Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[C:15]3[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:2]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]3[O:13][CH2:12][CH2:11][N:10]([S:7]([C:3]4[CH:2]=[C:1]([CH3:23])[CH:6]=[CH:5][CH:4]=4)(=[O:8])=[O:9])[C:15]=3[CH:16]=2)=[O:21])[S:26][CH:27]=1)[CH3:35]
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(C(=O)O)cc32)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C)c2)CCO3)n1

Procedure:
The title compound, MS (ISP)=472.1 (M−H)−, was produced as described in example 1, steps 1-6. Step 3 was performed using 3-methylbenzenesulfonyl chloride, furnishing 4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5 and yielded (2-{[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: O[C:2]([CH3:17])([CH2:15][CH3:16])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:25])C>>[CH2:15]([C:2]1([CH3:17])[C:3](=[O:25])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[O:6]1)[CH3:16]
Reactant: CCC(C)(O)C#CC(=O)c1ccc(SC)cc1
Reactant: CCO
Solvent: CCNCC
Product: CCC1(C)OC(c2ccc(SC)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.34 g of 4-hydroxy-4-methyl-1-{4-(methylthio)phenyl}-2-hexyn-1-one was dissolved in 200 ml ethanol, added dropwise 3 ml diethylamine diluted with 50 ml ethanol. The reaction solution was stirred at room temperature for 4 hours, and the solvent was removed in vacuo. The resulting residue was extracted with water and dichloromethane (100 ml×3). Concentration of the organic layer afforded crude 2-ethyl-2-methyl-5-{4-(methylthio)phenyl}-3(2H)-furanone, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].[OH-].[K+]>C(O)C.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[N:30][OH:31])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: ON=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 0 °C
Yield: 66.1 %

Procedure:
To a mixed solution (20 ml) containing 0.8 g of the 1-benzyl-4-[2-(4-pyrrolidinobenzoyl)ethyl]piperidine prepared in Example 59 and 0.7 g of hydroxylamine hydrochloride in ethanol was added a solution (7 ml) of 1.4 g of potassium hydroxide in methanol dropwise with warming at 50°-55° C. The mixture was further heated at 50°-55° C. for one hour, at the end of which time it was added to 200 ml of ice-water. The resulting precipitate was collected by filtration, rinsed and dissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude crystals. Recrystallization from dichloromethane-ether yielded 0.55 g of colorless crystals melting at 153°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1cccc(S)c1
Product: COc1cccc(Sc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-methoxy-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-methoxy-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 363 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9])#[CH:2].C(N(CC)C(C)C)(C)C.Br[C:20]1[C:21]2[N:22]([N:26]=[C:27]([Cl:29])[N:28]=2)[CH:23]=[CH:24][CH:25]=1.Cl>CN(C)C=O.[Cu]I>[Cl:29][C:27]1[N:28]=[C:21]2[C:20]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:9])=[CH:25][CH:24]=[CH:23][N:22]2[N:26]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: C#Cc1ccccc1N
Agent: [Cu]I
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1C#Cc1cccn2nc(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-ethynyl-phenylamine (126.0 mg, 1.075 mmol) and N,N-diisopropylethylamine (2 mL, 10 mmol) in N,N-dimethylformamide (1 mL) at room temperature under an atmosphere of nitrogen was added 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol), bBis(triphenylphosphine)palladium(II) chloride (10.0 mg, 0.0142 mmol) and copper(I) iodide (7.0 mg, 0.037 mmol). The mixture was stirred at room temperature for 18 hours then was poured into 0.1N hydrochloric acid (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water (2×20 mL) and saturated aqueous sodium chloride (20 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified using prepartory silica gel plates (20 cm×20 cm 100% dichloromethane). 2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenylamine was isolated as a yellow solid (0.158 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.7 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.07 (t, J=7.0 Hz, 1H), 6.77-6.67 (m, 2H), 4.81 (br s, 2H). MS=269, 271 (MH)+.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:19]=[CH:18][O:17][CH:16]=1>>[O:17]1[CH:18]=[CH:19][C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])=[CH:16]1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1ccoc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccoc1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-bromofuran. The title compound (445 mg) was obtained as a pale-yellow solid, m/z 249 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
Into a 250 mL round bottomed flask were added 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 40.6 mmol) and 120 mL dry THF. The solution was cooled in an ice bath at 0° C. and NaH (2.40 g, 60.0 mmol) was added in three portions. After 20 min, p-toluene-sulfonyl chloride (8.70 g, 45.63 mmol) was added, and the reaction mixture was allowed to warm to rt over 30 min. The reaction mixture was concentrated and hexanes was added to obtain a precipitate, which was collected and washed with ice cold 2M NaOH. The crude product was recrystallized from EtOAc/hexanes to afford 17.8 g (92%) of the title compound as a light tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.49 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 2.32 (s, 3H); MS: m/z 476.8/478.8 [MH+].
Reaction SMILES: [OH:1][CH:2]1[CH:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:15])[C:4](=[CH2:16])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:12]([CH:11]1[CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:15])[C:4](=[CH2:16])[CH2:3][C:2]1=[O:1])([CH3:14])[CH3:13]
Reactant: C=C1CC(O)C(C(C)C)CC2=C(C)CCC12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C=C1CC(=O)C(C(C)C)CC2=C(C)CCC12
Yield: 90.8 %

