Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CCO
Reactant: Fc1cccc(F)c1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2c(F)cccc2F)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 43.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 226 mg of 4-chloro-6-(2,6-difluorophenyl)pyrimidine and 84 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 114 mg of 4-(2,6-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (87)).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][CH2:5]1.C(N(CC)CC)C.[N:32]1[C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=[C:34]([CH:42]=O)[N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[N:32]1[C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=[C:34]([CH2:42][NH:3][CH:4]2[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][N:12]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[CH:15]=[CH:14][C:13]3=[O:24])[CH2:8][CH2:9]2)[N:33]=1
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(nn4)OCCO5)CC3)c2c1
Yield: 242.4 %

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride (145 mg, 0.399 mmol) in chloroform (20 ml) and MeOH (2 ml) was treated with triethylamine (0.62 ml, 4.49 mmol) and stirred for 0.25 h before addition of 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (226 mg, 1.360 mmol). The reaction was stirred for 0.5 h before addition of NaBH(OAc)3 (577 mg, 2.72 mmol). After 1 h of stirring at rt more NaBH(OAc)3 (577 mg, 2.72 mmol) was added. After a further 1 h still more NaBH(OAc)3 (577 mg, 2.72 mmol) was added. The reaction was then stirred for a further 0.5 h before addition of sat. aq NaHCO3 (20 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (473 mg, 70%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH:8]1[CH2:18][CH2:17][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:15]([O:14][C:12]([CH:11]1[CH2:17][CH2:18][N:8]([CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:9][CH2:10]1)=[O:13])[CH3:16]
Reactant: CC(C)(C)CC=O
Reactant: CCOC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3,3-Dimethylbutyraldehyde (5.26 ml, 42.0 mmol) was added to a solution of ethyl isonipecotate (6.6 g, 42.0 mmol) in methanol/acetic acid (99:1, v/v, 50 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.43 g, 54.6 mmol) was added, and the mixture was stirred at room temperature for 4 days then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% EtOAc:75% cyclohexane) to yield the title compound (7.16 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=O)[CH:7]=1.ClN1C(=[O:24])CCC1=O.C(#N)C.O.FC(F)(F)C(O)=O>CN(C)C=O>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-:24])=[CH:8][CH:7]=1
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: [O-][n+]1ccc(OCc2ccc(F)cc2F)cc1
Reaction time: 15 h

Procedure:
4-[(2,4-difluorobenzyl)oxy]-pyridin-2 (1H)-one (from Step 2) (8.60 g, 36.3 mmol) was stirred in 150 ml dimethylformamide and treated with N-chlorosuccinimide (5.4 g, 39.9 mmol). After 15 hours, the precipitate was collected by filtration (5.11 g, 52%) yeilding a lustrous white solid. The mother liquor was diluted to 500 ml with diethyl ether, providing 2.47 g (25%) in a second crop. 1H-NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 7.60 (quartet, J=6.34 Hz, 1H), 7.43 (d, J=7.58 Hz, 1H), 7.31 (dt, J=10.08, 2.21 Hz, 1H), 7.14 (dt, J 8.65, 1.79 Hz, 1H), 6.44 (d, J=7.49 Hz, 1H), 5.28 (s, 1H). 19F-NMR (400 MHz, DMSO-d6) δ−109.58 (quintet, J=7.75 Hz, 1F), −113.68 (quartet, J=8.68 Hz, 1F). LC/MS tr=4.47 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 272, 274 3:1 (M+H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:26])[C:23](Br)(Br)[C@H:20]3[S:19](=[O:27])[C:18]2([CH3:29])[CH3:28])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Bi].[Cl-].[Na+].[Al]>ClCCl.CO>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:26])[CH2:23][C@H:20]3[S:19](=[O:27])[C:18]2([CH3:29])[CH3:28])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Br)(Br)[C@H]2S1=O
Agent: [Al]
Agent: [Bi]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1=O
Temperature: 22.5 °C
Reaction time: 23.5 h

