Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][CH2:27][O:26][C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OCCOc1ccc(OCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCCOc3ccc(OCCO)cc3)ccc2c1
Yield: 79.1 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), hydroquinone bis(2-hydroxyethyl)ether (10.6 g, 53.3 mmol), N,N-dimethylaminopyridine (DMAP, 2.71 g, 22.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.34 g, 48.7 mmol) and NEt3 (13 mL, 93.3 mmol) in DMF (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under vacuum and the residue was partitioned between HCl (3N, 100 mL) and CH2Cl2 (200 mL). The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, Rf=0.15) and then recrystallized from ethyl ether and hexane to give the title compound as a white solid (6.01 g, 31% yield). Mp 76-78° C. 1H NMR (CDCl3) δ 7.7-7.64 (m, 3H), 7.42-7.38 (m, 1H), 7.15-7.08 (m, 2H), 6.74-6.72 (m, 4H), 4.45-4.36 (m, 2H), 4.1-3.85 (m, 7H), 3.90 (s, 3H), 2.13 (br. t, 1H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 174.6, 157.5, 153.0, 152.8, 135.4, 133.6, 129.2, 128.8, 127.1, 126.1, 125.9, 118.8, 115.7, 115.3, 105.5, 69.7, 66.6, 63.1, 61.4, 55.2, 45.2, 18.4. MS (API) m/z 428 (M+NH4)+. Anal. calcd. for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.01; H, 6.39.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][O:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCOS(C)(=O)=O)CC1
Yield: 104 %

Procedure:
Suspend 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (5.07 g; 11.96 mmol) and TEA (35.88 mmol; 5.0 mL) in DCM (50 mL) and cool in ice bath. Add methanesulfonyl chloride (14.35 mmol; 1.1 mL) dropwise over 9 min and stir for 30 additional min. Quench with saturated sodium bicarbonate, dry over MgSO4, filter and evaporate to provide the title compound (6.246 g; 104%) as a foam. MS (ES): m/z=502 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)ccc1Cl
Yield: 46 %

Procedure:
The title compound is prepared from 3-amino-4-chloro-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 46% of theory; LC (method 4): tR=1.28 min; Mass spectrum (ESI+): m/z=341/343 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3].O.O.[OH-].[Li+]>O1CCOCC1>[F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3]
Reactant: COC(=O)c1cnc(C(C)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(F)(F)c1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
Methyl 5-(1,1-difluoroethyl)pyrazine-2-carboxylate (0.65 g, approx. purity 85%) was dissolved in dioxan (2 mL) and water (2 mL) was added, followed by lithium hydroxide monohydrate (54 mg, portionwise). After stirring at RT for 90 mins, the mixture was concentrated to 2 mL and Et2O (20 mL) added. The mixture was then extracted with NaOH (1 N, aq., 20 mL), and the aqueous portions acidified with 6N HCl to pH 2. The aqueous portion was then extracted with EtOAc, dried over MgSO4 and evaporated to afford the title compound as a white solid (119 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.11 (t, J=18.8 Hz, 3H), 9.01 (d, J=1.3 Hz, 1H), 9.47 (d, J=1.3 Hz, 1H)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.Cl>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 90 °C

Procedure:
Sodium hydride (1.1 g.; 23 mM; 50% w/w oil dispersion) was added to a stirred solution of spiro [pyrrolidine-3,3'-indoline]-2,2',5-trione (2.1 g.; 9.7 mM) in DMF (40 ml.), under an atmosphere of nitrogen. The mixture was stirred until effervescence had ceased and then heated to approximately 90° C. 3,4-Dichlorobenzyl chloride (2.2 g., 11.2 mM) was added dropwise. The reaction mixture was then allowed to cool to ambient temperature, stirred for 16 hours, and poured into water. The aqueous mixture was acidified (concentrated hydrochloric acid) and extracted with ethyl acetate (2×150 ml.). The combined extracts were washed with water (3×150 ml.), brine (150 ml.), dried MgSO4) and evaporated. The residual oil was purified by chromatography on silica gel (150 g.) using an increasing gradient of ethyl acetate in toluene as eluant. Fractions were monitored by TLC (SiO2 : 50% v/v EtOAc/toluene) and those containing the major component (relative flow value : 0.5) were evaporated to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.6 g , m.p. 205°-207° C. (recrystallised twice from MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:30]([O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH3:31]>C(Cl)(Cl)Cl>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]([NH:35][C:33]([O:32][CH2:30][CH3:31])=[O:34])=[S:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CCOC(=O)N=C=S
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)NCCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-(2-aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.43 g) in dry chloroform (50 ml) was added, dropwise, a solution of ethoxycarbonylisothiocyanate (1.31 g) in dry chloroform (25 ml). The reaction was stirred for 18 hours at room temperature before evaporating the solvent and triturating the residue with ether to afford a solid which was recrystallised from diisopropyl ether to give the title compound, yield 2.6 g, m.pt. 144°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:15])[CH2:10][CH2:11][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 75 %