Procedure:
A solution, cooled to -10°, of 1.10 g of 6-hydroxy-7-isopropyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene (isomer A) in 50 ml of acetone was treated within 10 minutes with 2 ml of Jones reagent (5.3 mM CrO3) and the reaction mixture obtained then poured on to ice-cold bicarbonate solution. Extraction with ether, washing the extracts with bicarbonate solution and water, drying with sodium sulphate, concentration and distillation under reduced pressure yielded 990 mg (yield 90%) of 7-isopropyl-1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene (isomer A) in the form of a colourless oil; b.p.0.01 ca 75°; IR(film):νmax = 3100, 1708, 1642, 1460, 1440, 1390, 1370, 1255, 1205, 1140, 1090 1062, 1005, 970, 900, 800 cm-1. The compound has a sweet, spicy, woody odour. In analogous manner there were obtained from 1.10 g of the B-isomer of 6-hydroxy-7-isopropyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene, 890 g (yield 81%) of the B-isomer of the corresponding 6-oxo-octahydroazulene; b.p.0.01 ca 75°; IR(film): νmax = 1390, 1710, 1642, 1470/60/40, 1390, 1370, 1265, 1180, 1092, 1062, 1000, 970, 900 cm-1. The compound has a fresh woody, slightly spicy, camphorous odour.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: Clc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(Cl)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-chloroindole, the title compound is prepared as in example 1. 90 mg (60%). NMR (400 MHz, CDCl3): δ 0.85 (t, 3H), 2.15 (m, 1H), 2.22 (m, 1H), 2.34 (m, 1H), 2.59 (m, 1H), 2.98 (m, 2H), 6.82 (t, 1H), 6.87 (m, 2H), 7.00 (m, 2H), 7.11 (d, 1H), 7.16 (d, 1H), 8.12 (s, 1H, NH).
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=O)[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8](OC)=[O:9].[NH2:22][C:23]([NH2:25])=[S:24]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:7]1[C:6](=[O:5])[NH:25][C:23](=[S:24])[NH:22][C:8]1=[O:9]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1OC1C(=O)NC(=S)NC1=O
Temperature: 10 °C
Reaction time: 2.17 h
Yield: 89.6 %

