Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(CC(O)C2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCCc1nc(C)n(CC(=O)C2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 6-butyl-3-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.3 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.35 g) and methylene chloride (15 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr and extracted with chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.22 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:18]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOCCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 128.5 %

Procedure:
To 0.975 grams (five millimoles) of 4-hydroxy-4'-cyanobiphenyl dissolved with 1.08 grams (5.5 millimoles) of 1-bromo 2-(2-ethoxyethoxy)-ethane in 25 mls. of acetonitrile, 1.4 grams (ten millimoles) of finely ground potassium carbonate were added. The reaction mixture was refluxed overnight. Thin layer chromatographic analysis indicated total conversion. The reaction mixture was cooled and filtered and the product was washed with acetonitrile and evaporated to a white solid. The product was recrystallized from isopropanol and dried in vacuo to two grams (93% yield) of a compound having the following formula structure: ##STR22##
Reaction SMILES: [NH4+]=[S:2].[CH3:3][O:4][C:5]1[C:14]2[O:13][CH2:12][O:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]=[C:28]([CH3:30])[O:27][N:26]=3)=[CH:21][CH:20]=2)[C:16]#[N:17])[CH:6]=1.C1COCC1.O>C(O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[C:14]2[O:13][CH2:12][O:11][CH2:10][C:9]=2[CH:8]=[C:7]([CH:15]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:29]=[C:28]([CH3:30])[O:27][N:26]=3)=[CH:23][CH:24]=2)[C:16]([NH2:17])=[S:2])[CH:6]=1
Reactant: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCOC2
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCOC2

Procedure:
After adding 90 ml of a 20% aqueous solution of ammonium sulfide to a solution of 29.2 g of a crude (8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in 240 ml of an ethanol:THF=2:1 mixed solvent, the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (28.2 g, crude product) as a light yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CS(C)=O.[C-:24]#[N:25].[K+]>C(OCC)C>[C:24]([C:10]([OH:18])([CH2:9][CH2:8][C:7]1[C:6]([CH3:19])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]=1[OH:11])[CH3:17])#[N:25]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)Oc1c(C)c(C)c(O)c(CCC(C)(O)C#N)c1C

Procedure:
A solution of 26.4 g. (0.1 mol.) of (±)-6-acetoxy-2-hydroxy-2,5,7,8 -tetramethylchroman in 200 ml. of dimethylsulfoxide was rapidly stirred as 32.5 g. (0.5 mol.) of granular KCN was added by sifting so that a uniformly dispersed suspension was obtained. The resulting mixture was cooled to 15° centigrade as 47.0 ml. of 12N aqueous H 2 SO 4 was added over 1.25 hours as the internal temp. was maintained at 20° centigrade. Tlc at this point showed a major, slower-running spot in addition to traces of starting material. The material was poured into diethylether and H 2 O. The ether solutions were washed with water and brine, dried over NaSO4 and stripped of solvent to yield (±)-2-cyano-4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl) butan-2-ol as a gum.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:1].[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCc1ccccc1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)NCCCc4ccccc4)n32)cc1
Reaction time: 0.25 h