Procedure:
A 86.6 g quantity of 6,6-dibromo-2,2-dimethylpenam-3-carboxylic acid 1-oxide diphenylmethyl ester (Compound 1) [compound of the formula (1) wherein X═Y═Br, R=diphenylmethyl, n=1] was dissolved in 300 mL of dichloromethane. To the solution was added 36 mL of methanol with stirring and then added a suspension of 1.05 g of metal bismuth in 112 mL of 20% aqueous solution of sodium chloride. While maintaining at 20 to 25° C., to the mixture was added 10 g of aluminum powder, each 1 g, at intervals of 10 minutes, thereafter the mixture was refluxed with heating. After 23.5 hours, the reaction mixture was cooled to room temperature, an organic layer was separated and washed with diluted hydrochloric acid and 5% aqueous solution of sodium chloride. The organic layer was concentrated to give 2,2-dimethylpenam-3-carboxylic acid 1-oxide diphenylmethyl ester (Compound 2) [compound of the formula (2) wherein R=diphenylmethyl, n=1].
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3].Br[CH2:19][CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:16][CH2:17]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Yield: 83.5 %

Procedure:
5.3 g (20.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 50 ml of N,N-dimethylformamide, and then 3.8 g (27.0 mmol) of 3-bromo-1-propanol and 8.6 g (62 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 150 ml of water and extracted with ethylacetate (100 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH2Cl2) to obtain 4.8 g (yield 85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:13]([NH2:15])=O>>[CH3:12][C:4]1[S:3][C:2]2[N:1]=[CH:13][N:15]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(C)sc1N
Product: Cc1cc2c(O)ncnc2s1
Temperature: 25 °C
Yield: 25 %

Procedure:
Into a 25-mL round-bottom flask placed ethyl 2-amino-5-methylthiophene-3-carboxylate (500 mg, 2.70 mmol, 1.00 equiv) in 10 mL of formamide was stirred for 8 h at 180° C. in an oil bath. After completion of the reaction, the reaction mixture was cooled down to room temperature and then quenched with water/ice, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (2:1) to provide the resulted 6-methylthieno[2,3-d]pyrimidin-4-ol (114 mg, 25%) as a yellow solid. MS (ES, m/z): 167 [M+H+].
Reaction SMILES: [H-].[Na+].C[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=O.[C:12]([C:16]([CH3:18])=[O:17])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[CH3:11][O:10][CH2:8][CH2:7][CH2:6][C:5](=[O:4])[CH2:18][C:16](=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COCCCC(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCCC(=O)CC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
1.8 mol of sodium hydride was added to the solvent ethylene glycol dimethyl ether, and 1 mol of methyl 4-methoxybutanoate was added thereto and stirred at room temperature for 10 minutes. Then, 1.2 mol of t-butylmethylketone was added to the solution which was then stirred at 92° C. for 19 hours. Then, the solution was cooled to room temperature and quenched in 36% hydrochloric acid, after which water and dimethylether were added to and mixed with the solution, and water was removed therefrom. The resulting organic material was washed with 1 wt % sodium hydroxide and then with saturated saline and concentrated, and the residue was fractionated, thereby obtaining the intermediate 8-methoxy-2,2-dimethyloctan-3,5-dione at a yield of 14%.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].Cl[C:19]1[C:20]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:25][C:21]=2[N:22]=[CH:23][N:24]=1.O>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:20]3[C:19]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]#[N:10])=[N:24][CH:23]=[N:22][C:21]=3[O:25][C:26]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: N#CCCCCCN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC#N)c23)cc1

Procedure:
Add 1.15 g (8.9 mmol) DIEA and 0.67 g (5.9 mmol) 6-aminocapronitrile to 1.0 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 10 ml DMF and heat for 2 h to 120° C. After cooling, add water to the mixture and extract three times with ethyl acetate. Wash the organic phase with water, with dilute hydrochloric acid and with saturated sodium chloride solution, dry, and concentrate by evaporation. 1.2 g (98% of theor.) of a yellow oil is obtained, and is used as the raw product in further reactions.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(Cl)=O)C.O.[NH3:37]>C1COCC1>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])[C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([NH2:37])=[O:11])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(=O)O
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(N)=O
Reaction time: 1 h

