Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)CCC.C(OC([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)C)C.C(=O)([O-])[O-].[K+].[K+]>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.O>[NH:29]1[CH:33]=[C:32]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1000 mL round bottom flask was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.00 g, 35.23 mmol), 1-butanol (25.0 mL), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.66 g, 52.85 mmol), water (25.0 mL) and potassium carbonate (12.17 g, 88.08 mmol). This solution was degased 4 times, filling with nitrogen each time. To the solution was added tetrakis(triphenylphosphine)palladium(0) (4.071 g, 3.523 mmol). The solution was degased 4 times, filling with nitrogen each time. The mixture was stirred overnight at 100° C. After being cooled to room temperature, the mixture was filtered through a bed of celite and the celite was rinsed with ethyl acetate (42 mL). The filtrate was combined, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated under vacuum with a bath temperature of 30-70° C. to give the final compound 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 78%. LC-MS: 316.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](N(CC)CC)[CH3:25]>CO>[C:24]([C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)#[CH:25]
Reactant: CCN(CC)CC
Reactant: Nc1nc2ccnc(-c3cccc(Br)c3)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2nccc3nc(N)nn23)c1
Reaction time: 0.25 h

Procedure:
A suspension of 2.0 g of 5-(3-bromophenyl) [1,2,4]triazolo[1,5-c]pyrimidin-2-amine in 45 ml of triethylamine was flushed with argon and stirred 15 minutes. A 17 mg portion of palladium II acetate and 34 mg of triphenyl phosphine were added followed by 1.06 g of ethynyl trimethylsilane. The mixture was heated to reflux, then allowed to stand overnight under argon, then again heated at reflux for 5 hours and then cooled. A 34 mg portion of palladium II acetate, 68 mg of triphenyl phosphine and 2.12 g of ethynyl trimethylsilane were added and this mixture was refluxed 15 hours. The mixture was cooled, evaporated, taken up in 200 ml of chloroform, washed with 100 ml of saturated aqueous potassium bicarbonate, dried, filtered and evaporated giving a brown glass. This glass was taken up in 50 ml of methanol and 200 mg. of anhydrous potassium carbonate were added. This mixture was sealed, stirred overnignt and then evaporated. The residue was taken up in 100 ml of chloroform, washed with 50 ml of dilute aqueous potassium bicarbonate, dried, filtered through hydrous magnesium silicate and evaporated. This solid was crystallized from chloroform-cyclohexane, giving 300 mg of the desired product, mp 170°-172° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1.[OH-].[Na+]>O.C(#N)C>[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH:23][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:16][CH2:15]1
Reactant: NCCCN1CCOCC1
Reactant: C=CC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)NCCCN1CCOCC1
Reaction time: 3.5 h

Procedure:
In a 1 liter capacity round bottom flask equipped with a stirrer were put 90.5 g (1.0 mole) of acrylic acid chloride and 300 cc of acetonitrile and, as a polymerization inhibitor, 0.5 g of hydroquinone, and then, after the contents were cooled to 5°-10°C, 143 g (1.0 mole) of 3-morpholinopropylamine was added dropwise thereto over the course of 3.5 hours while stirring. Afterwards, the reaction mixture was stirred additionally for 2 hours at 40°-50°C. Next, a solution of 40 g of sodium hydroxide in 100 cc of water was added thereto and then the mixture was stirred for 30 minutes. After removal of the sodium chloride which separated, 152 g (77.0%) of a fraction of 144°-146°C/0.1 mmHg were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:24]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:24])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 0.936 g, 2.38 mmol) was taken up in ammonia (7M in MeOH, 10 mL, 70.00 mmol) and the resulting mixture was bubbled with argon and then heated in the microwave reactor at 120° C. for 1 h. The solvent was evaporated. Ammonia (7M in MeOH, 6 mL, 42 mmol) was added and the reaction was bubbled with argon and heated again using MW for 60 min at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 10 mL, 70 mmol) was added. The reaction was bubbled with argon and then heated using MW for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 20 mL, 140 mmol) was added. The reaction was heated again using MW for 1 h at 120° C. The solvent was evaporated and the resulting residue was taken up in DCM (60 mL) and brine (×2) and poured into a phase separator. The organic phase was dried with MgSO4, filtered and evaporated to give the title compound (0.736 g, 82% yield) as a mixture of isomers: 1H NMR (500 MHz, CDCl3) δ ppm 1.09 (td, 1H), 1.27-1.49 (m, 3H), 1.62-1.74 (m, 2H), 1.93-2.01 (m, 2H), 2.37 (s, 3H), 3.04-3.18 (m, 3H), 3.34 (s, 3H), 6.90 (d, 1H), 7.20 (d, 1H), 7.38 (dd, 1H); MS (MM-ES+APCI)+m/z 376 [M+H]+.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[CH2:18]=[O:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([CH2:18][OH:19])=[CH:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-c2ncco2)cc1
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1cnc(-c2ccc(Cl)cc2)o1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 60.7 %

