Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred solution of 4-fluoro aniline (16a, 4g, 32.7 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 6.69 g, 36.0 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl to afford compound N-(4-fluorophenyl)-4-nitrobenzamide (18a). To a stirred solution of amide (18a, 8g, 30.7 mmol) taken in toluene lawessons reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) (10.18 g, 25.2 mmol) is added and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform finally purification by column chromatography to afford pure compound N-(4-fluorophenyl)-4-nitrobenzothioamide (19a). Treating the thioamide product (19a, 4g, 14.49 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 3h cyclization takes place to obtain the 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazole (20a) solid is precipitated from the reaction mixture filtered and washed with water to get 20a. Reduction of the nitro compound (20a, 1 g, 3.64 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h. After completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21a) The compound 4-(6-fluorobenzo[d]thiazol-2-yl)benzenamine (21a, 244 mg, 1 mmol) on reaction with 4-fluoro 3-methoxy benzaldehyde (22c, 152 mg, 1 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 4c as a light yellow solid (68%).
Reaction SMILES: COCN[C:5]([C:7]1[C:8]2[N:9]([N:15]=[C:16]([CH2:18][CH3:19])[CH:17]=2)[C:10](OC)=[CH:11][CH:12]=1)=[O:6].[CH2:20]([Mg]Br)[CH3:21].[Cl-].[NH4+].O1CC[CH2:28][CH2:27]1>>[CH2:18]([C:16]1[CH:17]=[C:8]2[C:7]([C:5](=[O:6])[CH2:20][CH3:21])=[CH:12][CH:11]=[C:10]([CH2:27][CH3:28])[N:9]2[N:15]=1)[CH3:19]
Reactant: CCc1cc2c(C(=O)NCOC)ccc(OC)n2n1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(=O)c1ccc(CC)n2nc(CC)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Example 349 (11.09 g) was dissolved in tetrahydrofuran (320 mL) in an argon atmosphere. While this solution was chilled in a ice salt water bath (−7° C.), ethyl magnesium bromide (100 mL, 0.91 mol/L tetrahydrofuran solution) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, a saturated aqueous ammonium chloride solution was added while the mixture was chilled in an ice bath. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel chromatography (hexane:ethyl acetate=2:3→1:2→1:4→ethyl acetate) afforded the title compound as a yellow powder (4.21 g).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]2)=[N:10][C:11]=1[NH2:12].[Cl:24][C:25]1[CH:26]=[N:27][N:28]([C:30]2([C:33](=N)OCC)[CH2:32][CH2:31]2)[CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:24][C:25]1[CH:26]=[N:27][N:28]([C:30]2([C:33]3[NH:12][C:11]4=[N:10][C:9]([N:13]5[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]5)=[CH:8][CH:7]=[C:6]4[N:5]=3)[CH2:32][CH2:31]2)[CH:29]=1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Yield: 81.2 %

Procedure:
Acetic acid (4.3 g, 67.2 mmol) was added to a solution of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate (890 mg, 3.36 mmol), ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (445 mg, 1.78 mmol) and triethylamine (0.8 mL, 5.92 mmol) in ethanol (25 mL) at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 16 h, then was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 20-60% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (600 mg). MS (ES+) (M+H) 415.2859.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)C.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1ccccc1Cl

Procedure:
A mixture of 35.1 g (0.15 mole) of 1-(o-chlorophenoxy)-2-hydroxybutyl chloride, 32.6 g (0.2 mole) of N-phenylpiperazine and 400 ml of 2-propanol was heated at reflux for 48 hr. The resulting reaction mixture was allowed to stand in a refrigerator overnight and filtered. The filtrate was treated with ethereal hydrogen chloride and precipitated with ether. Upon filtering, a white crystalline solid formed which was dissolved in dilute hydrochloric acid and the mixture was then neutralized with aqueous sodium hydroxide producing a crystalline precipitate. This was recrystallized with isopropanol yielding 36 g of the free base, m.p. 100°-101.5° C.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([Cl:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCl
Reaction time: 0.25 h

Procedure:
Into a dry 4-neck-round bottomed flask equipped with nitrogen inlet, addition funnel, therometer, mechanical stirrer and heating means, under nitrogen, are cautiously (to avoid foaming), charged 229 g. of oleic acid (99% pure, m.p. 4°; b.p. 286°/100 mmHg), 263 ml of toluene and 109 ml. of oxalyl chloride (b.p. 63°-64°), at a rate so as to keep the (internal) reaction temperature between 25°-30°, over a period of about 15 minutes. After addition is complete the funnel is washed with an additional 25 ml. toluene. The reaction mixture is stirred 25°-30° for about one-half hour, and then at about 50°-55° for 1 hour. The toluene is then distilled off (initially at 35°-40°/63 mm vapor pressure; then at 30°-25°/26 mm for 1.5 hours) to obtain oleyl chloride, which is promptly used for the following Step B.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][O:31]2>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:34]4[CH2:35][C@@H:30]5[CH2:36][C@H:33]4[CH2:32][O:31]5)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3C[C@@H]4C[C@H]3CO4)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and (1S,4S)-2oxa-5-aza-bicyclo[2.2.1]heptane, the title compound was prepared as off-white solid. MS: m/e=422(M+H+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH2:20].N1C=CC=CC=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH:20][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(NC(=O)C3CC3)ncc2c1

