Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=O)[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]2)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.O1CCCC1.O.C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:21][CH2:22][N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(C2(CC(=O)N(C)C)C=CCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
10.0 g of lithium aluminum hydride are placed in 200 ml of absolute tetrahydrofuran under a nitrogen atmosphere in a 1.5 liter sulfonation flask provided with reflux condenser, thermometer, stirrer and dropping funnel, and there is added dropwise while stirring within about 1 hour a solution of 42 g of 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-acetamide in 450 ml of absolute tetrahydrofuran in such a manner that the temperature does not exceed 30° C. Subsequently, the mixture is stirred overnight at an oil-bath temperature of 90° C., cooled to room temperature and treated first dropwise with 50 ml of ethanol and then with tetrahydrofuran/water (1:1) until the further addition of this mixture no longer gives rise to an exothermic reaction. The mixture is then treated with 50 g of potassium carbonate, whereupon the separated precipitate is removed by filtration under suction and rinsed with methylene chloride. After distillation of the solvent, the brown oil obtained is treated with 200 ml of 1 N hydrochloric acid and extracted twice with 500 ml of ether each time. The ethereal solution is washed once with 100 ml of water. The aqueous phases are combined and made alkaline by the addition of concentrated ammonium hydroxide solution while cooling with ice. The separated base is taken up twice in 500 ml of ether each time. The organic phase is washed twice with 50 ml portions of sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent is removed by distillation. The oil obtained is chromatographed on 400 g of neutral aluminium oxide. Elution with 2500 ml of toluene gives rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine in the form of a colorless oil which is dissolved in 200 ml of ethanol and treated with an excess of ethanolic hydrochloric acid. After distillation of the solvent, the residue is treated twice with a mixture of 100 ml of ethanol and 100 ml of toluene. Then, the solvent is removed by distillation in a water-jet vacuum. The crystals obtained are dissolved in ethyl acetate/ethanol (20:1) at boiling temperature. After standing for 6 hours, the separated crystals are removed by filtration under suction, and there is obtained rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine hydrochloride in the form of colorless crystals having a melting point of 161°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30](O)=O)[CH:15]=1>>[F:34][C:13]([F:12])([F:33])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[CH:15]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)n1
Product: Nc1ccc(-c2noc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.128 g, 0.60 mmol) and 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.12) (0.135 g, 0.403 mmol) according to the general procedure V. Obtained as a light yellow solid (0.022 g, 12%). MS (ISP) 452.1 [(M+H)+]; mp 229° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.F[P-](F)(F)(F)(F)F.[NH:36]1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([N:20]4[CH2:21][CH2:22][CH:23]([C:26]([NH2:36])=[O:28])[CH2:24][CH2:25]4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(C(=O)O)CC4)s3)n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(C(N)=O)CC4)s3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
1-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl} piperidine-4-carboxylic acid (100 mg, 0.25 mmol) obtained in Example 2 was dissolved in N,N-dimethylformamide (2 ml) and benzotriazolyloxy trispyrrolidino phosphonium hexafluorophosphate (263 mg, 0.50 mmol), diisopropylethylamine (0.18 ml, 1.03 mmol) and ammonium chloride (41 mg, 0.77 mmol) were added and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate was added to the reaction solution and the precipitated solid was collected by filtration and washed with water and title compound (89 mg, 89%) was obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1.[CH2:55]([C@@H:60]1[O:62][C@H:61]1[CH2:63]O)[CH2:56][CH2:57][CH2:58][CH3:59]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:63][C@H:61]2[C@H:60]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:62]2)=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:42][CH:41]=2)[N:34]=1
Reactant: CCCCC[C@@H]1O[C@H]1CO
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
0.44 g (2.55 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 0.67 g (2.55 mmol) of triphenylphosphine in 15 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 0.54 g (1.70 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine (prepared by EXAMPLE 3) and 0.25 g (1.70 mmol) of (2S,3S)-3-pentyl-2-oxiranylmethanol are then added. After a reaction time of 18 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 8:2hexane/ethyl acetate ). Recrystallization from 8:2hexane/ethyl acetate gives 0.28 g of (2S,3S)-3-pentyloxiran-2-ylmethyl 2-fluoro-6-(4-octyloxyphenyl)pyridin-3-yl ether having an [α]D° (2.4% in CH2Cl2) of -15.75°. ##STR70##