Procedure:
A solution of 4-(4-chlorophenyl)piperdin-4-yl amine hydrochloride (0.030 g, 0.1058 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.016 g, 0.1058 mmol) and triethylamine (0.074 ml, 0.5289 mmol) in n-butanol (1.0 ml) was heated to 100° C. for 2 days. Concentration and purification by SCX-2 Isolute column (2 g), eluting with 1M NH3/MeOH, followed by silica column chromatography (20% methanol in DCM) gave a white solid (0.026 g, 74%). LC-MS (LCT2) m/z 328 [M+H+], Rt 2.59 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH:7](P(C1C=CC=CC=1)(C1C=CC=CC=1)=O)[O:8][CH2:9][CH3:10])[CH3:4].[C:26]([O:30][C:31](=[O:50])[N:32]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]=O)=[CH:44][CH:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH2:3]([O:5][C:6](=[O:25])[C:7]([O:8][CH2:9][CH3:10])=[CH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:32]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:43][CH:44]=1)[CH3:4]
Reactant: CCCCCCCN(CCc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(OCC)P(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(C=C(OCC)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 43.8 %

Procedure:
To a suspension of 60% by weight sodium hydride oil dispersion (6.97 mmol, 277 mg) in anhydrous tetrahydrofuran (20 mL) cooled to 0° C. was added 2-diphenylphosphinoyl-2-ethoxyacetic acid ethyl ester (3.80 mmol, 1.26 g) followed by [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester (3.46 mmol, 1.2 g) dissolved in anhydrous tetrahydrofuran (15 mL). The resulting heterogeneous solution was heated to reflux for one hour. The mixture was cooled to room temperature, quenched by the addition of ethanol (2 mL) and diluted with water (20 mL). The aqueous layer was isolated and extracted with diethyl ether (3×). The organic layers were combined, washed with saturated NaHCO3 (2×), brine (1×), dried over anhydrous sodium sulfate, and concentrated to a crude yellow oil. The crude oil was chromatographed on silica gel (20% ethyl acetate/hexanes) to give 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-ethoxy-acrylic acid ethyl ester as a clear oil (700 mg, 44%).
Reaction SMILES: [CH3:1][CH:2]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=1)=[O:5]>CO.[C].[Pd]>[CH3:1][CH:2]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=1)=[O:5]
Reactant: CC(C)=CCCC(C)CC(=O)c1cn(CCCC(=O)O)c2ccccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)CCCC(C)CC(=O)c1cn(CCCC(=O)O)c2ccccc12
Yield: 52.9 %

Procedure:
A mixture of 4-[3-(3,7-dimethyl-6-octenoyl)-1-indolyl]butyric acid (267 mg) obtained in Ex. 30 and 10% palladium carbon (80 mg) in methanol was stirred at room temperature for 3 hours under a hydrogen atmosphere at 3 atm. The catalyst was removed and the solvent was evaporated. The residue was chromatographed on a silica gel column (3-10% methanol in chloroform as an eluent) to give 4-[3-(3,7-dimethyloctanoyl)-1-indolyl]butyric acid (142 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.CN(C)C=O.[Br:19]N1C(=O)CCC1=O>O>[Br:19][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Br)c(O)ccc2c1
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
Add 6-methoxynaphthalene-2-ol (20 g, 114.8 mmol) to dimethylformamide (DMF, 250 mL) at ambient temperature followed by N-bromosuccinimide (NBS, 21.5 g, 120 mmol) over a 30 minute period. After 45 minutes, dilute with water (800 mL), collect and dry the precipitate to provide 25.5 g (87%) of 1-bromo-6-methoxy-naphthalen-2-ol.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:8]3[CH2:9][C:10]([CH3:27])=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:8]3[CH2:9][C@H:10]([CH3:27])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: [H][H]
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=C(C)C[C@@H]32)C[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4C[C@H](C)[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Yield: 36.2 %