Procedure:
The carboxylic acid from Step D, Example 1 (20.0 mg, 0.0625 mmol), 3-phenylpropylamine (0.0089 mL, 0.0625 mmol), EDC hydrochloride (14.4 mg, 0.0751 mmol), HOBT (10.1 mg, 0.0751 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.250 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The crude product was purified by preparative HPLC using a gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the HCl salt. MS (es) m+1=389. 1H-NMR (CD3OD): δ7.72 (d, 2H, J=8.2 Hz); 7.71 (s, IH); 7.24 (d, 2H, J=8.2 Hz); 7.23 (t, 2H, J=7.9 Hz); 7.14 (t, 1H, J=7.6 Hz); 7.10 (d, 2H, J=7.3 Hz); 6.38 (bd, 1H, J=7.4 Hz); 4.70 (dd, 1H, J=11.6, 8.4 Hz); 3.81 (d, 1H, J=11.6 Hz); 3.14-3.22 (m, 2H); 2.53 (t, 2H, J=7.7 Hz), 1.73-1.80 (m, 2H).
Reaction SMILES: [Na:1].[CH2:2]([C:4]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])[O:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][O:5]1)C.CC1(CCO)OCC2(OCCO2)CO1>>[Na:1].[CH3:35][C:18]1[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])=[N:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][C:4]1([CH3:2])[O:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][O:5]1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: CC1(CCO)OCC2(CO1)OCCO2
Agent: [Na]
Product: Cc1c(OCCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 15.1 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 was repeated using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethanol obtained in the step (73b) above to obtain the title compound (298 mg, total 15.1% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[NH:9][C:10]([CH3:18])=[C:11]3[C:16]=2[CH:15]=[N:14][NH:13][C:12]3=[O:17])[CH:7]=1.C(N(CC)CC)C.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>ClCCl.O1CCCC1>[CH3:18][C:10]1[NH:9][C:8]([C:6]2[CH:7]=[C:2]([NH:1][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:3]=[CH:4][C:5]=2[O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]2[CH:15]=[N:14][NH:13][C:12](=[O:17])[C:11]=12
Reactant: Cc1[nH]c(-c2cc(N)ccc2Oc2ccccc2)c2cn[nH]c(=O)c12
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccccc2)c(-c2[nH]c(C)c3c(=O)[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
To a solution of Example 74f (0.05 g, 0.150 mmol) and triethylamine (0.084 mL, 0.602 mmol) in dichloromethane (1.504 mL) and tetrahydrofuran (1.504 mL) was added drop-wise ethanesulfonyl chloride (0.046 mL, 0.481 mmol). The reaction mixture was stirred for three hours at ambient temperature and concentrated. The residue was diluted with dioxane (3 mL) and 1 M sodium hydroxide (1 mL) and heated at 60° C. for 1 hour. The mixture was cooled and diluted with water and ethyl acetate adjusting the pH to 6 with 1 M HCl. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by chromatography (silica gel, 1-5% methanol in dichloromethane) afforded the title compound (0.03 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 11.41 (s, 1H), 9.83 (s, 1H), 8.04 (s, 1H), 7.43 (d, J=2.71 Hz, 1H), 7.26-7.33 (m, 2H), 7.22 (dd, J=8.82, 2.71 Hz, 1H), 7.00-7.08 (m, 2H), 6.90 (d, J=7.46 Hz, 2H), 3.15 (q, J=7.23 Hz, 2H), 2.59 (s, 3H), 1.24 (t, J=7.46 Hz, 3H). MS (ESI+) m/z 425 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.[Cl-].[Na+].O>[C:25]([O:13][CH:11]1[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10]1)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: OC1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a -70° C. solution of 2.50 g (9.9 mmol) of 2,6-diphenyl-4-hydroxypiperidine in 80 ml of dry tetrahydrofuran (THF), 4.2 mL (10.5 mmol) of n-butyllithium (2.5M in hexanes) is added dropwise. The mixture is warmed to -20° C. and stirred for 30 minutes. The solution is then cooled again to -70° C. and a solution of 2.2 g (9.9 mmol) of lauroyl chloride in 20 mL of dry THF is then added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is added to 250 mL of brine and then extracted with 2×200 mL of ether. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by liquid chromatography (LC) (silica gel, ethyl acetate/hexane) to give 3.2 g (74%) of the title compound as a white solid: mp 40°-42° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:35])([F:36])([F:37])[F:38])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: COc1cc(C(=O)Nc2ccc(C)c(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
30 mg (0.10 mmol) of the compound of Example 6A and 29 mg (0.10 mmol) of the compound of Example 25A were reacted and worked up analogously to the procedure of Example 16. This gave 32 mg (55% of theory) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15]C(=O)OC(C)(C)C)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[CH2:1]([NH:8][C:9]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(Cc2ccccc2F)(NCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCC(Cc2ccccc2F)(NCc2ccccc2)C1

Procedure:
tert-butyl 3-(benzylamino)-3-(2-fluorobenzyl)cyclohexylcarbamate was stirred in a solution of HCl in dioxane (4 M) at room temperature for 5 hours. The product, HCl salt of N1-benzyl-1-(2-fluorobenzyl)cyclohexane-1,3-diamine, was obtained after evaporation of solvent.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH2:32][O:33][CH3:34])=[CH:28][CH:29]=3)[O:24][CH2:23][C:22]2([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[CH3:35])(=O)=O)=CC=1.[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.[OH-].[Na+]>O1CCOCC1>[CH3:34][O:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]2[C:30]([CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:22]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=3)([CH3:35])[CH2:23][O:24]2)=[CH:29][CH:28]=1
Reactant: C1CNCCN1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCNCC2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
9-{7-(Methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman-4-yl}nonyl 4-methylbenzenesulfonate (540 mg, 0.843 mmol) and piperazine (2.2 g, 25.5 mmol) were dissolved in dioxane and then the mixture was refluxed for 2 hours. The mixture was cooled down to room temperature, basified to pH 13 using 5N-NaOH, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the organic solvent was removed under reduced pressure. The concentrate was subjected to column chromatography (methanol) to give 380 mg (yield: 81%, (3RS,4RS):(3RS,4SR)=5:4) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C@H:9]([C@@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)[C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7]1.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1.C(=O)(O)[O-].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[K]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C@H:9]([C@@H:10]([OH:11])[CH2:14][OH:13])[C@H:8]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C:7]1=[O:38]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CN2C[C@H](NC(=O)OC(C)(C)C)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2[C@@H](O)CO)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 204.8 %

