:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:77]([CH:74]2[CH2:76][CH2:75]2)[CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[C:80]=2[CH3:87])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CNC2CC2)c1C
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(OCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
A sol. of compound D4 (7.76 mmol, 4.86 g) in CH2Cl2 (63 mL) was treated with DMAP (1.94 mmol, 0.27 mg), HOBt (9.31 mmol, 1.26 g), EDC.HCl (19.40 mmol, 3.72 g), and DIPEA (31.04 mmol, 5.31 mL). After 30 min at rt, cyclopropyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine, 23.28 mmol, 4.45 g) was added and the mixture was stirred for 4 days at rt. The reaction was then diluted with CH2Cl2 (140 mL), washed with aq. 1M HCl (2×100 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.48 g, 42%). LC-MS: tR=1.27 min; ES+: 799.56.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O.Cl>CO.C(Cl)Cl.CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:28])[F:26])[CH:13]=[N:12]2)[C:3]([OH:29])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid methyl ester (149.4 mg, 0.36 mmol) in methanol (0.61 mL, 0.6M) was treated with a 4N aqueous sodium hydroxide solution (0.1 mL, 0.40 mmol) and stirred at 25° C. for 3 h. After this time, the reaction was poured into water (50 mL) and 90/10 methylene chloride/methanol (30 mL) and was acidified with a 2N aqueous hydrochloric acid solution and then was extracted into a 90/10 methylene chloride/methanol (3×30 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (130.6 mg, 90%) as a yellow solid. This material was used without further purification; ES+-HRMS m/e calcd for C20H21N2O3F3 [M+H+] 395.1577, found 395.1574.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.Cl.[Na].[OH-].[Na+].P(=O)(O)(O)O>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:7]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(N2CCc3ccccc32)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of cyanuric chloride (50 g, 271 mM), acetone (200 ml) and ice (300 g) was added, over ten minutes, a mixture of indoline (32 ml, 286 mM) and 2.5N hydrochloric acid (120 ml). To this stirred mixture was added, over one hour, a solution of sodium secondary phosphate which had been prepared by neutralising 2.5N sodium hydroxide (250 ml) with orthophosphoric acid to PH 7 to 7.5. The mixture was then stirred for one hour, filtered and the resultant solid was washed with water and dried at 80° C. There was thus obtained 2,4-dichloro-6-indolin-1-yl-1,3,5-triazine (72.4 g, 87% yield), a portion of which was recrystallised from toluene, mp 254°-256° C. NMR: DMSOd6 : 3.15-3.3 (2H, t, CH2CH2 --N), 4.05-4.3 (2H, complex, CH2CH2N--) (rotamers), 7.0-7.4 (3H, complex, aromatic), 8.15-8.4 (1H, complex, aromatic).
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(#N)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][C@H:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH2:11]2)=[CH:23][CH:22]=1)=[O:21]
Reactant: O=C(O)c1ccc(N2CC[C@H](NC(=O)c3cccnc3)C2)cc1
Reactant: Nc1ccccc1N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC#N
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](NC(=O)c3cccnc3)C2)cc1
Yield: 19.9 %

Procedure:
A solution of 399 (93 mg, 0.3 mmol), phenylene diamine (65 mg, 0.6 mmol), EDC (86 mg, 0.45 mmol), HOBT (53 mg, 0.33 mmol) and Et3N (125 μL, 91 mg, 0.9 mmol) in acetonitrile (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography using the gradient 5-20% MeOH in DCM as an eluent to afford the title compound (24 mg, 16% yield). 1H NMR (CDCl3) δ 8.97 (s, 1H), 8.66 (d, J=4.9 Hz, 1H), 8.21 (d, J=3.9 Hz, 1H), 7.87 (d, 2H, J=8.8 Hz), 7.52 (dd, J=5.1 Hz, J=8.0 Hz, 1H), 7.15 (d, 1H, J=7.9 Hz), 7.05 (t, J=8.1 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.76 (t, J=7.3 Hz, 1H), 6.66 (d, J=9.0 Hz, 2H), 4.78 (m, 1H), 3.80 (dd, J=6.7 Hz, J=10.2 Hz, 1H), 3.61 (m, 1H), 3.49 (m, 1H), 3.41 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H). LRMS: (calc) 401.2; (found) 402.2 (M+H1).
Reaction SMILES: [N:1]([N:3]([CH3:7])C(N)=O)=O.C(OC(C)C)(C)C.[OH-].[K+].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[S:27](=[O:30])(=[O:29])[NH2:28]>C(OCC)(=O)C.C(OCC)C>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](=[O:23])[CH:7]=[N+:3]=[N-:1])=[CH:20][C:19]=1[S:27](=[O:29])(=[O:30])[NH2:28]
Reactant: CN(N=O)C(N)=O
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccc(Br)c(S(N)(=O)=O)c1
Reaction time: 0.17 h

