Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH2:16][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ccc([N+](=O)[O-])cc1OCCCCl
Temperature: 75 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
2-methoxy-5-nitrophenol (50 g, 0.30 mol) was combined with 250 mL isopropyl alcohol. 1N sodium hydroxide solution, 310 mL (0.31 mol), was added to the mixture at such a rate that the temperature remained below 40° C. After the addition was completed, the mixture was stirred for at least 30 minutes. The reaction was then charged with 1-bromo-3-chloropropane (93.1 g, 0.59 mol) in a single portion. The mixture was heated to 75° C. and monitored periodically by high performance liquid chromatography (HPLC). After 8 hours, heating was discontinued and the reaction mixture was allowed to cool to ambient temperature overnight. The product gradually precipitated from the mixture as a light yellow/tan solid. Water, 200 mL, was added in a single portion and the resulting slurry was stirred for at least 30 minutes. The slurry was filtered and washed with water. The damp crude product was slurried in 650 mL methanol and heated to reflux until the solids had dissolved or mostly dissolved. The solution was allowed to cool gradually with stirring to ambient temperature over 3-5 hours or longer. The mixture was then cooled to 10-15° C. and held for at least 30 minutes. The solids were filtered and washed with cold methanol. The product was then dried in vacuo to give 60.3 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: c1c[nH]cn1
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(CCn3ccnc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 44.7 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), imidazole (0.011 g, 0.15 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated at 70° C. for 15 h. Imidazole (0.011 g, 0.15 mmol) was added and the reaction mixture was heated at 70° C. for 60 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration to afford a beige solid which was taken up in hot ethyl acetate then allowed to slowly cool to ambient temperature. The filtrate was concentrated to afford N2-(4-{4-amino-1-[2-(1H-1-imidazolyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (0.034 g, 0.067 mmol): RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.45 min. MS: M+ 508.2.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH2:12][N:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]([CH2:17][OH:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C1CCCCC1>[CH2:23]([O:18][CH2:17][CH:10]1[CH2:9][CH2:8][CH:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][N:11]1[S:13]([CH3:16])(=[O:15])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OCC1CCC(CO)N(S(C)(=O)=O)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OCC1CCC(COCc2ccccc2)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(6-ring): To a solution of (2RS,5RS)-(5-tert-butoxymethyl-1-methanesulfonyl-piperidin-2-yl)-methanol (2.80 g) in dichloromethane (20 ml) and cyclohexane (30 ml) was added benzyl 2,2,2-trichloroacetimidate (3.03 g) and trifluoromethanesulphonic acid (0.2 ml). The reaction mixture was stirred 1 h at room temperature, poured onto a saturated sodium bicarbonate solution and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 and 1:2 as eluents to obtain (2RS,5RS)-2-benzyloxymethyl-5-tert-butoxymethyl-1-methanesulfonyl-piperidine (3,6 g) as a syrup, MS: 369 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH2:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][C:5]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.CC(CC(O)CO)C>[Mo].C1(C)C(C)=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:4]([C:3]([O:2][CH3:1])=[O:30])=[CH:13][C:12]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: COC(=O)C1=C(Nc2ccc(C)cc2)CC(C(=O)OC)=C(Nc2ccc(C)cc2)C1
Agent: [Mo]
Agent: CC(C)CC(O)CO
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc(Nc2ccc(C)cc2)c(C(=O)OC)cc1Nc1ccc(C)cc1

