Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:8][OH:9])[CH2:7][O:6][CH2:5]1.[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22](OCC(Cl)(Cl)Cl)=[O:23])([CH3:12])[CH3:11]>C1COCC1>[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22]([O:9][CH2:8][C:4]1([CH3:3])[CH2:7][O:6][CH2:5]1)=[O:23])([CH3:12])[CH3:11]
Reactant: CC1(CO)COC1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC1(C)COC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.8 %

Procedure:
NaH (0.19 g, 4.80 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (10 mL), cooled to 0° C. and 3-methyl-3-oxetane methanol (0.41 g, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (1.33 g, 4.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 3-methyl-3-oxetane methanol in THF were added after 8 and 32 h, respectively. After 50 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5%, 10% and 20% MeOH in DCM (200 mL each)) and by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (3-methyloxetan-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (68.2 mg, 5.8%) as a white solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: C/C=C/CC(=O)O
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 89%), MS (ISP) m/z=413.4 [(M+H)+], mp 170° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[C:7]([NH2:10])=[CH:8][CH:9]=[C:4]([F:3])[N:5]=1
Reactant: BrBr
Reactant: Nc1ccc(F)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(F)nc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Bromine (1.96 g, 12.2 mmol) is added to a mixture of 2-fluoro-5-aminopyridine (1.37 g, 12.2 mmol) and sodium acetate (2 mg, 24.4 mmol) in acetic acid (30 mL) and stirred at rt for 4 hours. Acetic acid is evaporated off in vacuo. The residue is dissolved in EtOAc (50 mL), washed with saturated aqueous Na2CO3 (10 mL), water (20 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-bromo-3-amino-6-fluoropyridine (2.1 g) as a solid. MS: 190 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.04 (br, 2H), 6.77 (dd, H), 7.17(dd, H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[O:4][C@@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:36][C@H:37]([C:39](O)=[O:40])[CH3:38])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:36][C@H:37]([C:39]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[O:4][C@@H:3]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:40])[CH3:38])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To a stirred solution of methyl [(2R,3S)-3-amino-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate (70b) (130 mg, 0.398 mmol) in dichloromethane (4 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (125 mg, 0.514 mmol), HOBt (71 mg, 0.525 mmol), NMM (53 mg, 0.525 mmol) and EDAC-HCl (100 mg, 0.522 mmol). After stirring at ambient temperature under nitrogen for 48 h the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexane:ethyl acetate to afford the title compound (185 mg, 82%) as a white solid. TLC Rf=0.13 (1:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.21 (d, 3H, J=7.0 Hz), 3.46 (s, 2H), 3.80 (s, 3H), 4.23 (m, 1H), 4.55 and 4.68 (AB quartet, 2H, J=17.1 Hz), 5.16 (t, 1H, J=7.2 Hz), 5.72 (d, 1H, J=7.4 Hz), 5.87 (br d, 1H, J=7.0 Hz), 6.17 (br d, 1H, J=6.6 Hz), 6.66-6.87 (m, 3H), 7.19-7.33 (m, 4H), 7.37 (s, 5H). MS APCI, m/z=552 (M+1). LC/MS: 2.52 min.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 64 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-phenyl-5-methyl-oxazole, the title compound was obtained in 64% yield as a pale yellow solid. MS: (M−H)− 403.3.
Reaction SMILES: [Na].C(O[C:5]([NH:7][N:8]([CH2:11][CH3:12])[C:9]#[N:10])=[O:6])C.[CH2:13]([OH:15])[CH3:14]>>[CH2:11]([N:8]1[C:9]([O:15][CH2:13][CH3:14])=[N:10][C:5]([OH:6])=[N:7]1)[CH3:12]
Reactant: CCO
Reactant: CCOC(=O)NN(C#N)CC
Agent: [Na]
Product: CCOc1nc(O)nn1CC
Yield: 60 %