Procedure:
To a solution of (4S)-1-BOC-4-[(2,2-dimethylpropanoyl)(cis-4-methyl-cyclohexyl)amino]-L-proline (0.83 g, 2.05 mmol) prepared in Step C in THF was added dropwise TEA (0.32 ml, 2.27 mmol). Then, ethylchloroformate (0.24 g, 2.27 mmol) was slowly added dropwise at 0° C., and the reaction solution was stirred at the same temperature for 1 h. 28% Ammonia water (1 equivalent) was slowly added dropwise at 0° C., and stirred at the same temperature for additional 1 h. After the reaction finished, the reaction mixture was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=2/1) to give the title compound (0.62 g, 74%).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[CH2:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]#[CH:17]>CN(C=O)C.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.[Cu]I>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:17]#[C:16][CH2:15][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH:10]=1
Reactant: C#CCOCCNC(=O)OC(C)(C)C
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCC#Cc1cccnc1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
Under a nitrogen atmosphere, anhydrous triethylamine (45.5 mL, 326 mmol) and 3-bromopyridine (12.9 mL, 138 mmol) were added to a solution of tert-butyl 2-(prop-2-ynyloxy)ethylcarbamate (26.0 g, 125 mmol) in anhydrous DMF (400 mL), and the reaction was heated at 80° C. Dichlorobis(triphenylphosphine)palladium (II) (1.76 g, 2.51 mmol) and copper (I) iodide (0.96 g, 5.02 mmol) were then added, and the reaction was heated at 80° C. for one hour. The volatiles were removed under reduced pressure, and the residual black oil was dissolved in ethyl acetate (500 mL). The solution was washed with dilute aqueous sodium bicarbonate (1×200 mL) and brine (2×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a dark brown oil. The oil was purified by column chromatography on silica gel (350 g, eluting with 50:50 ethyl acetate:hexane), and the resulting dark oil was dissolved in hot methanol (200 mL) and treated with 10 g of activated charcoal. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was treated with additional activated charcoal (10 g) and filtered in the same way to provide 25.4 g of tert-butyl {2-[3-(pyridin-3-yl)prop-2-ynyloxy]ethyl}carbamate as a light amber-colored oil.
Reaction SMILES: C(=O)([O-])O.[Na+].[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[C:11]1=[O:17].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CC(C)=O.O>[CH2:22]([O:21][C:19]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][OH:6])[C:11](=[O:17])[C@@H:12]1[CH3:16])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H]1NCCN(CCCO)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1C(=O)N(CCCO)CCN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 100.6 %

Procedure:
Sodium hydrogencarbonate (976 mg, 11.6 mmol) was added to a solution of (S)-1-(3-hydroxy-propyl)-3-methyl-piperazin-2-one (example 20D; 1.00 g, 5.81 mmol) in acetone (5 mL) and water (5 mL), then a solution of benzyl chloroformate (1.04 g, 5.81 mmol) in acetone (1 mL) was added at 0° C. The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (1.79 g), which was directly used in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13](=C)[CH3:14].OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:14])[CH3:12]
Reactant: C=C(C)C
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Temperature: 180 °C
Reaction time: 4 h
Yield: 234 %

Procedure:
750 g (5 mol) of 4-tert.-butylphenol and 320 g of an acid-activated fuller's earth are introduced into a 10 liter autoclave and heated to 180° C. 1960 g (35 mol) of isobutylene and 3420 g (15 mol) of molten 2,2-bis-(4-hydroxyphenyl)-propane are simultaneously pumped in over a period of 4 to 5 hours at the aforementioned temperature. The mixture is then left to react with stirring for another 4 hours at 180° C. The hot reaction mixture is then filtered off from the catalyst, giving 6100 g of a crude mixture from which 2230 g (11.7 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane are obtained by fractional distillation.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][N:12]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[CH:14]=[N:13]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C1COCC1>[CH3:11][N:12]1[C:20]2[C:15](=[C:16]([NH:21][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[N:13]1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1ncc2c(NC(=O)Oc3ccccc3)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of phenyl chloroformate (1.1 mmol) in chloroform was cooled to 0° C. 1-methyl-1H-indazole-4-amine in dry THF was added to the reaction mixture dropwise at 0° C. Pyridine (1 mmol) was added to the reaction mixture. Reaction mixture was stirred at 0° C. for 30 minutes and was then stirred at room temperature for 15 hours.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH:10]=[CH2:11]>>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[CH:10]=[CH2:11]
Reactant: CC(C)N1CC(O)C1
Reactant: C=CCOc1ccccc1O
Product: C=CCOc1ccccc1OCC(O)CNC(C)C
Yield: 48 %