Procedure:
13.8 ml of a 2.42M (33.4 mmol) solution of n-butyl lithium in hexane were added dropwise during 5 minutes to a stirred solution of 6 g (33.4 mmol) of 2-(4-chlorophenyl)oxazole in 60 ml of dry tetrahydrofuran maintained at -60° C. under an argon atmosphere. The suspension was allowed to warm to -40° C. during 30 minutes and 6.9 g (230 mmol) of paraformaldehyde were added to a slurry in 15 ml of dry tetrahydrofuran. The mixture was allowed to attain room temperature during 1.5 hours and was stirred for a further 1 hour. 10 ml of saturated aqueous ammonium chloride were added to the mixture and the resulting suspension was partitioned between 300 ml of water and 200 ml of dichlormethane. The organic phase was separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed by evaporation under reduced pressure to given an oil. The oil was chromatographed on silica gel using 70% by volume ethyl acetate in hexane for the elution. The eluate was evaporated to yield 4.25 g (60%) of 2-(4-chlorophenyl)-5-oxazolemethanol of melting point 115°-116° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](I)=[C:11]([N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])C(OCC(C)C)=O)[O:10][N:9]=1)(=O)C.[CH2:35]1[O:43][C:42]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=2[O:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[O:36]1[C:37]2[CH:38]=[CH:39][C:40]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][O:10][C:11]=3[NH:14][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[CH:41][C:42]=2[O:43][CH2:35]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC(=O)OCCOc1noc(N(C(=O)OCC(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCO)c2-c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a stirring solution of 2-({5-[{[4-(tert-butyl)phenyl]sulfonyl}(isobutoxycarbonyl)amino]-4-iodo-3-isoxazolyl}oxy)ethyl acetate (Preparation 22) (2.41 g) in dioxane (25 ml) was added (3,4-methylenedioxyphenyl)boronic acid (0.72 g) followed by cesium carbonate (5.15 g) and water (3 ml). The reaction mixture was purged with nitrogen three times, after which time tetrakis(triphenylphosphine)palladium(0) (140 mg). The reaction mixture was heated to reflux for about 2 hours. Ethanol (50 ml) and sodium hydroxide (2M, 50 ml) were added to the reaction mixture and then this was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the solid residue was partitioned between saturated ammonium chloride solution (100 ml) and ethyl acetate (100 ml). The organics were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to yield the crude material as a brown oil. The crude material was purified by column chromatography (100 g silica, crude loaded with dichloromethane (10 ml)) using a gradient elution of hexane (50% to 0%) and ethyl acetate (50% to 100%) and also with methanol (5% in ethyl acetate) to yield the product as a light brown foam (770 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[S:12](=[O:14])(=[O:13])[N:11](C(OC)=O)[CH2:10][C:9]2([CH3:20])[CH3:19])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:9]([CH3:20])([CH3:19])[CH2:10][NH:11][S:12]2(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)N1CC(C)(C)N(Cc2ccc(OC)cc2)S1(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CN2C(C)(C)CNS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a suspension of methyl 5-(4-methoxybenzyl)-4,4-dimethyl-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide (17.56 g, 53.5 mmol) in methanol/water (300 mL, 2:1) was added 10 N NaOH (10.7 mL, 107 mmol) and the mixture stirred at room temperature for 4 h. The mixture was made acidic with 10 N HCl and washed with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (12.91 g, 89% yield). 1H NMR (500 MHz, CDCl3) δ: 7.34-7.32 (2H, m), 6.86-6.84 (2H, m), 4.74 (1H, brs), 4.18 (2H, s), 3.78 (3H, s), 3.24 (2H, s), 1.21 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([O:25][Si](C)(C)C)=[CH2:24])[CH:13]([CH3:15])[CH3:14]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:24]/[C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:25])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1OCC(C)C
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)COc1ccccc1C(=O)/C=C/c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
To a solution of commercially available 2-fluoro-5-formylbenzonitrile (2.49 g, 10 mmol) in dichloromethane (40 mL) was added (1-(2-isobutoxyphenyl)vinyloxy)trimethylsilane (1.49 g, 10 mmol), followed by titanium tetrachloride (1.5 eq). The reaction was stirred at room temperature for 5 hours and then heated at 40° C. for overnight. The reaction was cooled and quenched with 1 N HCl (40 mL). The mixture was stirred for 2 hours and diluted with dichloromethane/water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by the chromatography to give (E)-2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxoprop-1-enyl)benzonitrile as a white solid (1.60 g, 50% yield). 1H NMR (400 MHz, CDCl3): δ 7.88-7.75 (m, 2H), 7.70 (d, 1H), 7.57 (d, 1H), 7.54-7.45 (m, 2H), 7.28 (d, 1H), 7.08-6.98 (m, 2H), 3.84 (d, 2H), 2.17-2.03 (m, 1H), 1.00 (d, 6H). MS (EI) for C20H18FNO2: 268 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][N:25]([C:28]3[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=3)[CH2:24][CH2:23]2)[O:19]1>CN(C)C=O>[N:1]1([CH2:17][CH:18]2[CH2:22][O:21][C:20]3([CH2:23][CH2:24][N:25]([C:28]4[N:29]=[C:30]([O:36][CH3:37])[CH:31]=[C:32]([O:34][CH3:35])[N:33]=4)[CH2:26][CH2:27]3)[O:19]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: COc1cc(OC)nc(N2CCC3(CC2)OCC(CCl)O3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(N2CCC3(CC2)OCC(Cn2nnc4ccccc42)O3)n1
Temperature: 120 °C