Procedure:
76.8 g (0.176 mol) of t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-azetidinecarbamate are dissolved in 500 ml of tetrahydrofuran and 350 ml of water and the solution is heated to 60° C. for 24 hours with 13.0 g of p-toluenesulphonic acid. The mixture is cooled, neutralized with 10% aqueous potassium bicarbonate solution and evaporated. The residue is taken up in 300 ml of dioxan and treated with 21.8 g (0.1 mol) of di-t-butyl dicarbonate and 7.63 g of potassium carbonte. The mixture is stirred at room temperature for 24 hours and filtered. The solvent is then removed by evaporation. The crude product is recrystallized from acetonitrile. 61.3 g (88%) of t-butyl(3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-1,2-dihydroxyethyl]-2-oxo-3-azetidinecarbamate are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.O>CN(C)C=O>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:18]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzotrifluoride (4 g) in N,N-dimethylformamide (40 mL) was added trans-4-aminocyclohexanol (6.61 g), and the mixture was stirred at 90° C. for 4 hours under nitrogen atmosphere. After cooling to room temperature, water was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzotrifluoride (5.4 g) as a yellow solid.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][CH:24]([CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][C:26](Cl)=[O:27].Cl>C(=S)=S>[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[C:12]=1[C:26]([CH2:25][CH:24]([CH3:23])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27]
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(C)CCCC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)CCCC(C)CC(=O)c1c(O)cc(O)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Under the atmosphere of nitrogen, a solvent mixture of 27 ml of nitrobenzene and 23 ml of carbon disulfide was added to 6.613 g (52.4 mmol) of 1,3,5-trihydroxybenzene (1). To the mixture, 21 g (157.2 mmol, 3 equivalents) of granular aluminum chloride was added cooling with ice and stirred for two hours. Into the mixture thus formed, was added a nitrobenzene (8 ml) solution of 10.87 g (57.0 mmol, 1.09 equivalents) of 3,7-dimethyl-octanoyl chloride dropwise and were stirred at room temperature for 21 hours. The reaction mixture was poured into a cold dilute hydrochloric acid solution prepared by adding 5 ml of concentrated hydrochloric acid to 200 ml of ice and stirred and extracted from ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent. To the residue of distillation, a large volume of water was added and were distilled under reduced pressure to remove nitrobenzene solvent by steam distillation method. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain a crude reaction product. By subjecting the crude product to silica gel column chromatography (using 100 g of Wako Gel C-200, elution with hexane:ethyl acetate=7:3), 9.25 g of (2,4,6-trihydroxyphenyl) (2,6-dimethylheptyl) ketone (6) was obtained in the form of an oily substance.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (20 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (2.0 ml), and 3-chlorobenzoyl chloride (2.0 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2Cl)=[C:4]([F:24])[CH:3]=1.[CH3:25][O-:26].[Na+]>CO>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:26][CH3:25])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Br)cc1F

Procedure:
using 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-chloro-4-trifluoromethyl-6(1H)-pyrimidinone and sodium methylate in methanol there is obtained 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 137° C.;
Reaction SMILES: [Cl:1][CH:2]([Cl:18])[C:3]([NH:5][C@H:6]([CH2:16][F:17])[C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)=[O:4].CC1(C)C(C)(C)OB([C:27]2[S:31][C:30]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)O1>>[Cl:1][CH:2]([Cl:18])[C:3]([NH:5][C@H:6]([CH2:16][F:17])[C@H:7]([OH:15])[C:8]1[CH:13]=[CH:12][C:11]([C:27]2[S:31][C:30]([CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][CH:28]=2)=[CH:10][CH:9]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(CN3CCOCC3)s2)cc1)C(Cl)Cl

Procedure:
Following the general procedure of Example 22, Step 1 and making non-critical variations but using 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)acetamide (150 mg, 0.34 mmol) and 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)morpholine (114 mg, 0.37 mmol), followed by the general procedure from Example 2, step 2, the title compound is obtained (50 mg): 1H NMR (400 MHz, CDCl3) δ: 1.66 (bs, 1H), 2.53 (t, 4H), 3.71 (s, 2H,), 3.75 (t, 4H), 4.25-4.38 (m, 1H), 4.42-4.48 (m, 0.5H), 4.53-4.60 (m, 1H), 4.65-4.71 (m, 0.5H), 5.11 (d, 1H), 5.87 (s, 1H), 6.89 (d, J=3.5 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.16 (d, J=3.5 Hz, 1H), 7.39 (m, 2H), 7.59 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1)(=[O:27])=[O:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[N:32][CH:33]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(S(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(methylsulfonyl)pyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 25 mg, 0.125 mmol) to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=449 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.09-9.01 (m, 3H), 8.32-8.27 (m, 1H), 8.21-8.14 (m, 2H), 8.11-8.06 (m, 1H), 7.67-7.62 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.40 (s, 3H), 1.94 (s, 3H))