Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C@H:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=3)[C@H:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][O:11]2)=[CH:16][CH:15]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 75 °C

Procedure:
cis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane (74.3 g) was dissolved in a mixture of toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) by heating the mixture to 75° C. 2-Chloroethylpyrrolidin hydrochloride (46.2 g) was added in six portions at 75° C. with half an hour between each portion. After the last addition the mixture was heated at 75° C. for 4 hours. Water (1000 ml) was added and the mixture stirred until all salt was dissolved. The aqueous phase was separated and extracted with another portion of toluene (300 ml). The combined organic phases was dried over potassium carbonate and evaporated to an oil. The oil was dissolved in refluxing methanol (1000 ml) and the product crystallised by cooling in an ice bath.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([C:19]4[C:20]5[C:25]([C:26](Br)=[C:27]6[C:32]=4[CH:31]=[CH:30][CH:29]=[CH:28]6)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:41][C:42]2[CH:47]=[CH:46][C:45](OB(O)O)=[CH:44][CH:43]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([C:19]4[C:20]5[C:25]([C:26]([C:45]6[CH:46]=[CH:47][C:42]([CH:41]=[C:40]([C:52]7[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=7)[C:34]7[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=7)=[CH:43][CH:44]=6)=[C:27]6[C:32]=4[CH:31]=[CH:30][CH:29]=[CH:28]6)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1c2ccccc2c(-c2cccc(-c3ccc(-c4ccccc4)cc3)c2)c2ccccc12
Reactant: OB(O)Oc1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(=C(c1ccccc1)c1ccccc1)c1ccc(-c2c3ccccc3c(-c3cccc(-c4ccc(-c5ccccc5)cc4)c3)c3ccccc23)cc1
Yield: 73 %

Procedure:
Under an atmosphere of argon, 9-(3-(4-phenylphenyl)phenyl)-10-bromoanthracene (3.0 g, 6.2 mmole), 4-(2,2-diphenylvinyl)phenylboric acid (2.0 g, 6.7 mmole, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmole, 2% Pd) were suspended in toluene (20 ml). To the obtained suspension, a 2M aqueous solution of sodium carbonate (2.1 g, 20 mmole, 3 eq/10 ml) was added, and the resultant mixture was refluxed for 10 hours. The reaction mixture was filtered and washed with water and methanol, and a light yellow solid substance was obtained. The obtained solid substance was suspended in boiling toluene (30 ml). After the suspension was cooled while being left standing, the suspension was filtered, and a light yellow solid substance (3.0 g, the yield: 73%) was obtained. The result of examination of the obtained product in accordance with 1H-NMR was as follows:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][C@@H:36]([CH3:40])[C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[C@@H:36]([OH:35])[CH3:40])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)[C@H](C)O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.O[C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1cccc2cccnc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a stirred mixture of quinolin-8-ol (300 mg, 2.07 mmol) in THF (5 mL) was added (S)-methyl 2-hydroxypropanoate (215 mg, 2.07 mmol), PPh3 (647 mg, 2.47 mmol) and DEAD (430 mg, 2.47 mmol). The mixture was stirred at 25° C. for 16 hours. Subsequently, 1M HCl was added (10 mL) and the solution was washed with EtOAc (20 mL×3). The pH of the aqueous solution was raised by addition of aqueous NaHCO3 (10 mL), and then this solution was washed with EtOAc (10 mL×3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography to afford the product as a colorless oil (300 mg, 62.5% yield). LCMS (m/z): 233.1 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[N:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C([Sn](Cl)(CCCC)CCCC)CCC.[N-:32]=[N+:33]=[N-:34].[Na+].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:34][N:33]=[N:32][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc(=O)c2cc(C#N)ccc2[nH]1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
A mixture of 1.1 g of 2-Butyl-6-cyano-4(1H)-quinazolinone 3.2 g of tri-n-butyltin chloride and 640 mg of sodium azide in 30 ml of toluene is heated at reflux for 48 hours. The reaction mixture is cooled to room temperature and dry HCl gas passed through the reaction mixture for 10 minutes. The reaction mixture is diluted with hexane and filtered. The residue is dried, washed with water and dried to give 1.5 g of the desired product as a solid, m.p. 225° C.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:12]Br)[O:11][CH2:10][CH2:9][O:8]2)=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:12][O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[O:11][CH2:10][CH2:9][O:8]2)=[CH:3][CH:2]=1
Reactant: Oc1cccnc1
Reactant: BrCC1(c2ccc(-c3ccccc3)cc2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc(-c2ccc(C3(COc4cccnc4)OCCO3)cc2)cc1