Procedure:
To 37.63 gm (0.3163 mole) of benzotriazole and 35 gm of potassium carbonate in Dimethylformamide (DMF) (350 ml) was added slowly under stirring 82 gm of 2-chloromethyl-8-(4,6-dimethoxy-pyrimidin-2-yl)-1,4-dioxa-8-azaspiro[4,5]decane (intermediate for compound 7) in DMF (300 ml). After the addition, reaction mixture was heated to 120° C. and maintained for 30 hrs. The reaction mixture was cooled to room temperature 28° C. and filtered. The solvent was distilled off to get the product. It was a thick dark brown liquid. Yield of product was 90%
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[NH2:2].Br[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[N:20][CH:21]=1>C(N(CC)CC)C>[CH3:22][C:19]1[N:20]=[CH:21][C:16]([CH2:15][CH2:14][N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)[NH2:2])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: Cc1ccc(CCBr)cn1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N(N)CCc2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Methyl 4-hydrazinylbenzoate (1 g, 0.005 moles) and 5-(2-bromoethyl)-2-methylpyridine (1 g, 0.005 moles) was taken up in triethylamine (2.1 mL) and stirred at RT for 1 hr. The reaction was heated at 100° C., overnight. LCMS analysis of the reaction mixtures shows the formation of product. The reaction mixture was concentrated, water (20 mL) was added to the reaction mixture and the mixture extracted with ethyl acetate. The crude product was dissolved in ethyl acetate and purified by column chromatography using neutral alumina, using 100% ethyl acetate as the eluent. After chromatography 400 mg of Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate was obtained, 28.5% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH2:12])=[O:11])[C:5]([C:13]#[N:14])=[C:4]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:3]=1[C:21]#[N:22].[N:23]1([CH2:28][CH2:29][CH2:30]N)[CH:27]=[CH:26][N:25]=[CH:24]1>>[NH2:14][C:13]1[C:5]2[C:6](=[N:7][C:2]([NH:1][CH2:30][CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[C:3]([C:21]#[N:22])[C:4]=2[C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[S:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: Cc1ccc(-c2c(C#N)c(N)nc(SCC(N)=O)c2C#N)o1
Reactant: NCCCn1ccnc1
Product: Cc1ccc(-c2c(C#N)c(NCCCn3ccnc3)nc3sc(C(N)=O)c(N)c23)o1

Procedure:
“2c” is subsequently reacted analogously to steps 2.1 to 2.3 according to Example 2, using 3-imidazol-1-ylpropylamine as “E2” in step 2.2. 3-Amino-5-cyano-6-(3-imidazol-1-ylpropylamino)-4-(5-methylfuran-2-yl)thieno[2,3-b]-pyridine-2-carboxamide “A59” is obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1>O>[CH3:4][C:5]1[CH2:6][C:2]2[CH:3]=[CH:4][C:5]3[CH:3]=[CH:2][CH:1]=[CH:11][C:6]=3[C:1]=2[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=Cc2c(ccc3ccccc23)C1
Temperature: 25 °C