Procedure:
12.15 g sodium methylate was dissolved in 200 ml methanol and 21.1 g dimethyl-(o-methoxyphenoxy)malonate was added. Stirring was continued for 130 min. The mixture was cooled to 10° C. and 7.6 g thiourea was added. Stirring was continued for 24 h. The solvent was evaporated in vacuo. The residue was stirred with diethyl ether. The ether layer was filtered off and the solid was dissolved in 60 ml water and acidified to pH=4 with conc. acetic acid. The precipitated product was filtered and washed with methanol and dried at 30° C. and reduced pressure to give 19.8 g 5-(o-methoxyphenoxy)-2-thioxo-dihydro-pyrimidine-4,6-dione (or a tautomere thereof.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([CH3:19])[N:14]([CH:16]([F:18])[F:17])[CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:15]1[N:14]([CH:16]([F:17])[F:18])[C:13]([CH3:19])=[N:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3]
Reactant: BrBr
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)cn1C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(Br)n1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Bromine (0.54 g, 3.1 mmol), in 7 ml of methylene chloride, was added dropwise to a solution of 0.9 g (3.2 mmol) of 4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole stirring in 35 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. Another 0.3 g of bromine, in 5 ml of methylene chloride, were added and the reaction stirred overnight. Methylene chloride (250 ml) and saturated sodium bicarbonate (200 ml) were added and the organic layer separated and washed with saturated sodium bicarbonate and brine followed by drying over magnesium sulfate. Evaporating in vacuo gave a red oil residue. Flash chromatography on silica gel (20:1-10:1-5:1-3:1 hexane/ethyl acetate) afforded 0.7 g of 5-bromo-4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole as a white solid (m.p. 81-83° C.). NMR (CDCl3, 200 MHz) δ: 2.65 (s, 3H), 7.20 (t, 1H), 7.27-7.40 (m, 2H), 7.52 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.Cl[CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1cc(SC[Si](C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), and dimethylacetamide (50 mL) and stir at room temperature under argon atmosphere. Add chloromethyltrimethylsilane (1.3 g, 10 mmol) and stir overnight. Warm on a steam bath for 2 hours, cool, and dilute with water. Extract with ethyl ether, dry, evaporate to a light yellow solid (2.8 g) and recrystallize (CH3CN) to give 1.1 g (34%) of the title compound; mp 100-101° C.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:11]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC>[Br:11][CH:3]([C:2](=[O:1])[CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrBr
Reactant: CCOC(=O)CCC(C)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of ethyl 4-oxopentanoate (4.92 mL, 34.7 mmol) in Et2O (180 mL) at about 0° C. was added bromine (1.8 mL, 34.7 mmol) in Et2O (10 mL) and the reaction was stirred for about 3 h. To the reaction mixture was added saturated aqueous sodium thiosulfate (50 mL) and stirred for about 10 min. The reaction was warmed to ambient temperature. The organic layer was separated and the aqueous layer was back extracted with Et2O (30 mL). The combined organic layers were washed with water (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:20) to afford ethyl 3-bromo-4-oxopentanoate (3.29 g, 14.6 mmol, 43%). 1H NMR (CDCl3) δ 4.67-4.33 (m, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.29-3.22 (m, 1H), 2.90-2.86 (m, 1H), 2.42 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.C([O-])(=O)C.[Na+].[Cl-].O[NH3+:23].C(O)(=O)C>O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)#[N:23]
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 63.3 %

Procedure:
25 g of 2-fluorenecarboaldehyde, 11.6 g of sodium acetate, 9.7 g of hydroxy ammonium chloride and 150 ml of acetic acid were stirred at 130 for 18 hours. The reaction mixture was allowed to room temperature, poured into 200 ml of water and the precipitate was collected by filtration. The crude product was purified by column chromatography, giving 15.57 g (63%) of 2-cyanofluorene.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Cc1ccccc1N
Solvent: CS(C)=O
Product: Cc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-methylaniline (0.023 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 295 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>O>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[C:5]4[NH:10][CH:9]=[CH:8][C:6]=4[N:7]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:3]=3)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
In a sealed tube was placed 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidine (20 mg, 0.064 mmol), 4-aminobenzonitrile (31 mg, 0.26 mmol), TFE (0.21 mL) and TFA (0.04 mL, 0.51 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC TLC, eluting with 5% Acetone/CH2Cl2 to give the product as a light yellow solid (10.5 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNC1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(F)cc2)C1
Yield: 76 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 4-fluoro-benzoyl chloride to afford the title compound as a colourless oil (4.3 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.Cl.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccncc2)CCCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1(C2CCNCC2)CCCC1