Procedure:
To 4-bromo-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (46 mg, 140 μmol) and pyridine (110 μl, 1.4 mmol) in dichloromethane (3.0 mL) at ambient temperature was added dropwise cyclopropanecarbonyl chloride (60 μl, 0.66 mmol). After 1 h the mixture was poured into saturated aqueous sodium bicarbonate, extracted twice into dichloromethane and the combined organic phases dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (57 mg, quant.). 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.26 (s, 1H), 8.27-8.14 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.49-7.33 (m, 1H), 7.21 (t, J=9.2 Hz, 2H), 2.25 (s, 3H), 1.98-1.84 (m, 1H), 0.90-0.78 (m, 4H). LCMS (Method E): RT 5.299 min, M+H+=399.0 & 401.0.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([NH:35][C@@H:36]([CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[C:37](O)=[O:38])=O)(C)(C)C.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.CC(=O)OCC>[NH2:35][C@@H:36]([CH2:40][CH2:41][OH:42])[C:37]([NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:38]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC(=O)[C@@H](N)CCO)CC4)n3)ccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
50 mg (0.12 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 44 mg (0.13 mmol) of (S)-2-tert-butoxycarbonylamino-4-(tert-butyldimethylsilanyloxy)butyric acid (preparation analogous to Tetrahedron, 2005, vol. 61, #43 p. 10277-10284) were dissolved in 1 ml of DCM together with 50 μl (0.29 mmol) of N-ethyldiisopropylamine and stirred at 0° C. for 5 min. 73 mg (0.14 mmol) of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and 50 μl (0.29 mmol) of ethyldiisopropylamine were then added. The mixture was stirred further at 0° C. for 1 h, diluted with EA and washed by shaking with water and a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated. A 1.25 M HCl solution in methanol was then added to the residue, and the mixture was stirred for 1 h. The methanolic solution was evaporated, and the product was purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)O)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CN(C)C=O.[Br-].[Li+]>[N:46]([CH:21]([C:23]1[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=1)[CH2:20][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[C:12]([Cl:19])[CH:11]=1)=[N+:47]=[N-:48]
Reactant: CN(C)Cc1ccc(C(O)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)N=[N+]=[N-])o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
To a stirring solution of 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanol (2.18 mmol) in toluene (13.5 mL) and dimethylformamide (2.7 mL) at 0° C. was added diphenyl phosphoryl azide (5.46 mmol, 2.5 eq.) followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (5.46 mmol, 2.5 eq.). The reaction mixture was stirred 5 min at 0° C. then warmed to room temperature and stirred 16 h. The mixture was next diluted with saturated aqueous lithium bromide solution (25 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a dark brown syrup that was purified by column chromatography using 30% acetone/dichloromethane to give the product as a brown syrup (1.65 mmol, 76%). MS (ESI) m/z 462.4; HRMS: calcd for C25H24ClN5O2+H+, 462.16913; found (ESI, [M+H]+ Obs'd), 462.1693.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:10](CC1C=CC=CC=1)[C@H](C1C=CC=CC=1)C)[CH2:7][CH2:8][CH3:9])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([NH2:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC[C@H](N)CC(=O)OCC
Reaction time: 16 h

Procedure:
To a solution of (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 59 mmol) in EtOH (50 mL) was added Pd(OH)2 (20% in carbon) (2 g). The mixture was stirred under hydrogen atmosphere with 40 psi for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue (8.2 g, 87%) was used in the next step of the synthesis without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH3:13])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][C:10]#[N:11])[N:7]=1.[Cl:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:3](=[O:14])[N:4]([CH3:13])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][C:10]#[N:11])[N:7]=2)[CH2:21][CH2:20]1.[CH2:17]([OH:18])[CH2:16][CH2:28][CH3:27]
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: Cn1c(=O)c(Br)nn(CCC#N)c1=O
Product: CCCCO
Product: Cn1c(=O)c(N2CCC(Oc3ccccc3Cl)CC2)nn(CCC#N)c1=O
Yield: 58 %