Procedure:
To a solution of 4.6 g of sodium in 150 ml of absolute ethanol there is added dropwise at 60° C 31.4 g of 2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester. The solution is subsequently refluxed for 4 hours. From the cooled solution there precipitates, after the addition of 12 g of glacial acetic acid, sodium acetate, which is separated by filtration. The filtrate is concentrated in vacuo to dryness, and the residue is extracted with 200 ml of chloroform. The extract is again concentrated to dryness and the residue is recrystallised from cyclohexane. There is obtained 18.8 g (60% of theory) of 1-ethyl-5-ethoxy-3-hydroxy-1,2,4-triazole, m.p. 64° to 67° C.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl>CO>[NH:1]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C@H:2]([C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 5.80 g of BOC-Val-Gly-OEt dissolved in 10 ml of methanol, under cooling, was added 23 ml of 1N aqueous sodium hydroxide and the mixture was stirred for one hour, followed by adjustment of pH to 8.0 with 1N hydrochloric acid. The reaction mixture was concentrated under reduced pressure to evaporate methanol, and the aqueous layer was washed with diethyl ether and then adjusted to pH 2.0 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was treated with n-hexane and recrystallized from ethyl acetate-n-hexane to give 4.76 g (yield: 90.5%) of BOC-Val-Gly-OH melting at 101° to 107° C. Rf1 =0.20.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:26])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:26][CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: NC/C=C/c1ccccc1
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(NC/C=C/c1ccccc1)C2

Procedure:
Starting from 1.02 g (0.005 mol) of 5-acetylamino-2-tetralone and 1.7 g (0.01 mol) of trans-cinnamylamine-hydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.1 g (61.6% of theory) and with a melting point of 257° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: COc1ccccc1S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Sc1ccc2c(c1)C=C(C)C(C)(C)O2
Yield: 68.8 %

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (9.6 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), then sodium tert-butoxide (11.0 g), 2-methoxybenzenethiol (5.3 g) and tetrakis(triphenylphosphine)palladium(0) (0.45 g) were added and the mixture heated under reflux under a nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed first on silica using 1:1 hexane:dichloromethane as the eluent and then on silica using 24:1 hexane:ethyl acetate as the eluent to yield 6-(2-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (8.12 g) as an oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(N)ccc2o1
Reactant: CS(=O)(=O)Cl
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1

Procedure:
Patent application WO0248132 describes a method for the synthesis of dronedarone using 2-n-butyl-5-nitro-benzofuran which is reduced, under pressure, with hydrogen in the presence of platinum oxide as catalyst in order to form 2-n-butyl-5-amino-benzofuran. This benzofuran derivative is then subjected to the action of methanesulfonyl chloride, which gives 2-n-butyl-5-methanesulfonamido-benzofuran which is treated with 4-[3-(di-n-butylamino)-propoxy]-benzoyl chloride to give dronedarone.
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=3[CH:4]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(O)c2cc3ccccc3s2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-(4-methoxybenzyl)-benzo[b]thiophene was prepared by the method of Example 47B with α-(2-benzo[b]thienyl)-4-methoxybenzyl alcohol (1.9 mmoles) 0.50 g), triethylsilane (2.0 mmoles, 0.32 mls), CH2Cl2 (20 ml) and TFA (3.7 mmoles, 0.30 ml). Recrystallization with hexanes and chloroform provided 0.40 (85%) of a pink solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Yield: 99.4 %

Procedure:
To a solution of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (2.5 g) in acetone (30 ml) was added 6 N hydrochloric acid (1 ml) and treated in a substantially similar manner to those of Example 2-6) to give a viscous oil (2.10 g) of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[NH:26][C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.CN(C=O)C>CC#N>[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[N:26]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: BrCc1ccccn1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
K2CO3 (44 mg, 0.32 mmol) and 2-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) were added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20. mg, 0.11 mmol) in DMF (3.0 mL, 39 mmol). After stirring at room temperature for 2 hours, the reaction was heated to 50° C. for 35 minutes. The reaction mixture was diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (8.9 mg, 30%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)[CH:2]=[CH2:3].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCOCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 123 %

