Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1.[ClH:37]>CO>[ClH:37].[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:17])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: COc1ccccc1N1CCN(CCN)CC1

Procedure:
9.24 g of 2-[4-(2-methoxyphenyl)piperazin-1-yl)-N-(triphenylmethyl)ethanamine are dissolved in 400 ml of methanol and, after homogenization, a stream of gaseous hydrochloric acid is passed into the solution for 10 min. The precipitate is collected, rinsed with methanol and dried under vacuum. 5.33 g of white solid are obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: N#Cc1ccc(CO)cc1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and (4-cyanophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H14N4O3, 335. Found, 335.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH:10]([CH3:12])[CH3:11])[CH3:9])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[CH:30][C:25]([OH:31])=[CH:26][CH:27]=2)([CH3:9])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: CC(C)C(C)(O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C(C)(c1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
A mixture of 5a (56.0 g, 193 mmol), p-TSA (36.0 g, 193 mmol) and phenol (25.0 g, 251 mmol) was heated to 95 for 1 h. After cooling to room temperature, the reaction mixture was partitioned between DCM and water. The separated organic phase was washed with water, three times with saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo to afford the title compound 5b. This was used without further purification in the subsequent step.
Reaction SMILES: [Br:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]2[C@@H:14]([OH:17])[CH2:15][O:16][C@H:3]12.[ClH:18].O1CCOCC1>>[ClH:18].[Br:1][C@H:2]1[CH2:6][NH:5][C@@H:4]2[C@@H:14]([OH:17])[CH2:15][O:16][C@H:3]12
Reactant: CC(C)(C)OC(=O)N1C[C@H](Br)[C@H]2OC[C@H](O)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CO[C@H]2[C@@H]1NC[C@@H]2Br
Temperature: 25 °C

Procedure:
Bromide (111) (2.14 g, 6.95 mmol) was dissolved in 4N HCl/dioxan (30 mL) with stirring at ambient temperature. The purple solution was stirred for 1 hour then reduced in vacuo and evaporated three times from diethyl ether to give a purple crystalline solid crude (3R,3aR,6S,6aS)-6-bromohexahydro-2H-furo[3,2-b]pyrrol-3-ol hydrochloride (112) (Yield 1730 mg) which was used without further purification. HPLC-MS 208.0/210.0 [M+H]+.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].S1(CCCC1)(=O)=O>>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 140 °C
Yield: 16 %

Procedure:
A mixture of potassium fluoride (61.5 g; 1.06 mole), 2-chloronitrobenzene (157.5 g; 1.0 mole) and sulpholane (88.8 g; 0.74 mole) was heated to 140° C. for 28 hours. 2-Fluoronitrobenzene was obtained in 16% yield together with 61% recovered 2-chloronitrobenzene.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[C:26]([C:30]2([CH2:55][OH:56])[CH2:35][CH2:34][CH2:33][N:32]3[N:36]=[C:37](/[CH:39]=[CH:40]/[C:41]4[CH:46]=[CH:45][C:44]([N:47]5[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]5)=[C:43]([O:53][CH3:54])[CH:42]=4)[N:38]=[C:31]23)[CH:27]=[CH:28][CH:29]=1.C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([C:30]2([CH:55]=[O:56])[CH2:35][CH2:34][CH2:33][N:32]3[N:36]=[C:37](/[CH:39]=[CH:40]/[C:41]4[CH:46]=[CH:45][C:44]([N:47]5[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]5)=[C:43]([O:53][CH3:54])[CH:42]=4)[N:38]=[C:31]23)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3(CO)c2cccc(F)c2)ccc1-n1cnc(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(C=O)c2cccc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 138.2 %

Procedure:
Dess-Martin periodinane (304 mg) was added to a solution of (8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol (165 mg) in methylene chloride (10 mL), and the reaction solution was stirred in a nitrogen atmosphere at room temperature for four hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 227 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:30][C:31](Cl)=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:31](=[O:32])([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.423 g. of chloroformic acid n-octyl ester as in Example 1. The 0.721 g. of brownish oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.620 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-octyl carbonate obtained melts at 51.64° and has a clearing point of 67.7°. UV (EtOH): ε 270 = 26000.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31].O>O1CCCC1>[OH:29][C:24]1([CH2:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc21
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (17 ml) in THF (tetrahydrofuran) (210 ml) was added n-butyllithium (67 ml, 1.6N in hexane) at -78° C. under N2. The solution was stirred for 30 minutes at 0° C. and then cooled to -78° C. To the solution was added ethyl acetate (12 g) and the mixture was stirred for 30 minutes at the same temperature to give Li-enolate solution. A solution of 5-t-butyldiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (10 g) in THF (50 ml) was cooled to -78° C., the above Li-enolate solution (35 ml) was added, and stirred for 1 hour at the same temperature. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-hydroxy-1-ethoxycarbonylmethyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (8.0 g). 2.72 (2H, t, J=6.6 Hz), 2.90 (2H, t, J=8.0 Hz), 4.30 (2H, t, J=7.0 Hz), 5.78 (1H, t, J=4.4 Hz), 6.33 (1H d, J=8 Hz), 6.6-6.9 (2H, m), 7.1-7.8 (20H, m) MS m/z: 624 (M+ +1)
Reaction SMILES: C1C2C3C=[C:11]4[C:16](=CC=3SC=2C=CC=1)[CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4.[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29]=2C2C=CC=C(C)C1=2)[CH3:21]>C(Cl)Cl.CCCCCC>[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29]=2[C:16]2[C:15]1=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12][CH:11]=2)[CH3:21]
Reactant: CCn1c2ccc3ccccc3c2c2cccc(C)c21
Reactant: O=Cc1ccc2cc3c(cc2c1)sc1ccccc13
Solvent: CCCCCC
Solvent: ClCCl
Product: CCn1c2ccc3ccccc3c2c2cccc(C=O)c21
Yield: 17.2 %