Procedure:
When 1-(iso-propyl)-3-azetidinol and 2-allyloxyphenol were reacted in the same manner as in Example 6, 1-(2-allyloxyphenoxy)-3-(iso-propylamino)-2-propanol melting at 76°-79° C was obtained. The yield was 48%.
Reaction SMILES: [Si]([O:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][Cl:21])=[CH:17][C:12]=2[O:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(C(C)(C)C)(C)C>Cl.O1CCOCC1>[Cl:21][CH2:20][CH2:19][O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9](=[O:8])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[O:11][C:12]=2[CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(-c2ccc(Cl)cc2)oc2cc(OCCCl)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccc(OCCCl)cc2OC1c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
66.5 g (152 mmol) of 3-tert-butyldimethylsilyloxy-6-(2-chloroethoxy)-2-(4-chlorophenyl)benzofuran are dissolved in 500 ml of a 4 M hydrogen chloride solution in dioxane at RT under argon and stirred for 1.5 h. The mixture is concentrated to result in 49.2 g of a residue which is stored under argon and reacted further without purification.
Reaction SMILES: [Br-].[O:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Zn+])=[CH:6][CH:5]=1)[CH3:3].I[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:23][CH:24]=2)=[C:15]([CH3:34])[CH:14]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:3][O:2][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]2[CH:14]=[C:15]([CH3:34])[C:16]([C:20]3[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[S:23][CH:24]=3)=[C:17]([CH3:19])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1

Procedure:
A THF solution of 4-methoxylbenzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-(4-methoxybenzyl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3) 8.69 (d, J=5.2 Hz, 2H), 7.66 (d, J=4.9 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.86 (d, 2H), 6.80 (s, 1H), 6.75 (s, 2H), 3.80 (s, 2H), 3.78 (s, 2H), 1.98 (s, 6H); ESI-MS: m/z 399.9 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[O:24])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:27]([O-:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>ClCCl>[CH2:29]([O:28][P:27]([CH:23]([C:13]1[C:12](=[O:25])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([F:26])[CH:10]=2)[N:15]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:14]=1)[OH:24])(=[O:34])[O:31][CH2:32][CH3:33])[CH3:30]
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: CCOP([O-])OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5.0 ml dichloromethane solution of 500 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde were added 0.23 ml of diethyl phosphite and 0.22 ml of 1,8-diazabicyclo[5.4.0]-7-undecene at −40° C., followed by overnight stirring at room temperature. Aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with chloroform and then washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 400 mg of diethyl[[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)methyl]phosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH:7](Cl)[C:6]=2[CH:19]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:21]#[CH:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH:7]([N:26]3[CH2:27][CH2:28][N:23]([CH2:20][C:21]#[CH:22])[CH2:24][CH2:25]3)[C:6]=2[CH:19]=1
Reactant: C#CCN1CCNCC1
Reactant: COc1ccc2c(c1)Sc1ccc(Cl)cc1C(Cl)C2
Product: C#CCN1CCN(C2Cc3ccc(OC)cc3Sc3ccc(Cl)cc32)CC1

Procedure:
In a manner analogous to that described in Example 1, from 8,10-dichloro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin and N-(2-propynyl)-piperazine there is obtained 1-[8-chloro-10,11-dihydro-3-methoxy-dibenzo[b,f]thiepin-10-yl]-4-(2-propynyl)-piperazine, the dimethanesulfonate of which melts at 177°-180° C.