Procedure:
A reaction mixture containing 14 g of allyl(4-chlorobutyl) ether, 14 g of 4-hydroxybenzoic acid, 14 g of potassium carbonate and 50 mL of dimethylformamide was stirred at 90° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with toluene. The toluene layer was well washed with water, and then toluene was distilled off. 20 g of sodium hydroxide, 50 mL of water and 200 mL of ethanol were added to the resulting residue, followed by refluxing for 2 hours. Ethanol was distilled off, and hydrochloric acid was added to make the reaction mixture acidic. The mixture was extracted with diethyl ether and dried over anhydrous magnesium sulfate. A residue obtained by distilling the solvent was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid.
Reaction SMILES: [Br:1]C1C=CC(C(O)=O)=CC=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH:26]([OH:28])[CH3:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)=[CH:14][CH:13]=1>>[Br:1][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=1[C:18]1[O:19][C:20]([CH:26]([OH:28])[CH3:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Product: CC(C)c1nc(-c2ccccc2Br)oc1C(C)O

Procedure:
By the sequence above as preparation 78, 4-bromo-benzoic acid is converted to 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22]I>CN(C=O)C>[Cl:19][CH2:20][CH2:21][CH2:22][S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10]
Reactant: ClCCCI
Reactant: O=S(O)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(CCCCl)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 mmol 3,4-difluoro-benzenesulfinic acid and 36.8 mmol triethylamine in 100 ml DMF was added 70.7 mmol 1-chloro-3-iodopropane and the mixture stirred at RT for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH2:14]([O:16][CH:17]=[CH:18][C:19](Cl)=[O:20])[CH3:15]>N1C=CC=CC=1>[CH2:14]([O:16][CH:17]=[CH:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:8][CH:9]=1)=[O:20])[CH3:15]
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: CCOC=CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccc(-n2ccnc2C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
4-(2-methyl-1H-imidazol-1-yl)aniline (40.7 g, 232 mmol; RN: 74852-81-6, Maybridge, J. Med. Chem., 48(6), 1729-1744; 2005) was dissolved in dry pyridine (290 mL), 3-ethoxyacryloyl chloride (36.1 g, 268 mmol) was then added dropwise at 0°/−10° C. The resulting mixture was stirred at 0° C. for 2 hours and at r.t. overnight. The reaction mixture was quenched with 100 mL of water, and pyridine was distilled i.v., the residue was taken up with water and the pH was adjusted to pH=10, by adding K2CO3, the resulting suspension was extracted with AcOEt and concentrated. The resulting solid was stirred with hexane and filtered to afford the title product (58 g; 92%). C15H17N3O2, MW: 271.32.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH2:23])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH:23][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: C/C=C/C(=O)Cl
Product: C/C=C/C(=O)NCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 81.1 %

Procedure:
Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200° C. Analysis: Calculated for C19H24N6O: % C, 64.75; % H, 6.86; % N, 23.85; Found: % C, 64.25; % H, 6.68; % N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCCC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 76.3 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 4-aminobutyric acid (0.54 g, 0.0052 mol) were refluxed as above for 7 hours. Crystallisation of the product from EtOH yielded 1.1 g (76%) of 102 as a white solid: mp=218-220° C.; Rf0.78 (A): Rf0.84 (C): Rf0.28 (D): 1H NMR (DMSO-d6); IR (cm−1): 2800-3250 (OH), 3050 (C═CH), 2680 (C—H), 1760 (C═O), 1712 (bs, C═O), 1560 (C═C), 1430 (C═C), 1397 (C—O), 1305 (C—O), 727 (C═CH); MS m/z (rel intensity) 277 (18), 276 (100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-trifluoromethylphenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.