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])(=O)C.[Na+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CI
Reactant: Nc1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)CNc1ccc2ccccc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
A mixture of 2-napthylamine (compound I, FIG. 3B) (1.43 g, 10 mmol), ethyl iodoacetate (2.14 g, 10 mmol), and sodium acetate (1.64 g, 20 mmol, dissolved in 2 ml of water) was stirred at 90° C. for 3 hours. The solid material obtained upon cooling was filtered and recrystallized from hexane to yield 1.5 g ethyl N-(2-naphthalenyl)glycinate (compound II, FIG. 3B) (yield, 65%, mp 83-84° C.) (Ramamurthy and Bhatt, J. Med. Chem. 32:2421-2426, 1989). A solution of above product (2.29 g, 10 mmol) in ethanol (10 ml) was refluxed with hydrazine hydrate (0.6 g, 12 mmol) for 10 hours. Solvent and excess reagent were distilled under vacuum. The product was recrystallized from ethanol to yield 1.8 g of N-(2-naphthalenyl) glycine hydrazide (compound III, FIG. 3B) (yield 82%, mp 147-148° C.). A mixture of compound III (2.15 g, 10 mmol) and 3,5-dibromo-2,4-dihydroxybenzaldehyde (3 g, 10 mmol) in ethanol (5 ml) was refluxed for 3 hours. The hydrazone that crystallized upon cooling was filtered, washed with ethanol, and recrystallized from ethanol to give 3.8 g (78%) of GlyH-101. Melting point (mp)>300° C., ms (ES−): M/Z 492 (M−); 1H nmr (DMSO-d6): δ 4.1 (s, 2H, CH2), 6.5-7.5 (m, 9H, aromatic, NH), 8.5 (s, 1H, CH═N), 10.4 (s, 1H, NH—CO), 11.9 (s, 1H, OH), 12.7 (s, 1H, OH). Compounds GlyH-102-109, GlyH-114-127 and AceH401-404 were synthesized similarly by condensing appropriate hydrazides with substituted benzaldehydes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][Zn]C.C1(C)C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([CH3:11])[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-Triazine (1.0 g, 5.56 mmol) in 10 ml of dioxane was treated with a 1.2 molar solution of dimethylzinc in toluene (4.63 ml, 5.56 mmol). The mixture was stirred overnight at room temperature, poured into 100 ml of water and extracted with ethyl acetate. Chromatography on silica gel using heptane/ethyl acetate 9:1 v/v gave the title compound (225 mg, 25%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[CH:4]([C:13](OCC)=[O:14])[CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][N:2]1[CH:7]([CH3:8])[C:6]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:3]1[CH:4]([CH2:13][OH:14])[CH2:5]2
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1CC2C(CO)CC1(C)C(C)N2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of ethyl 2,3,4,8-tetramethyl-2-azabicyclo-[2.2.2]octane-6-carboxylate (18.3 g, 76.5 mmol) in ether (200 mL) was added to a slurry of lithium aluminum hydride (5.8 g, 153 mmol) in ether (60 mL). The mixture was stirred for 1 hour, cooled to 0° C. and quenched by the sequential addition of water (5.8 mL), 15% NaOH (5.8 mL), and water (17.4 mL). The aluminum salts were removed by filtration and the filtrate was concentrated in vacuo to afford 14.8 g (98%) of 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6-methanol as a colorless oil. The product was dissolved in ether and treated with 4.9N ethereal.HCl to afford 9.1 g of the hydrochloride salt as a white solid, m.p. 158°-159° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.Cl>>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCCCc1cnc2ccccc2c1Nc1ccc(C(=O)O)cc1
Yield: 29 %

Procedure:
0.520 g of the product of Step F of Example 1 and 0.390 g of 4-amino benzoic acid were introduced into 6 ml of 2N hydrochloric acid and the solution was refluxed for 63 hours. The precipitate was filtered off, washed with water and taken up in 10 ml of 2N sodium hydroxide in 40 ml of water, then washed with ethyl acetate. The aqueous phase was taken up in acetic acid and the precipitate was filtered, washed with water, separated out and taken up in ether. After drying, 220 mg of the expected product melting at 276° C. were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:33]1[NH:34][C:35]2[CH:36]=[CH:37][CH:38]=[C:39]3[C:45](=[O:46])[NH:44][CH2:43][CH2:42][C:41]=1[C:40]=23.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2[NH:34][C:35]3[CH:36]=[CH:37][CH:38]=[C:39]4[C:45](=[O:46])[NH:44][CH2:43][CH2:42][C:41]=2[C:40]=34)=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: O=C1NCCc2c(-c3ccc(O)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound YY, 4-iodophenol (220 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenyl phosphino)ferrocenedichloro palladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 2-(4-hydroxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 39 mg (15%) as a beige solid: m.p. 300° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.00 (m, 2H), 3.37 (m, 2H), 6.92 (d, J=8.7 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H), 7.49 (m, 3H), 7.65 (dd, J=7.5, 0.9 Hz, 1H), 8.04 (br t, 1H), 9.73 (br s, 1H), 11.40 (br s, 1H). MS (electrospray, MH+): 279. Anal. (C17H14N2O2) C, H, N.