Procedure:
A mixture of 2-([1,1'-bipheny]-4-yl)-2-(bromomethyl)-1,3-dioxolane (16 g.), 3-hydroxypyridine (5.7 g.) and potassium carbonate (9 g.) were refluxed with stirring in N,N-dimethylacetamide (75 ml.) for 18 hours. After refluxing, the mixture was allowed to cool and was thereafter poured into water (150 ml.). The resultant aqueous solution was extracted twice with ether. The combined ether fractions were washed once with 5% aqueous sodium hydroxide and 4 times with water. The washed ether fractions were then dried, filtered and the solvent evaporated to yield 3-[[2-([1,1'-biphenyl]-4-yl)-1,3-dioxolan-2-yl]methoxy]pyridine as an oil.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:35]([CH3:37])[CH3:36])[C:24](=[O:34])[C:25]([F:33])([F:32])[C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])=[O:21])[C:15]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:35]([CH3:37])[CH3:36])[C:24](=[O:34])[C:25]([F:33])([F:32])[C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])=[O:21])[C:15]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[N:14][CH:13]=1
Reactant: CCCNC(=O)C(F)(F)C(=O)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CCCNC(=O)C(F)(F)C(=O)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A suspension of the product from Example 1 (0.29 g) in dichloromethane (4 mL) and anisole (0.17 mL) was cooled in an ice-water bath. Trifluoromethanesulfonic acid (0.23 mL) was added to the mixture dropwise. The dark colored, gummy reaction mixture was allowed to warm to room temperature. After 30 minutes, the reaction mixture was cooled in an ice-water bath and was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts were washed (saturated sodium bicarbonate, brine), dried, and evaporated. The crude product was purified by trituration with ether to yield the title compound as a white solid (0.16 g); TLC: Rf =0.19, methanol:dichloromethane (5:95); NMR: 0.75 (d,3), 0.82 (t,3), 0.86 (d,3), 1.40-1.50 (m,2), 2.20-2.30 (m,1), 3.08 (q,2), 4.50 (q,2), 4.82 (dd,1), 5.17 (broad s, 2); MS: m/z=464 (M+1).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:7]1=[O:15]
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1Cc2ccccc2N1C1=NCCS1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COc1ccc(C=C2C(=O)N(C3=NCCS3)c3ccccc32)cc1
Yield: 53.7 %

Procedure:
To a warmed benzene solution of 1-(2-thiazolin-2-yl)-indolin-2-one (2.0 g, 7.2 mmol) and p-methoxybenzaldehyde (1.5 g, 11 mmole) is added piperidine (0.6 ml). The mixture is heated at reflux temperature for 2 hours. The reaction mixture is then washed with NaHSO3 solution, diluted HCl and water. The organic phase is dried over anhydrous MgSO4 and concentrated in vacuo. The residue is recrystallized once each from acetone/hexane, acetonitrile and CHCl3 /methanol and gives 1.3 g (43%) of the product (m.p. 164.5°-167° C, softens at 149° C).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][CH:10]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)C.C(OCC)C>O.O1CCCC1>[F:36][C:34]([F:35])([F:37])[C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1)[C:23]([N:21]([CH:10]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][C:6]([OH:39])=[O:5])[CH3:22])=[O:38]
Reactant: CCOC(=O)CCCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCCC(=O)O)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 108 mg (1.93 mmol) of potassium hydroxide in 1 ml of water is added at room temperature to a solution of 970 mg (1.84 mmol) of 5-[(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-6-(1H-indol-3-yl)-hexanoic acid ethyl ester in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours and then 10 ml of water and 20 ml of diethyl ether are added. The aqueous phase is separated off and rendered acidic with 6N hydrochloric acid. Ethyl acetate is then added and the product is extracted. The combined organic phases are washed with brine, dried over magnesium sulfate and concentrated by evaporation. The title compound crystallises out from diethyl ether/hexane in the form of white crystals. M.p.: 152-157° C.; MS (EI): 500 (M+.), 370, 241, 229,130; TLC: (ethyl acetate/acetic acid 99:1) Rf =0.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([CH3:10])[N:4]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:7]1[CH:6]=[C:5]([CH3:10])[N:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: COc1nc(C)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1nc(C)cc(Cl)n1
Yield: 2.3 %

Procedure:
2-Methoxy-6-methylpyrimidin-4(3H)-one (12 g, 85.71 mmol, 1 eq) was heated for 30-40 min at 100° C. in POCl3 (85 ml). The reaction mixture was then concentrated and diluted with ice-water (100 ml). The aqueous phase was rendered alkaline (pH˜9) with NaHCO3 and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with saturated sodium chloride solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% ethyl acetate/hexane). The desired product was in the form of a light-yellow solid. Yield: 2.3% (300 mg, 1.8987 mmol) after 2 stages
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B([C:48]1[CH:53]=[CH:52][C:51]([S:54]([N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)(=[O:56])=[O:55])=[CH:50][CH:49]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:48]2[CH:53]=[CH:52][C:51]([S:54]([N:57]3[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]3)(=[O:56])=[O:55])=[CH:50][CH:49]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)c1C
Temperature: 25 °C

