Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Br[CH2:23][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH2:23][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:18])(=[O:14])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOP(=O)(CCBr)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCOC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I)OCC
Reaction time: 12 h
Yield: 41.4 %

Procedure:
To a stirred solution of sodium diatrizoate (7.1 g, 11.2 mmol) in dry dimethylformamide (50 ml) at room temperature under a blanket of argon was added a solution of diethyl 2-bromoethylphosphonate (3.02 g, 12.3 mmol, 1.1 eq.) in dimethylformamide (10 ml). After stirring for 12 hours, the solvent was evaporated under vacuum to give a white solid that was washed with 300 ml of saturated aqueous NaHCO3, and then extracted with a 2:1 mixture of chloroform-ethanol (3×200 ml). The organic extract was dried (MgSO4), filtered, and evaporated under vacuum to give 3.61 g (41%) of product as a white solid. Recrystallization from acetonitrile gave analytically pure material; mp 249-251° C.; MH+ (779). The 1H-NMR (300 MHz) spectrum was consistent with the desired material.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=O)[CH2:4][C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1
Reactant: CN(C)C(=O)CC1(C)Oc2ccccc2-n2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCC1(C)Oc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the amide of formula 3, N,N,4-trimethyl-4H-pyrrolo-[2,1-c][1,4]benzoxazin-4-acetamide (5 g), described in Example 14, in 150 ml of ether is added dropwise to a suspension of lithium aluminum hydride (2.6 g) in anhydrous ether (350 ml). The reaction mixture is stirred at room temperature for 4 hr. Decomposition of the mixture with 11 ml of water gives a white precipitate, which is collected on a filter and washed with ether. The filtrate is extracted with 2% aqueous HCl. The extract is rendered basic with a 10% solution of NaOH and extracted with chloroform. The chloroform extract is dried (MgSO4), filtered and evaporated to give the title compound, nmr (CDCl3) δ 1.61 (s, b 3H), 2.18 (s, 6H), 2.25 (m, 4H), 5.98 (m, 1H), 6.30 (6, J = 3.5 Hz, 1H), 6.9 - 7.5 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9]([Si:12](OS(C(F)(F)F)(=O)=O)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=c1ccc(Br)c[nH]1
Product: CC(C)[Si](Oc1ccc(Br)cn1)(C(C)C)C(C)C

Procedure:
5-Bromo-2(1H)-pyridinone is allowed to react with triisopropylsilyl-trifluoromethanesulfonate to afford 5-bromo-2-(triisopropylsilyloxy)pyridine having the formula IV. ##STR16##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>CN(C=O)C>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[C:22]([F:27])[CH:21]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Nc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 150 °C

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 4-bromo-2-fluoroaniline (155 mg, 0.82 mmol) in DMF (2.5 ml) was heated at 150° C. for 45 minutes. After cooling to ambient temperature the mixture was treated as described in Example 3 to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (150 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13][Br:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Br)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)ccc1CBr
Temperature: 70 °C
Yield: 76.1 %

Procedure:
A mixture of ethyl 5-bromo-2-methylbenzoate (7.52 g, 30.9 mmol), N-bromosuccinimide (6.05 g, 34.0 mmol) and benzoyl peroxide (0.75 g, 3.10 mmol) in carbon tetrachloride (150 ml) was heated to 70° C. in an oil bath for 18 h. After this time, the mixture was cooled to room temperature and the solids removed by filtration. The filtrate was then concentrated under reduced pressure and purified by flash chromatography (silica, gradient 1-10%, ethyl acetate/hexanes) afforded ethyl 5-bromo-2-(bromomethyl)benzoate (7.57 g, 76%) as a clear oil: 1H NMR (300 MHz, CDCl3) 8.09 (d, J=2.2 Hz, 1H), 7.61 (dd, J=8.3, 2.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.90 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1>C(O)C>[CH2:14]([O:13][C:5](=[O:12])[CH:6]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCC
Yield: 84.9 %

Procedure:
60.17 g of sodium ethoxide were dissolved in 1127 ml of ethanol. To this solution, 336.4 g of diethyl malonate and 115.0 g of (4-chlorophenyl) methyl chloride were added and the mixture was refluxed for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure and water was added to the residue. After extraction with ethyl acetate, the ethyl acetate was dried with sodium sulfate anhydride. After removing the solvent under reduced pressure and purification with distillation, 172.6 g of 2-[(4-chlorophenyl)methyl]malonic acid diethyl ester were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 97.2 %