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[OH:16][C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[N:14][NH:13][C:12]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[S:15]
Reactant: O=Cc1ccc(O)cc1O
Reactant: NNC(=S)Nc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(C=NNC(=S)Nc2cccc3ccccc23)c(O)c1
Reaction time: 40 h
Yield: 17.3 %

Procedure:
A solution of 4-(naphth-1-yl)-3-thiosemicarbazide (26 mg, 0.12 mmol) and 2,4-dihydroxybenzaldehyde (20 mg, 0.144 mmol) in dimethylformamide (1 mL) was shaken with 4 Å molecular sieves for 60 h. PS-TsNHNH2 resin (29 mg, 0.085 mmol) was added and shaking continued for 40 h, then the resin was filtered off. The solvent was removed under vacuum and the residue dissolved in ethanol. The solvent was again removed and the process repeated to give the title compound (7 mg, 18%) as a solid. MS (ES−) m/e 336 [M−H]−.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[CH:12]1(CC(Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N>C(Cl)Cl.C(C(C)=O)C>[CH:12]1([CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(Cl)CC1CCCCC1
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COC(=O)CC(=O)CC1CCCCC1
Yield: 98.9 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 176.7 g (1.1 mol) of cyclohexylacetyl chloride. The subsequent reaction time after the ammonia had been metered in was 6 hours at a pH of 9.5. This gave 196 g (GC purity 75.0%) of methyl 4-cyclohexylacetoacetate (yield 74.5%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[I:19]Cl>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClI
Reactant: C=CCCCOCc1ccccc1
Solvent: C1CCOC1
Product: ICCCCCOCc1ccccc1
Reaction time: 0.75 h

Procedure:
5-Benzoxy-1-pentene (30 mmol, 5.7 g) was hydroborated with BH3 -THF (10 mmol) at 0° C. for 1 hr. Iodinemonochloride (20 mmol, 1.0 ml) was added at room temperature; after 45 min,the product was isolated via chromatography (alumina): yield 5.63 g (88% based on ICl); bp 125° C./0.25 torr; m/e 318.1 (Calcd 318.2); IR (neat) 1705(C=O), 1205(C-I)cm-1 ; NMR (neat) δ 1.7 (broad envelope, 6, alkyl), 3.0 (t, 2, --CH2I), 4.2 (t, 2, --CH2O--),7.6 (m, 5, ArH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([N:21](C=O)[CH3:22])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.Cl.[OH-].[Ca+2].[OH-]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([NH:21][CH3:22])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reaction time: 4 h
Yield: 97.7 %

Procedure:
A suspension of 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 164 cm3 of acetic acid and 164 cm3 of an aqueous 17.5% hydrochloric acid solution is heated at a temperature close to 100° C., with stirring, for 4 hours. After cooling to a temperature close to 10° C., 165 cm3 of 30% slaked lime is added at between 10° and 20° C. The product is drained and washed with 3 times 150 cm3 of water, 3 times 150 cm3 of ethanol and 3 times 150 cm3 of diethyl ether. 13.64 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 354°-356° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:23][CH:24]=[C:25]([C:29]([OH:31])=[O:30])[C:26](O)=[O:27])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1(OC2C=CC=CC=2)C=CC=C[CH:33]=1>C(O)C>[O:27]=[C:26]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:13]=2)[NH:23][CH:24]=[C:25]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C(O)C(=CNc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1=O

Procedure:
The compound of title 4 (2.55 g, 5.36 mmol) was added under stirring to 21 mL boiling diphenylether. The mixture was heated to reflux for 15 minutes while the resulting ethanol was distilled off. After cooling, ether was added to the resulting suspension. The precipitate (the title compound) was filtered off and dried in vacuo.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[CH:32]([C:35]1[S:36][CH:37]=[C:38]([C:40]([N:42]2[CH2:66][C:46]3([CH2:49][N:48]([CH2:50][CH2:51][C:52]4[CH:53]=[C:54]([CH:63]=[CH:64][CH:65]=4)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][C:60]([OH:62])=O)[CH2:47]3)[O:45][CH2:44][CH2:43]2)=[O:41])[N:39]=1)([CH3:34])[CH3:33].[CH2:67]([NH:69][CH2:70][CH:71]([O:74][CH3:75])[O:72][CH3:73])[CH3:68].C(N(CC)CC)C>CN(C=O)C>[CH3:73][O:72][CH:71]([O:74][CH3:75])[CH2:70][N:69]([CH2:67][CH3:68])[C:60](=[O:62])[CH2:59][CH2:58][O:57][CH2:56][CH2:55][C:54]1[CH:63]=[CH:64][CH:65]=[C:52]([CH2:51][CH2:50][N:48]2[CH2:49][C:46]3([CH2:66][N:42]([C:40]([C:38]4[N:39]=[C:35]([CH:32]([CH3:33])[CH3:34])[S:36][CH:37]=4)=[O:41])[CH2:43][CH2:44][O:45]3)[CH2:47]2)[CH:53]=1
Reactant: CCNCC(OC)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)O)c4)C3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC(OC)OC)C(=O)CCOCCc1cccc(CCN2CC3(C2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.201 g) was added in one portion to a stirred solution at 0° C. of 3-(3-(2-(8-(2-isopropylthiazole-4-carbonyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenethoxy)propanoic acid trifluoroacetate salt (0.25 g) (example 176 step b), N-ethyl-2,2-dimethoxyethanamine (0.059 g) (U.S. Pat. No. 2,707,186) and triethylamine (0.283 ml) in DMF (4 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and aq brine, the organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.250 g.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:35][CH:34]=3)[C:31](=[O:44])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1>O1CCOCC1.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>[CH:39]1([C:36]2[CH:37]=[CH:38][C:33]([N:32]3[C:31](=[O:44])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]3[C:20]3[CH:21]=[N:22][C:17]([CH3:1])=[CH:18][CH:19]=3)=[CH:34][CH:35]=2)[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2ccccc2nc(-c2ccc(Cl)nc2)n1-c1ccc(C2CCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(C3CCCC3)cc2)cn1
Yield: 27.4 %

Procedure:
6-chloro-3-pyridinecarboxaldehyde (0.177 g, 1.20 mmol) and CuCl2 (0.335 g, 2.40 mmol) were added to a solution of 2-amino-N-(4-cyclopentylphenyl)benzamide (0.350 g, 1.20 mmol) in EtOH (30 mL), and refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organics were washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 15% to 60% EtOAc in heptane, afforded 2-(6-chloropyridin-3-yl)-3-(4-cyclopentylphenyl)quinazolin-4(3H)-one (0.260 g, 54%). Pd(PPh3)4 (0.150 g, 0.12 mmol), K2CO3 (0.270 g, 1.90 mmol), and trimethylboroxine (0.18 mL, 1.20 mmol) were added to a solution of 2-(6-chloropyridin-3-yl)-3-(4-cyclopentylphenyl)quinazolin-4(3H)-one (0.260 g, 0.65 mmol) in dioxane (15 mL) and heated to reflux temperature for 20 minutes. The reaction mixture was filtered through Celite®, washed with EtOAc. The filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 30% to 100% EtOAc in heptane, to afford the title compound as a white solid (0.068 g, 27%). 1H-NMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.84-8.00 (m, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.50-7.70 (m, 2H), 7.17-7.31 (m, 4H), 7.11 (d, J=8.0 Hz, 1H), 2.85-3.06 (m, 1H), 2.38 (s, 3H), 1.85-2.09 (m, 2H), 1.34-1.84 (m, 6H). MS (APCI) m/z: 382 (M+H)+.