Procedure:
0.1-0.8 part of molybdenum or vanadium(IV) oxide acetyl-acetonate is then added as a catalyst, or a V4A wire gauze is wound around the stirrer. A stream of air, preheated if appropriate, of about 15 liters per hour is then introduced through an immersed tube at a temperature of 103° C. for about 8-9 hours. The stream of waste gas is passed over a separator for the water of reaction, over a cooler and over a washing column, for example with polyethylene glycol dimethyl ether, for absorption of xylene emissions. The current concentration of the oxygen is measured in the stream of waste gas. It is about 15% by volume on average. In this apparatus arrangement, the oxygen content of the air is utilized to the extent of about 25%. Samples are taken hourly for liquid chromatography (HPLC), and a conversion curve, expressed in percent by weight, of starting material and product is thus plotted. The 1st derivation (angle of the tangents) should decrease constantly from about 50% of the conversion. About 20% of the xylene (149 parts with 24 parts of propionic acid) is then distilled off. The remaining majority of the xylene is then distilled off by steam distillation, an aqueous suspension of 2,5-di-p-toluidino-terephthalic acid dimethyl ester finally being obtained. The xylene removed by steam distillation is purified and used for the preparation of the SucEst. The 2,5-di-p-toluidino-terephthalic acid dimethyl ester is isolated by filtration over a heated pressure suction filter (preferably fitted with a stirrer). The crystal-line crude product (226 parts by weight, melting point 205°-207° C.) on the suction filter is blown out with steam until it is odorless. It is then washed with methanol. 195 parts of methanol-moist 2,5-di-p-toluidino-terephthalic acid dimethyl ester (=97% of theory, based on the SucEst,) of melting point 215°-220° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33]>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Product: COc1ccc(CN(Cc2cc(F)ccc2F)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and 2-(bromomethyl)-1,4-difluorobenzene. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.31 (s, 2H), 4.33 (s, 2H), 6.74-7.06 (m, 7H), 7.95 (d, 2H, J=8 Hz), 8.09 (d, 2H, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][CH2:49][CH2:50][C:51]1[S:52][CH:53]=[CH:54][CH:55]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:48]([CH3:47])[CH2:49][CH2:50][C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CNCCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (4.52 g, 13.7 mmol) was dissolved in N,N-dimethylformamide (6 ml) and dichloromethane (6 ml). 1-Hydroxy-7-azabenzotriazole (1.86 g, 13.7 mmol) was added as a solid. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.63 g, 13.7 mmol) was added. The solution was stirred for 15 min at 0° C. A solution of N-methyl-N-(2-(2-thienyl)ethyl)amine in dichloromethane (6 ml) was added. Ethyldiisopropylamine (2.37 ml, 13.7 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml). The mixture was washed with 1 N hydrochloric acid (150 ml) and saturated sodium hydrogen carbonate solution (150 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silcia (100 g), using ethyl acetate/heptane (1:2) as eluent to give 5.57 g of N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:9](=[C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:11]=1[CH3:12])[NH:8][CH2:7][CH2:6]2.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:22]([N:8]1[C:9]2[C:5](=[C:4]([CH3:20])[C:3]([CH2:2][OH:1])=[C:11]([CH3:12])[C:10]=2[NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:6][CH2:7]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Cc1c(CO)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCc2c(C)c(CO)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
N-(5-Hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.5 g) was dissolved in DMF (15 ml) and 1-iodooctane (2.6 g) and K2CO3 (1.5 g) were added, which was followed by stirring under a nitrogen atmosphere at 50° C. for 2 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0-10/1) to give 1.0 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)[CH3:12]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc(C=C)cc1
Product: C=Cc1ccc(C#CC=CC(=O)OCC)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-vinyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (420 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (d, J=8.3, 2H), 7.39-7.37 (d, J=8.3, 2H), 6.73-6.66 (dd, J=17.5, 10.8, 1H), 6.38-6.35 (d, J=11.4, 1H), 6.14-6.12 (d, J=11.4, 1H), 5.81-5.77 (d, J=17.6, 1H), 5.33-5.30 (d, J=10.9, 1H), 4.29-4.24 (q, J=7.1, 2H), 1.35-1.32 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.92, 139.62, 132.12, 129.28, 127.83, 123.14, 119.76, 101.77, 86.19, 60.44, 21.66, 14.42. Anal. Calcd. for C14H14O2: C, 79.62; H, 6.24; Found C, 79.37; H, 6.48.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)(=[O:18])=[O:17])[CH:20]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: Nc1cccc(S(=O)(=O)N2CCCCC2)c1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2cccc(S(=O)(=O)N3CCCCC3)c2)nc1N
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(piperidine-1-sulfonyl)-phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ˜9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2×30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (˜0.6 g) used in the next step without purification. MS (ES+): m/z 348 (M+H)+.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])C.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH3:18])[C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])[CH3:15]
Reactant: CCOC(=O)C1CC(C)CCC1=O
Reactant: CCNCC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)C1CC(C)CCC1=O
Yield: 65.1 %

Procedure:
5-Methyl-2-oxo-cyclohexanecarboxylic acid ethyl ester (45) (5.9 g, 32 mmol), DMAP (1.12 g, 10 mmol) and diethylamine (4.7 g, 65 mmol, 6.7 mL) in toluene (90 mL) were heated at reflux for 4 days. The reaction was allowed to cool and the toluene was removed under reduced pressure to give a yellow oil. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-50% B, 80 g) to afford 4.4 g (65%) of 5-methyl-2-oxo-cyclohexanecarboxylic acid diethylamide (46) as a yellow oil. The structure was confirmed 1H NMR (300 MHz, CDCl3) δH 0.8-1.05 (9H, m, CH3 and N(CH2CH3)2), 1.05-2.10 (5H, m, 5-CH and 4- and 6-CH2), 2.15-2.80 (2H, m, 3-CH2), 2.95-3.55 (5H, m, 1-CH and N(CH2CH3)2).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:17][CH2:16][CH2:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[C:22]#[N:23])[CH:10]=2)[CH2:6][C:7]21[CH2:12][CH2:18][CH2:19][C:20]1[CH:21]=[CH:13][CH:14]=[CH:15][C:16]=1[CH2:17]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12CCCc1ccccc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCCc4ccccc4C2)C3)c1
Temperature: 100 °C
Reaction time: 0.7 h
Yield: 56 %