Procedure:
The compound 23 (oil) is prepared from the triazine 3a and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 58%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl[CH2:19][C:20]([N:22]1[C:28](=[O:29])[CH:27]2[CH:23]1[CH2:24][CH2:25][CH2:26]2)=[O:21]>[I-].[K+].O.C(OCC)(=O)C>[C:12]([O:17][CH2:19][C:20]([N:22]1[C:28](=[O:29])[CH:27]2[CH:23]1[CH2:24][CH2:25][CH2:26]2)=[O:21])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)O
Reactant: O=C(CCl)N1C(=O)C2CCCC21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(=O)N1C(=O)C2CCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
In a four-necked flask with a volume of 500 mL, which was equipped with a thermometer, a stirrer, a dropping funnel, and a nitrogen introducing tube, 9.7 g (70 mmol) of potassium carbonate, 0.7 g (4 mmol) of potassium iodide, 100 mL of dimethylformamide, 25.8 g (300 mmol) of methacrylic acid, and 18.8 g (100 mmol) of 6-chloroacetyl-6-azabicyclo[3.2.0]heptan-7-one obtained in Synthesis Example 3 were charged, and the mixture was stirred at an internal temperature of 25° C. for 5 hours. To the reaction mixture, 100 mL of ethyl acetate and 50 mL of water were added, and a liquid separation operation was then carried out. The obtained organic layer was concentrated under reduced pressure and then purified by means of silica gel column chromatography, thereby obtaining 17.1 g (72 mmol) of 6-methacryloyloxyacetyl-6-azabicyclo[3.2.0]heptan-7-one having the following properties.
Reaction SMILES: [C:1]1([C:7]2(C(O)=O)CCC[CH2:8]2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)C(C1C=CC=CC=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:1]([CH:2]([CH2:3][CH2:4][CH3:5])[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19])[CH2:7][CH3:8]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CCCC(CCC)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-propylpentanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.94 (d, J=6.9, 1H), 7.72 (s, 1H), 7.62 (d, J=7.7, 1H), 7.56 (d, J=7.7, 1H), 7.47 (t, J=7.7, 1H), 4.48 (dt, J=7.3, 14.6, 1H), 3.52 (d, J=13.0, 1H), 3.48 (d, J=13.0, 1H), 2.84 (ddd, J=3.0, 7.7, 16.7, 1H), 2.74 (dd, J=3.1, 9.5, 1H), 2.52-2.45 (m, 1H), 2.38-2.34 (m, 2H), 2.27 (dd, J=7.6, 9.5, 1H), 2.22 (td, J=4.6, 9.5, 1H), 1.90 (dt, J=7.3, 11.5, 1H), 1.84-1.75 (m, 2H), 1.73-1.61 (m, 2H), 1.48-1.27 (m, 6H), 1.20-1.08 (m, 1H), 0.88 (t, J=7.0, 3H), 0.83 (t, J=7.1, 3H); MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: BrCCCBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCBr)c(C)c1

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 moles), K2CO3 (17.5 g, 144 mmoles), and 1,3-dibromopropane (30 g, 144 mmoles) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was removed on a rotary evaporator, and the crude solid was extracted into dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g). Purification was effected by flash chromatography over a silica gel column (SiO2, 150 g; eluted with 7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The material thus purified weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59°-61° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:7][C:6]=1[O:27][CH3:28].[OH-].[Na+]>CO.O1CCCC1.O>[CH3:12][O:11][C:10]1[CH:9]=[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:5]=1[C:4](=[O:29])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(=O)c1c(OC)cc(OCCOc2ccc3ccccc3c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OCCOc2ccc3ccccc3c2)cc(OC)c1C(=O)C(=O)O
Yield: 93.2 %

Procedure:
A solution of 2,6-dimethoxy-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.45 g of purified 2,6-dimethoxy-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 154° C. with decomposition. Analysis Calculated for C22H20O7 : C, 66.66; H, 5.09.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:19]([C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=4)=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])=[CH:9]1)[CH2:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:55][CH2:56][OH:57]>C(#N)C.O>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[C:19]([C:30]4[S:31][CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[N:34]=4)=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11](=[O:39])[C:10]([C:40]([N:42]2[CH2:43][CH2:44][N:45]([CH2:55][CH2:56][OH:57])[CH2:46][CH2:47]2)=[O:41])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: OCCBr
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCNCC2)cn3C(COC)COC)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(CCO)CC2)cn3C(COC)COC)cn1
Temperature: 55 °C
Yield: 33.9 %

Procedure:
1-{5-[1-(1,3-Dimethoxypropan-2-yl)-4-oxo-3-(piperazin-1-ylcarbonyl)-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea (Example 140, 180 mg, 0.267 mmol) was dissolved in acetonitrile (15 mL). Potassium carbonate (73.7 mg, 0.53 mmol) was added, followed by the addition of 2-bromoethanol (40 mg, 0.32 mmol) and the mixture was heated to 55° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated and dried to give the crude compound. The crude was dissolved in water (10 mL) and the pH was adjusted to 2. The aqueous solution was washed with ethyl acetate, then basified to pH˜8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 65 mg (34%) of 1-{5-[1-(1,3-dimethoxypropan-2-yl)-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-4-oxo-1,4-dihydroquinolin-6-yl]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}-3-ethylurea as an off-white solid.