Procedure:
p-Toluenesulfonic acid (50 mg) was added to the organic layer, and the reaction mixture was heated under reflux with water separation for 1 h. After cooling to room temperature the organic layer was washed with sodium bicarbonate (aqueous 2 wt %, 50 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The yield of 2-methyl-3H-benz[e]indene was 4.1 g or 89%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CN(C=O)C.O>[CH2:1]([O:8][CH2:9][C:10](=[O:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)COCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)COCc1ccccc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
3-Benzyoxypropan-2-ol 16 (40 g, 0.24 mol) was added to a suspension of pyridinium chlorochromate (155.2 g, 0.72 mol) in DMF (150 ml) at 25° C., stirred at 65° C. for 3 h, and then diluted with water (75 mL) (Step 14). The mixture was extracted with ether (2×50 mL) and the combined ether layers were washed with water (3×50 mL) dried (MgSO4) and the solvent removed by roto-evaporation. Distillation gave 31 g (77%) of 3-benzyloxypropan-2-one; 17 bp 104-106 (10 mm). 1H NMR (CDCl3) δ 2.16 (s, 3H, CH3), 4.05 (s, 1H, OH), 4.59 (s, 2H, OCH2), 7.5 (s, 5H, phenyl).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[N:25]=[C:26]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[NH:25][C:26]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][N:1]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=O
Reactant: N#Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
To a solution of 4-Azidoacetyl-benzonitrile (1.5 g, 8.06 mmol) in dioxane 25 mL was added 2-methyl-5-nitrophenyl isocyanate (1.43 mg, 8.06 mmol) (commercially available), and triphenylphosphine (2.11 g, 8.06 mmol). The reaction mixture was placed in an oil bath preheated to 100° C. and stirred for 30 min. After evaporation of the solvent under reduced pressure, the solid residue was recrystallized from ethanol to give the title compound as yellow micro crystals (1.16 g, 45%).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:19])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:19][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ccccn2)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ccccn3)c2cc1OC
Temperature: 130 °C
Reaction time: 7 h
Yield: 20.7 %

Procedure:
Dimethyl sulfoxide (1.5 ml) was added to 5,6-dimethyl-[2,2′]-bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (101 mg), and cesium carbonate (147 mg), and the mixture was stirred at 130° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (12 mg, yield 20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C(=O)C(C)(C)C)[CH:5]=[C:4]([CH3:15])[C:3]=1[NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.[OH-].[Na+].CO>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:15])[C:3]=1[NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: Cc1cc(OC(=O)C(C)(C)C)cc(Br)c1NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(Br)c1NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
N-(2-bromo-6-methyl-4-pivaloyloxyphenyl) 3-nitrobenzamide and an aqueous solution of sodium hydroxide were added to methanol, and the resulting mixture was stirred at 70° C. for 3 hours. The solvent was removed under a reduced pressure to obtain a residue. The resulting residue was dissolved in ethyl acetate, washed with aqueous 2N hydrochloric acid solution, and then dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to obtain N-(2-bromo-6-methyl-4-hydroxyphenyl) 3-nitrobenzamide. Then, the desired title product was prepared according to the conditions as described in Example 1-3 (Yield: 97%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[C:7]1=[O:17])[CH3:4].[C:18]1([N:24]2[C:28]3([CH2:33]CNC[CH2:29]3)[C:27](=[O:34])[NH:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:16][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][CH:6]([CH2:5][N:3]3[CH2:2][CH2:33][C:28]4([N:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:25][NH:26][C:27]4=[O:34])[CH2:29][CH2:4]3)[C:7]2=[O:17])=[CH:12][CH:11]=1
Reactant: CN(C)CC1CCc2ccc(F)cc2C1=O
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Product: O=C1c2cc(F)ccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
5.0 g of 2-[(dimethylamino)methyl]-7-fluoro-3,4-dihydro-1(2H)-naphthalenone hydrochloride (1:1) and 5.85 g of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one are suspended in absolute ehtanol (55 ml) and stirred overnight while a slow stream of nitrogen is bubbled through. The solid that forms is filtered off and washed with ether to give the title compound (7.7 g), melting point 162°-165° C.