Procedure:
To a solution of 6′-bromo-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-inden]-1′(3′H)-one (200 mg, 0.59 mmol) and 3-cyanophenylboronic acid (130 mg, 0.885 mmol) in Cs2CO3 (2 M, 1 mL) and 1,4-dioxane (4.2 mL) under N2 was added Pd(PPh3)2Cl2 (20 mg). The mixture was stirred at 100° C. for 0.7 h. After cooled to room temperature, the organic layer was dried and concentrated to give the residue, which was purified by TLC to give 3-(1′-oxo-1′,3′,5,7,8,9-hexahydrospiro[benzo[7]annulene-6,2′-indene]-6′-yl)benzonitrile (120 mg, 56%).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:54][C:55]([CH3:60])([CH3:59])[C:56](O)=[O:57]>C1COCC1.O>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@H:17]([CH3:20])[CH2:18][O:19][C:56](=[O:57])[C:55]([OH:54])([CH3:60])[CH3:59])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: CC(C)(O)C(=O)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](COC(=O)C(C)(C)O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Yield: 0.1 %

Procedure:
200 mg (0,612 mmol) of (S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol was dissolved in THF (2 ml). PPh3 (169 mg; 0,643 mmol) was added and the mixture cooled to 0° C. To this, a solution of DEAD (95 mg; 0,612 mmol) and 2-hydroxy-isobutyric acid (64 mg; 0,612 mmol) in THF (2 ml) was added dropwise via cannula. After four hours the reaction mixture was poured in cold water, extracted with ether and dried over Na2SO4. Removal of the solvent and silica gel column chromatography (eluent hexane/ethyl-acetate 85/15) of the residue afforded 232 mg (91%) of 2-hydroxy-2-methyl-propionic acid(S)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propyl ester (K1) as a yellow oil.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+]>O1CCOCC1>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:9]1)([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(=O)NC(C)(C(N)=O)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C2=NC(C)(C(C)C)C(=O)N2)cc1

Procedure:
A mixture of 24.8 g (0.10 mol) of N-(1-carbamoyl-1,2-dimethylpropyl)-p-toluamide in 263 mL of a 2N sodium hydroxide solution (0.50 mol NaOH) is heated with 100 mL p-dioxane and heated on a stream bath for 72 hours. The p-dioxane is removed in vacuo and the remaining aqueous solution is cooled to 5°-10° C. After carefully acidifying to pH 3-4 with concentrated sulfuric acid, the reaction mixture is extracted with a total of 750 mL methylene chloride. The organic phase is washed with 200 mL of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo to give a yellow solid residue, weighing 22.1 g. The nmr spectrum is consistent with the desired structure. This compound can be recrystallized from acetonitrile to give analytically pure 4-isopropyl-4-methyl-2-p-tolyl-2-imidazolin-5-one mp 151°-154° C.
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1cnc(Cl)cn1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4C)nc3)C3CC3)CC2)cn1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg, Intermediate 20), 2-chloro-5-methylpyrazine (15 mg) and ethyldiisopropylamine (35 μL) in N-methyl-2-pyrrolidinone (1.0 mL) is heated in a microwave oven for 30 min at 200° C. After removal of the solvent the residue is purified by HPLC(H2O/MeOH/TFA) to give the title compound. LC (method 3): tR=0.92 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.O>C(Cl)Cl>[C:24]([O:23][C:21](=[O:22])[C:20]1[CH:28]=[CH:29][C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:18][CH:19]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reaction time: 4 h
Yield: 87.1 %

Procedure:
Trifluoromethanesulfonic anhydride (1.04 ml, 6.2 mmol) was added to a cooled (5° C.) solution of tert-butyl 4-hydroxybenzoate (1 g, 5.1 mmol) in a mixture of DCM (25 ml) and TEA (1.1 ml, 7.8 mmol). After 4 h at 5° C., water was added. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (eluent: cyclohexane/iPr2O 95/5) to yield the above-titled compound as a colorless oil (1.45 g). 1H NMR (CDCl3): 8.09 (2H, d, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz), 1.60 (9H, s).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30](I)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[NH:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[CH:41]1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30]([C:45]3[CH:44]=[C:43]4[C:48](=[CH:47][CH:46]=3)[NH:40][CH:41]=[CH:42]4)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cccc(F)c3)cc(-c3ccc4[nH]ccc4c3)c2)c1CCC(=O)O
Yield: 30.5 %

Procedure:
A similar procedure as described in Example 5, step 2 was used, starting from 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (116 mg, 0.18 mmol) and 1H-indol-5-ylboronic acid (66 mg, 0.54 mmol) to obtain 4-(2-(2-carboxy-ethyl)-3-{6-[3′fluoro-5-(1H-indol-5-yl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (35 mg, 31%) as an amorphous light yellow solid: ES(+)-HRMS m/e calculated for C39H40FNO6 (M+Na)+ 660.2732, found 660.2735.