Procedure:
To a stirred solution of compound ethyl 2-(4-hydroxyphenyl)acetate (30 g, 0.16 mol) in acetonitrile (300 mL) was added K2CO3 (114.9 g, 0.83 mol) and 2-(chloromethyl) quinoline (42.7 g, 0.19 mol) at RT. The reaction mixture was refluxed for 16 h, filtered and the resulting solid residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (50 g, 93%) as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17](Cl)[CH:18]=2)[C:13]=1[OH:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:31][N:32](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:31]#[N:32])[CH:18]=2)[C:13]=1[OH:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(Cl)ccc2c1O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(C#N)ccc2c1O
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(6-chloro-4-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate (0.2186 g, 0.593 mmol), zinc(II) cyanide (0.0695 g, 0.593 mmol), XPhos Palladacycle (0.044 g, 0.0593 mmol) and sodium bicarbonate (0.005 g, 0.0593 mmol) in anhydrous DMF (3.0 mL) was heated in a microwave at 100° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The Combined organic layer was washed with 5% lithium chloride solution, brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 15% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C20H21FNO4: 358.2. Found: 357.9.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@@H:21]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][C@H:23]([C:34]([O:36]C)=[O:35])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+].CO>[C:30]([O:29][C:27]([N:25]1[CH2:26][C@@H:21]([N:20]([C:18]([C:8]2[C:9]([NH:11][CH2:12][C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][CH:7]=2)=[O:19])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:22][C@@H:23]([C:34]([OH:36])=[O:35])[CH2:24]1)=[O:28])([CH3:32])([CH3:33])[CH3:31]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ccco2)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Yield: 84.1 %

Procedure:
1-tert-Butyl 3-methyl (3R*,5S*)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-1,3-dicarboxylate (250 mg) was dissolved in 2 M aqueous sodium hydroxide solution (1 ml) and methanol (2 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The mixture was adjusted to pH 3 with 1 M hydrochloric acid, and the precipitate was collected by filtration to give the object compound (205 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C>[CH3:33][NH:29][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and methylamine (1 M solution in MeOH, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (40 mg, 33%) as an off white solid. MS: m/e=324.4 [M+H]+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([NH:22]N)[CH:18]=[C:19]([CH3:21])[CH:20]=1.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]([CH3:27])=O.O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:30]([O:29][C:24]([C:25]1[NH:22][C:17]2[C:16]([CH:27]=1)=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=2)=[O:28])[CH3:31]
Reactant: Cc1cc(C)cc(NN)c1
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1cc2c(C)cc(C)cc2[nH]1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
In a flask fitted with a Dean-Stark trap, p-toluenesulfonic acid monohydrate (132 g, 0.69 mol) in 500 ml of benzene was heated at reflux for 2 hours. A solution of 3,5-dimethylphenylhydrazine hydrochloride (34.5 g, 0.2 mol), ethyl pyruvate (23.2 g, 0.2 mol), and p-toluenesulfonic acid monohydrate (0.85 g, 0.005 mol) in 500 ml of benzene, which had been refluxed for 2 hours with water removed through a Dean-Stark apparatus was then added. The resulting mixture was heated at reflux and stirred overnight. After cooling, the solution was treated with saturated sodium bicarbonate solution and diluted with methylene chloride. The organic portion was washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by ISCO (hexane/EtOAc, 0-30%, 40 min) to give yellow solids, which was recrystallized from hexane/ethyl acetate (10%) to give colorless needles (35.6 g, 82%). 1H NMR (DMSO-d6, 400 MHz): δ 11.68 (brs, 1H, exchangeable with D2O, NH), 7.12 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 4.33 (q, J=6.8 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:28]C(=O)OC(C)(C)C)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:28][C@H:14]([CH:2]([OH:1])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:21]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C(O)[C@@H](N)CCCCNC(=O)N1CCOCC1)c1ccccc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 830 mg (1.7 mmol) of tert-butyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate in 100 mL of ethyl acetate was bubbled with hydrogen chloride gas for 5 min and the reaction allowed to stir for 10 min before being conentrated under reduced pressure to afford 720 mg (>99%) of N-((5S)-5-amino-6-hydroxy-7-oxo-7-{[(1R)-1-phenylethyl]amino}heptyl)-4-morpholinecarboxamide hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=8 Hz, 1H), 7.97 (m, 1H), 7.82 (m, 2H), 7.31 (m, 4H), 7.22 (m, 1H), 6.50 (m, 1H), 4.94 (qnt, 1H), 3.83 under water peak (m, 2H), 3.50 (t, J=5 Hz, 4H), 3.22 (t, J=5 Hz, 4H), 2.98 (m, 2H), 1.20-1.61 (m, 9H). ES-LCMS m/z 393 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Yield: 94 %