Procedure:
Using the procedure outlined in 8A, 7-ethyl-8-methyl-7H-benzo[c]carbazole gave a 17.2% of 7-ethyl-7H-benzo[c]carbazole-8-carbaldehyde, mp 148°-149°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Na+].[I-:13].O>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([I:13])=[N:3][CH:4]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1I
Temperature: 97.5 °C

Procedure:
To a stirred mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.5 mmol) in anhydrous DMF (20 mL) was added NaI (12.0 g, 80 mmol) was added in one portion and the resulting mixture was heated at 95-100° C. for 2 days. The reaction mixture was cooled to room tempearture and poured into water. It was then extracted with EtOAc and the combined extracts were washed with aqueous 10% Na2S2O3. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 5-Chloro-2-iodo-3-nitro-pyridine. Mass spectrum m/z: 285.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[C:18]([O:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:31][CH:30]=3)=[CH:12]2)=[C:4]([F:17])[CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 75.1 %

Procedure:
According to Scheme 19 Step 1: The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 2.81 mmol, 0.89 g, Example 1 Step 2) and 4-(tert-butoxycarbonyl)aminophenylboronic acid (1.5 eq, 4.20 mmol, 1.00 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 2 hours at 80° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 50 g SiO2, CH2Cl2/AcOEt 90/10). The resulting brown solid washed twice with acetonitrile to afford tert-butyl 4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (2.11 mmol, 0.90 g, 75%) as a beige solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1.C(Br)(Br)(Br)[Br:16].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCCl>[Br:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1cc(CO)c2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: N#Cc1cc(CBr)c2ccccc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.4 %

Procedure:
To a solution of 4-(hydroxymethyl)-2-naphthalenecarbonitrile (200 mg) in dry DCE (5 mL), CBr4 (542.8 mg) and (Ph)3P were added, the resulting mixture was stirred at r.t. for 40 min and then quenched with 40 mL of water. The aqueous phase washed with DCM (3×40 mL). The combined organic extracts were dried, concentrated, and purified by flash chromatography (CH/AcOEt from 8:2 to 1:1) to give the title compound (216 mg) as a white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH:5]1[CH2:9][C:8](=O)[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=O.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][N:2]([CH3:18])[CH2:3][CH:5]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1
Reactant: CN(C)C(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A solution of 2.91 g (11.8 mmol) N,N-dimethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide and 15 ml anhydrous tetrahydrofuran was dropped into a suspension of 1.41 g (35 mmol) lithium aluminum hydride and 30 ml tetrahydrofuran. The reaction was refluxed overnight then cooled to room temperature. To the solution was added 1.5 ml water, 1.5 ml 15% sodium hydroxide and 4.5 ml of water. The resulting precipitate was filtered. The filtrate was concentrated under reduced pressure, dissolved in dichlromethane, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was bulb to bulb distilled giving 1.5 g (58%) of N,N-dimethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as a clear liquid. This material was used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([F:38])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:27]([F:38])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(Br)ccc1OC1CCOCC1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOCC2)c(F)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-bromo-2-fluoro-phenoxy)-tetrahydro-pyran (Intermediate 16) in analogy to Example 1a): MS (ISN): 496.1 and 498.2 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:16][C:10]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(O)c2c(C)cccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2c(C)cccc2O)cc1
Reaction time: 11 h
Yield: 85.8 %