Procedure:
26 g of freshly prepared N-nitroso-N-methyl urea were introduced portionwise at 0° to -5° C. into a stirred two-phase mixture of 200 ml of diethyl ether (or diisopropyl ether) and 80 ml of 40% aqueous potassium hydroxide solution, the ice-cold etheral diazomethane solution was separated in the separating funnel and dried over a small amount of solid potassium hydroxide at -10° C. during 3 hours. The dry solution of the diazomethane in diethyl ether (or diisopropyl ether) was cooled to -5° C. to -10° C. in a 500 ml three-neck flask provided with stirrer, inner thermometer and KOH drying tube. A suspension of 16.8 g of 4-bromo-3-sulfamoylbenzoyl chloride was added in small portions into 40 ml of anhydrous ethyl acetate, the temperature of the reaction mixture not being allowed to exceed +5° C. After the addition of 4-bromo-3-sulfamoylbenzoyl chloride stirring was continued for another 10 minutes at +5° C. and the fair yellow crystalline precipitate of 4'-bromo-3'-sulfamoyl-diazoacetophenone was filtered off. The 4'-bromo-3'-sulfamoyl-diazoacetophenone so obtained was introduced without further purification in small portions into a stirred mixture cooled to 0° C. of 30 ml of diethylene glycol dimethyl ether and 20 ml of concentrated HCl (37%). After nitrogen development had finished, stirring was continued for another 10 minutes at 0° C., 150 ml of water were added and after dwelling for 1 hour at 0° C. the crystalline precipitate of 4'-bromo-3'-sulfamoyl-2-chloroacetophenone was filtered off. Colorless crystals, melting point: 152° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)(=[O:3])[NH2:2].[H-].[Na+].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:37](=O)[O:38]C1C=CC=CC=1.O>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:37](=[O:38])[NH:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[F:28])[CH:21]=[CH:20]2)(=[O:3])[NH2:2]
Reactant: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)cc4F)c3)c2cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
After dissolving 6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (100 mg, 0.3 mmol) in N,N-dimethylformamide (0.5 ml), there was added sodium hydride (12 mg, 0.3 mmol) while cooling on ice and the mixture was stirred at room temperature for 15 minutes. After adding phenyl N-(2,4-difluorophenyl)carbamate (79 mg, 0.3150 mmol), the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate and tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the filtrate was distilled off under reduced pressure. The obtained crystals were suspended in ethanol and diluted with hexane, and then the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (84 mg, 0.1718 mmol, 57.28%) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]1[O:18][CH2:17]1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>C(O)C>[OH:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[CH2:17][CH:16]([OH:18])[CH2:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(C)CCCCCCCCCCCOCC1CO1
Reactant: OCCNCCO
Solvent: CCO
Product: CCCCC(C)CCCCCCCCCCCOCC(O)CN(CCO)CCO
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
In a 10 ml round bottomed flask, 12-methylhexadecylglycidylether (100 mg, 0.32 mmol), diethanolamine (35 mg, 0.33 mmol), and ethanol (1 ml) were placed. The content of the flask was stirred for 1 hour at 80° C. in a nitrogen atmosphere. The mixture was condensed under reduced pressure, and the resulting residue was purified by silica gel flush chromatography. As a result, 88 mg of the title compound was obtained as a pale yellow oil (yield: 66%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1ccc(C(C)=O)cc1
Yield: 76.4 %

Procedure:
A solution of 4-acetylbenzenesulfonamide (0.726 g, 3.64 mmol), acetic anhydride (0.7 ml, 7.42 mmol) and DMAP (22.26 mg, 0.182 mmol) in pyridine (0.7 ml) was stirred at room temperature 16 hrs. The volatiles were removed under reduced pressure, the residue was taken up in toluene (5 mL) and concentrated again (3×). The residue was dissolved in EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The solid residue was triturated in Et2O and filtered to give N-[(4-acetylphenyl)sulfonyl]acetamide (670 mg, 2.78 mmol, 76% yield) as a pale yellow solid. MS ESI: [M+Na]+ m/z 264.0. 1H NMR (500 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.13 (d, J=9.9, 2H), 8.01 (d, J=9.9, 2H), 2.62 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][Si:4]([CH3:54])([CH3:53])[CH2:5][CH2:6][O:7][CH2:8][N:9]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=4)=[C:14]2[N:13]=[C:12]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[C:11]=1[Br:44].[CH2:55](Br)[CH:56]=[CH2:57]>CN(C=O)C.O>[CH2:57]([N:30]([C:12]1[C:11]([Br:44])=[C:10]([N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:3])([CH3:53])[CH3:54])[CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:50])[CH3:52])[N:15]2[N:16]=[CH:17][C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=4)=[C:14]2[N:13]=1)[CH:31]1[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]1)[CH:56]=[CH2:55]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NaH (60%, 40.2 mg, 1.00 mmol) was added in one portion to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate (205 mg, 0.25 mmol) in DMF (6 mL). After stirring at room temperature for 30 min, the mixture was cooled to 0° C. and allyl bromide (60.8 mg, 0.50 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-(allyl(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carboxylate: LCMS tR=1.99 Min (5 min run, UV254nm), Mass calculated for M+855.3, observed LC/MS m/z 856.3 (M+H).