Procedure:
A solution of 1-bromomethyl-3-nitrobenzene (2.16 g, 10 mmol), morpholine (1.76 g, 20.2 mmol) and triethylamine (1.0 mL) in THF (60 mL) was heated for two hours at 60° C. The solvent was evaporated, water was added and the product was isolated by extraction with ether. The ether extract was dried over Mg2SO4 and the solvent was evaporated. The crystalline residue was used in the next step without further purification. The product, 4-(3-nitrobenzyl)morpholine, was obtained in 94% yield (2.09 g).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([C:18]4(C(O)=O)[CH2:20][CH2:19]4)[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:24].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[NH2:39][C:18]1([C:14]2[CH:13]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:24])[CH2:4][CH2:5]4)[CH:17]=[N:16][CH:15]=2)[CH2:20][CH2:19]1
Reactant: CN1C(=O)CCc2cc(-c3cncc(C4(C(=O)O)CC4)c3)ccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cc(-c3cncc(C4(N)CC4)c3)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To solution of 1-(5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)cyclopropanecarboxylic acid (0.551 g, 1.52 mmol) in toluene (20 mL) were added TEA (0.185 g, 1.83 mmol) and diphenylphosphoryl azide (0.419 g, 1.52 mmol) and then the reaction mixture was heated to reflux for 4 h. After cooling to 0° C., a 1 M solution of sodium trimethylsilanoate in THF (3.04 mL, 3.04 mmol) was added and the mixture was stirred for 45 min at room temperature. After quenching with 0.1 M aq. HCl (40 mL), the aqueous solution was washed with ether (2 times), then basified with 1 M aq. NaOH and then extracted with DCM (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.333 g, 71%) as a yellow foam. MS: 294.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]=[C:22]([CH3:26])[C:23](O)=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:23](=[O:24])[C:22](=[O:21])[CH3:26])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(=O)C(=O)O
Product: CC(=O)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-oxo-propanoic acid (127-17-3) as starting materials; MS (EI) 373.0(M+H) +.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[C:17]([CH2:21][N:22]2[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[N:23]2)[CH:18]=[CH:19][CH:20]=1.Cl.CN(C)CCCN=C=NCC>CO>[NH2:8][C:7]1[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[NH:4][C:3](=[O:12])[C:2]=1[NH:1][C:27]([C:25]1[CH:24]=[N:23][N:22]([CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:31])([F:13])[F:30])[CH:16]=2)[CH:26]=1)=[O:28]
Reactant: CCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCn1c(N)c(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5,6-diamino-1-ethyl-1,3-dihydropyrimidine-2,4-dione (2 g, 11.76 mmol) and 1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxylic acid (3.5 g, 12.94 mmol) in methanol (50 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.47 g, 12.94 mmol), and the reaction mixture was stirred for 16 hours at room temperature. Solvent was removed under reduced pressure, and the residue was washed with water and methanol. The product was dried under vacuum to provide N-(6-amino-1-ethyl-2,4-dioxo(1,3-dihydropyrimidin-5-yl))(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)carboxamide, a compound of formula (16).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:12]1=[O:13].[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)C>[CH2:18]([NH:30][C:12](=[O:13])[CH:11]([S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:16][C:15]([OH:14])=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CC(Sc2nc3ccccc3s2)C(=O)O1
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)C(CC(=O)O)Sc1nc2ccccc2s1

Procedure:
A mixture of 7 parts of (benzothiazol-2-ylthio)succinic anhydride, 4.8 parts of dodecylamine and 60 parts of diethyl ether is heated at 35° for 3 hours. Filtration of the resulting mixture gives a mixture of the two isomeric mono(dodecylamides), melting at 117°-121°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]3[N:11]([N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH:10]=[CH:9]2)[C:3]=1[OH:22].[F:23][S:24]([F:37])([F:36])([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C=O)C.O>[OH:22][C:3]1[C:4]([N:8]2[C:15]3[N:11]([N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH:10]=[CH:9]2)=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([S:24]([F:37])([F:23])([F:34])([F:35])[F:36])[CH:26]=1
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1O
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1O)c1cccc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
80 mg (0.192 mmol) of the compound of Example 71A and 48 mg (0.192 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid were dissolved in 1.5 ml anhydrous DMF, and 88 mg (0.231 mmol) of HATU and 40 μl (0.231 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 30 min and then stirred into about 10 ml of water. The resulting precipitate was filtered off with suction and dissolved in 3 ml of methanol, and 385 μl (0.385 mmol) of 1 M aqueous sodium hydroxide solution were added. The mixture was then stirred at RT for 30 min and then, by preparative HPLC, separated completely into its components (Method 33). The product fractions were combined and freed from the solvent. The residue was triturated with a mixture of 5 ml of pentane and 1 ml of dichloromethane at RT. Filtration with suction and drying of the solid under high vacuum gave 32 mg (32% of theory) of the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=1.[CH:16](=[O:19])[CH2:17][CH3:18]>O1CCCC1>[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([CH:16]([OH:19])[CH2:17][CH3:18])[CH:11]=[CH:10][N:9]=1
Reactant: CCC=O
Reactant: COc1cccnc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1ccnc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (38.7 mL; 10 M in tetrahydrofuran (THF)) was dissolved in THF (600 mL) and cannulated to a solution of 2,3-dimethoxypyridine (3) (22.4 g; 161 mmol) in THF (200 mL) at −78° C. The reaction mixture was then warmed to 0° C. and stirred for 1 hour. The propionaldehyde (29.1 mL; 403 mmol) was added dropwise at −78° C. The reaction mixture was warmed to 25° C. and stirred for 16 hours. The reaction mixture was subsequently quenched with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, concentrated under reduced pressure and purified by chromatography (SiO2; 2-10% ethyl acetate/hexane) to give the 2,3-dimethoxy-4-(1′-hydroxypropyl)pyridine (4) product (18.6 g; 59%) as a colorless oil.