Procedure:
3α-Hydroxy-2β-methoxy-16-methyl-5α-pregn-16-ene-11,20-dione (187 mg.) in ethyl acetate (50 ml.) was hydrogenated over 10% palladium-on-carbon catalyst (60 mg.) at atmospheric pressure for 20 minutes, during which time 11 ml. of hydrogen was taken up. The catalyst was filtered off and the filtrate evaporated to a white foam (190 mg.) which was purified by preparative T.L.C. in ethyl acetate/petrol 3/2, run 3 times, to give 88 mg. of impure product which was purified by preparative T.L.C. in ethyl acetate/benzene (1/1) and recrystallisation from ether/petrol to give title compound (68 mg.) as fine white crystals, m.p. 180°-182°, [α]D + 69.5° (c 0.2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][C:5]([N:7]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[O:11][CH2:10][CH2:9][CH2:8]4)=[O:6])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Product: O=C(CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH2:33]([N:35]1[CH2:40][C:39]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[O:38][CH2:37][C:36]1=[O:46])[CH3:34]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:43]2[CH2:44][CH2:45][C:39]3([O:38][CH2:37][C:36](=[O:46])[N:35]([CH2:33][CH3:34])[CH2:40]3)[CH2:41][CH2:42]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: CCN1CC2(CCNCC2)OCC1=O
Reactant: NC(=O)C(O)c1c(F)cc(Br)cc1F
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1CC2(CCN(C(C(N)=O)c3c(F)cc(Br)cc3F)CC2)OCC1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 121.8 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (0.86 g, 3.2 mmol) and triethylamine (1.4 mL, 9.7 mmol) in anhydrous acetonitrile (5 mL) was added neat methanesulfonyl chloride (0.33 mL, 4.2 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had progressed to completion. To this mesylate intermediate mixture was added more triethylamine (1.4 mL, 9.7 mmol) followed by 4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.11 g, 0.48 mmol). The reaction mixture was heated at 90° C. for 3 h until the starting material was consumed. The reaction was diluted with water and was extracted with ether (3×35 mL). The combined ether phases were dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) afforded the title product (261 mg, 18% yield). MS(ES)+ m/e 446 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 1.64-1.71 (m, 1 H) 1.73 (dd, J=4.17, 2.65 Hz, 1 H) 1.90-1.99 (m, 2 H) 2.19-2.27 (m, 1 H) 2.54-2.66 (m, 1 H) 2.67-2.73 (m, 1 H) 2.75-2.81 (m, 1 H) 3.15 (s, 2 H) 3.41 (q, J=6.91 Hz, 2 H) 3.98 (s, 2 H) 4.69 (s, 1 H) 5.68 (br. s., 1 H) 7.15-7.25 (m, 2 H) 7.36 (br. s., 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:19]1([CH2:25][CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([CH2:25][CH:26]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=CCc1ccccc1
Yield: 69.3 %

Procedure:
To a solution of 12.15 mL (45.78 mmol) of t-butyldiethylphosphonoacetate in 100 mL of THF under argon at 25° C. is added 1.83 g (45.78 mmol) of 60% NaH in oil dispersion. The reaction mixture is stirred at 25° C. for 45 minutes at which time 5.41 mL (41.62 mmol) of phenylacetaldehyde is added. After 30 minutes at 25° C. the reaction is partitioned between 1 N HCl and ethyl ether. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash silica gel chromatography affords 6.3 g (69%) of t-butyl 4-phenylbut-2-enoate as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[O:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:34]=2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[S:19][C:18]([CH3:28])=[N:17][C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH2:29][C:30]2[O:31][CH:32]=[C:33]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:34]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCNCC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
4-{1-[5-(4-Fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-3-[4-(4-fluoro-phenyl)-oxazol-2-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.130 g) was dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness at reduced pressure and the residue was chromatographed over silica gel. Elution with a gradient of 0 to 10% [9:1 methanol/conc. ammonia solution] in dichloromethane provided the title compound as a pale yellow gum (0.013 g), mass spectrum (API+) 481 [MH+], C25H22F2N4O2S requires 480.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]4[O:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[C:27]=4[C:34]=3[CH3:35])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2([OH:33])[C:27]3[C:34]([CH3:35])=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)[CH2:18][CH2:19]4)[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=3[O:30][C:29]2([CH3:31])[CH3:32])=[CH:3][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: Fc1ccc(Br)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(F)cc3)C(C)(C)O4)CC2)cc1
Yield: 84 %

Procedure:
Using 1-bromo-4-fluorobenzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 84%. mp. 142–144° C. (hexane).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9](O)=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([NH:23][CH3:21])=[O:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reaction time: 14 h
Yield: 15.9 %

Procedure:
To a mixture of 0.78 g of 2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxylic acid and 5 ml of tetrahydrofuran was added 0.67 g of 1,1'-carbonyldiimidazole with stirring under ice-cooling and the mixture was stirred for 1 hour. Then, 6.3 ml of 40% methylamine (methanol solution) was added therein. The resultant mixture was stirred under ice-cooling for 1 hour and then at room temperature for 14 hours. An aqueous potassium carbonate solution was added therein and the mixture was extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.13 g of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 178°-179° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1ccn2c(n1)nc1ccccc12
Temperature: 120 °C
Yield: 44.8 %

Procedure:
1,1′ Bis(diphenylphosphino)ferrocnee]dichloropalladium(II),w/DCM (0.033 g, 0.040 mmol) was added to a solution containing 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.386 g, 1.209 mmol), Copper(I) iodide (0.015 g, 0.081 mmol), and Potassium carbonate (0.806 ml, 1.612 mmol) in DMF. The solution was heated in the microwave for 15 minutes at 120° C. The reaction was cooled to room temperature. Diluted with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated. Purified by Combiflash column using 0% to 80% ethyl acetate in hexanes to afford tert-butyl (2-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)phenyl)carbamate (0.13 g, 0.361 mmol, 44.7% yield).