Procedure:
1.75 g of 1-pyridin-4-yl-cyclopentanecarboxylic acid ethyl ester are dissolved in a mixture of 100 ml of MeOH and aqueous HCl (32%) and the mixture obtained is hydrogenated in the presence of 175 mg of PtO2 as a catalyst under pressure for 5 hours. From the mixture obtained the catalyst is removed by filtration and solvent is evaporated. 1-Piperidin-4-yl-cyclopentanecarboxylic acid ethyl ester in the form of a hydrochloride salt is obtained. 13C-NMR (CD3OD): 176.73, 61.33, 57.71, 45.08, 45.00, 42.14, 33.80, 25.49, 25.43, 25.36, 14.58.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc2cc(C(=O)OC)ccc2c1
Yield: 84.6 %

Procedure:
To a stirred solution of 6-hydroxy-2-naphthoic acid methyl ester (0.500 g, 2.47 mmol) in acetone (25 mL) at rt was added Cs2CO3 (0.886 g, 2.72 mmol) followed by methyl bromoacetate (0.257 mL, 2.72 mmol) dropwise. After 18 h at this temperature, it was diluted with EtOAc (200 mL). This layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from MeOH:H2O to afford the product (0.573 g, 85%) as a solid; 1H NMR (DMSO-d6) δ3.71 (s, 3H), 3.87 (s, 3H), 4.95 (s, 2H), 7.30 (dd, J=2.6, 8.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.92 (dd, J=1.6, 8.6 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 8.55 (s, 1H); mass spectrum [(+) ESI], m/z 275 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:16]
Reactant: Cc1nc(-c2ccccc2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: Cc1nc(-c2ccccc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.9 mmol) and 2-methyl-6-phenylnicotinic acid (D23) (50 mg, 0.24 mmol) as a yellow solid. MS(ES): MH+ 340, M-H+ 338
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Cl:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Br[CH:14]([CH2:22][CH2:23]Br)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl>CC1CCCO1.BrC(CCBr)C(OC(C)(C)C)=O.C[Si](C)(C)[O-].[K+]>[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:14]2([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23][CH2:22]2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Reactant: Clc1cn[nH]c1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)C1(n2cc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 126.7 %

Procedure:
Into a flask was added potassium trimethylsilanolate (20.85 g, 146.31 mmol), 4-chloro-1H-pyrazole (15 g, 146.31 mmol) and 2-methyltetrahydrofuran (400 mL). The mixture was stirred for 5 min followed by the addition of tert-butyl 2,4-dibromobutyrate (27.84 mL, 146.31 mmol) over a period of 20 to 30 seconds. The reaction mixture was stirred for 60 min. Potassium trimethylsilanolate (20.85 g, 146.31 mmol) in 2-methyltetrahydrofuran (80 mL) was added over a period of 5 min. The reaction mixture was stirred for 1 h before adding tert-butyl 2,4-dibromobutyrate (1 mL, 5.3 mmol). After 30 min, an additional portion of tert-butyl 2,4-dibromobutyrate (2 mL, 10.5 mmol) was added. The mixture was stirred for 40 min before adding tert-butyl 2,4-dibromobutyrate (1 mL, 5.3 mmol) and potassium trimethylsilanolate (2 g, 14 mmol). The reaction mixture was stirred for 18 h. Hydrochloric acid (146.31 mL, 146.31 mmol) was added and the mixture was stirred for 5 min. The layers were separated, and the organics were washed with water (200 mL) and concentrated under reduced pressure. Toluene (100 mL) was added and the mixture was concentrated to dryness to afford tert-butyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarboxylate (45 g). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 1.57 (q, 2H), 1.75 (q, 2H), 7.44 (s, 1H), 7.51 (s, 1H); MS (EI+) (M+) 242; GCMS retention time: 2.37 minutes (Method O).