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.20 g, 0.50 mmol) in dimethoxyethane (10 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.030 g, 0.11 mmol), palladium (II) acetate (0.013 g, 0.055 mmol), 1-(4-boronophenylsulfonyl)piperidine (0.183 g, 0.68 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to {6-chloro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.133 g, 58%) as a solid. MS calcd. for C25H25ClNO4S [(M−H)−] 470, obsd. 470.5.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O>O1CCCC1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH:18]1[CH2:19][CH2:20][CH:21]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:22][CH2:23]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OC1CCC(OC2CCCCO2)CC1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCC(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To a solution of the 1H-indazol-5-ol (250 mg) obtained in Reference Example 4 in tetrahydrofuran (15 ml) were added 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanol (373 mg, 1.86 mmol), triphenylphosphine (538 mg, 2.05 mmol) and dibenzyl azodicarboxylate (667 mg, 2.24 mmol) at 0° C. After 1 hour, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and a 1M-aqueous sodium hydroxide solution (50 ml) was added to the resulting residue, followed by extraction with chloroform (50 ml×2). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-{[4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]oxy}-1H-indazole (244 mg, 41%).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([OH:19])=[S:18])=[C:11]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([O:19][CH3:1])=[S:18])=[C:11]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
Oxalyl chloride (0.70 mL, 9.6 mmol) was added to a solution of 5-chloro-3-phenylthioindole-2-carboxylic acid (0.97 g, 3.2 mmol) in chloroform (50 mL) under nitrogen. The reaction was refluxed for 3 h, cooled and reduced to dryness in vacuo. The resulting solid was dissolved in chloroform and added to methanol at 0° C. The methanol was removed in vacuo and the crude product chromatographed on silica gel with 20% ethyl acetate in hexane. The title compound was obtained as a solid, mp 193°-196° C. Anal. Calc. for C16H12ClNO2S: C, 60.47; H, 3.81; N, 4.42. Found: C, 60.09; H, 3.50; N, 4.67.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C(OC([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:16]([O:21][CH3:22])[CH:17]=2)[CH:12]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=O)C.O.[OH-].[K+].CN(C)[CH:45]=[O:46]>CO.ClCCl>[CH2:24]([O:23][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([CH:45]=[O:46])=[CH:20][N:11]=[C:12]2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:17][C:16]=1[O:21][CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1C=Cc2cc(OC)c(OCc3ccccc3)cc2C1Cc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(Cc2ncc(C=O)c3cc(OC)c(OCc4ccccc4)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To N,N-dimethylformamide (0.36 mL) at 0° C. was added phosphorous oxychloride (0.84 mL, 0.80 g, 10.9 mmol.) dropwise. The mixture was warmed to room temperature and stirred×30 minutes. The mixture was recooled in an ice-bath, and 7-benzyloxy-6-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (2.15 g, 2.11 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath×2 hours at 60° C. The mixture was cooled, poured into water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (3×20 mL), saturated aqueous sodium chloride solution (1×20 mL) and dried over anhydrous magnesium sulfate. Concentration of the solvent in vacuo gave a viscous oil that was dissolved methanol (20 mL), and a solution of powdered potassium hydroxide (0.63 g, 10.5 mmol) in methanol (5 mL) was added dropwise. The mixture was stirred overnight (14 hours) at room temperature. The mixture was poured into water (100 mL) and extracted with diethyl ether (3×30 mL). The combined organic extracts were washed with water (30 mL), saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. Concentration gave an orange foam that was dissolved in dichloromethane (100 mL), and maganese (IV) oxide (3 g, 34.8 mmol.) was added in one portion. The mixture was stirred at room temperature×2 hours. Silica gel (5 g) was added to the mixture. The mixture was filtered through a silica gel pad. The silica gel pad was washed with 50% ethyl acetate in hexanes (200 mL). Concentration of the combined filtrates and precipitation from ethyl acetate with hexanes gave 7-benzyloxy-6-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (1.00 g, 2.42 mmol, 53%) as a yellow solid.
Reaction SMILES: [OH-].[K+].[I:3]I.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:12]=2)[CH:7]=[CH:6]1>CN(C=O)C.O>[I:3][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[NH:5][CH:6]=1
Reactant: II
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(I)c[nH]c2c1)N1CCOCC1

Procedure:
Potassium hydroxide (422 mg, 7.543 mmol, 3.47 eq), iodine (1.103 g, 4.347 mmol, 2.0 eq) and (1H-indol-6-yl)(morpholino)methanone (500 mg, 2.173 mmol, 1.0 eq) in DMF (10 mL) were stirred at room temperature for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated in vacuo. White solid. Yield: 600 mg (77% of theory)
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.CS([Cl:32])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:32][C@@H:6]1[CH2:7][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: CN(C)c1ccc(CCN2CCC[C@@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reaction time: 2 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-dimethylaminophenethyl)pyrrolidine (4.91 g, 19.8 mmol) was dissolved in 60 ml of dichloromethane. 3.11 g (24.4 mmol) of diisopropylethylamine and 2.75 g (24.0 mmol) of methanesulfonyl chloride were added to the obtained solution under stirring under cooling with ice. They were stirred under cooling with ice for 1 hour and then at room temperature for 2 hours. The reaction mixture was distributed into dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (9:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-dimethylaminophenethyl)piperidine in the form of a light yellow solid (3.03 g, 57%)