Procedure:
To a solution of (2-benzyloxy-6-methylphenyl)-(4-methoxyphenyl)-methanol (2.39 g, 7.15 mmol) in methanol (50 mL), a 20% palladium hydroxide catalyst (0.36 g) was added and furthermore 36% HCl (0.36 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 11 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.40 g, 86%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1.[O-:25][CH2:26][CH3:27].[Na+].C(O)C>C(Cl)(Cl)Cl>[Cl-:2].[CH2:26]([O:25][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1)[CH3:27]
Reactant: Clc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vial was charged with a magnetic stirring bar, 4-chloro-2-morpholino-8-phenylchromenylium chloride (78) (50 mg, 138 μmol), chloroform (1.0 mL), and a solution of sodium ethoxide in ethanol (21%, 108 μL, 290 μmol). The mixture was magnetically stirred at room temperature for 1 hour to give 4-ethoxy-2-morpholino-8-phenylchromenylium chloride (80).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]I)=[CH:4][CH:3]=1.C([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)C1C=CC=CC=1>>[OH:25][C:22]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(CCCI)cc1
Product: OC1(CCCc2ccc(F)cc2)CCNCC1

Procedure:
The title compound was prepared from 3-(4-fluorophenyl propyliodide and 1-benzyl-4-piperidone as described in Example 122.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:48]=[CH:47][C:24]([C:25]([O:27][CH2:28][C@@H:29]2[C@@H:33]([O:34][C:35](=[O:43])[C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C@:32]([F:45])([CH3:44])[C@H:31](O)[O:30]2)=[O:26])=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:50].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:35]([O:34][C@H:33]2[C@:32]([F:45])([CH3:44])[C@@H:31]([Br:50])[O:30][C@@H:29]2[CH2:28][O:27][C:25](=[O:26])[C:24]2[CH:47]=[CH:48][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:43])=[CH:37][CH:38]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccc(Cl)cc2)[C@H]1OC(=O)c1ccc(Cl)cc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O[C@@H]1Br
Temperature: -22 °C

Procedure:
Anhydrous dichloromethane (530 mL) was added to a 1 L of dry round-bottomed flask and cooled to −22° C. Triphenylphosphine (19.5 g, 74 mmol) was added and then added the β-lactol (2b, 23.5 g, 53 mmol). To that solution, carbon tetrabromide (26.3 g, 79.5 mmol, solid) was added portionwise over 5 min. at −22° C. The reaction was slowly warmed up to room temperature and once reaction was complete, the solution was passed through a short pad of silica gel (148 g in a 600 mL of fritted disc Buchner funnel) to remove any brown color polar impurities. The colorless filtrate was concentrated to dryness under reduced pressure and the solid residue was dissolved in ethyl ether (170 mL). Hexanes (50 mL) was added slowly until a precipitate started to form. The product was collected as a light yellow solid via filtration and dried (0.2 mm Hg, 25° C., 17 h) to afford 21.23 g, (79%) with an anomeric ratio of α/β>65:1. The product was contaminated with 3-4% of triphenylphosphine oxide which had no effect on the next reaction step. 1H NMR (CDCl3): δ 8.05 (m, 2H, arom.), 7.95 (m, 2H, arom.), 7.47-7.40 (m, 4H, arom.), 6.33 (s, 1H, C1-H), 5.22 (m, 1H, C3-H), 4.84 (m, 1H, C4-H), 4.76 (m, 1H, C5-Ha), 4.62 (m, 1H, C5-Hb), 1.69 (d, 3H, CH3, J=21.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])[CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>>[O:23]=[S:22]1(=[O:24])[CH2:21][CH2:20][CH2:19][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1N1CCOC1=O
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCOC1=O

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (2 g), oxazolidin-2-one (0.67 g), potassium carbonate (2.06 g), copper(I) iodide (0.73 g) and N,N′-dimethylethylenediamine (0.83 mL) was added toluene (16 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give methyl 4-nitro-2-(2-oxo-oxazolidin-3-yl)benzoate (960 mg). To a solution of ethanol (24 mL) and water (5 mL) were added ammonium chloride (0.11 g) and iron (0.79 g), and a solution of the obtained methyl 4-nitro-2-(2-oxooxazolidin-3-yl)benzoate (960 mg) in ethanol (19 mL) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg). Using the obtained methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg) and 3-chloropropane-1-sulfonyl chloride (0.49 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (495 mg) was obtained.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:6][C:7]=1[CH2:8][CH3:9].[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:16]1([CH:2]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:3]2[CH:4]=[C:5]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:6][C:7]=2[CH2:8][CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCc1sc(C2CCOCC2)cc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCc1sc(C2CCOCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a mixture of 4-{4-[chloro(cyclohexyl)methyl]-5-ethylthiophen-2-yl}tetrahydro-2H-pyran (725 mg) synthesized above, methyl 4-aminobenzoate (671 mg), sodium iodide (666 mg) and N,N-dimethylacetamide (15 mL) was added sodium carbonate (471 mg), and the mixture was stirred overnight at 100° C. under an argon atmosphere. To the reaction mixture was added 1N hydrochloric acid to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (710 mg, 75%) as a white solid.