Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]2)=[CH:21][CH:20]=1>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]3)=[CH:21][CH:20]=2)[N:7]=1
Reactant: Nc1ccc(N2CCC[C@@H](O)C2)cc1
Reactant: Clc1ncnc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCN(c2ccc(Nc3ncnc(Cl)n3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine in dioxane was added diisopropylethylamine, followed by the addition of (R)-1-(4-aminophenyl)piperidin-3-ol. The reaction mixture was stirred at 110° C. for 1 hour, and LCMS (liquid chromatography-mass spectrometry) showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=5:1, to afford (R)-1-(4-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)piperidin-3-ol.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(-c2ccncc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(-c2ccncc2)cc1Br
Temperature: 60 °C

Procedure:
Bromine (26.0 g, 163 mmol) is added to a stirred solution of 4-(4-methoxyphenyl)pyridine (13.6 g, 73.5 mmol) in acetic acid (500 mL) and heated at 60° C. for 72 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with aqueous ammonia (400 mL of 6M) and extracted with ethyl acetate (3×200 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 95% t-butylmethyl ether/4.5% methanol/0.5% aqueous NH3(25%)) and recrystallised from ether-cyclohexane to give 4-(3-bromo-4-methoxyphenyl)pyridine as a pale-yellow crystalline solid, m.p. 82-84° C.
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.O[CH:19]([C:32]1[CH:33]=[C:34]([Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[O:35][CH:36]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:15]([CH:19]([C:32]1[CH:33]=[C:34]([Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[O:35][CH:36]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](CC)(CC)CC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Reaction time: 48 h

Procedure:
A solution of diphenylphosphonyl azide (143 mg, 0.52 mmol in THF (2 ml) was added over a period of 15 minutes to a solution of 4-(1-hydroxytridecyl)-2-triethylsilylfuran (200 mg, 0.52 mmol), triphenylphosphine (140 mg, 0.52 mmol) and diethyl azidocarboxylate (90 mg, 0.52 mmol) in THF (10 ml) at room temperature. After stirring for 2 days, the mixture was evaporated in the presence of a minimum amount of silica gel. The residue was purified by flash chromatography on silica using 5% ethyl ether/hexane to give the titled azide.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.CI.[C:18](=O)([O-])O.[Na+]>C(O)C>[NH:1]=[C:2]1[N:6]([CH3:18])[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3]1
Reactant: O=C([O-])O
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: Cn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: 20 °C
Yield: 27.9 %

Procedure:
2-Amino-6-trifluoromethoxybenzothiazole (7.1 g) and methyl iodide (4.3 g) in absolute ethanol (20 cc) are heated for 18 hours to boiling. The mixture is then cooled to a temperature in the region of 20° C. The precipitate formed is separated by filtration and washed with absolute ethanol (2×20 cc). The solid is taken up in distilled water (100 cc) heated to 60° C., and the solution obtained is treated with sodium hydrogen carbonate (2.6 g). The precipitate is separated by filtration and recrystallized in a boiling mixture (50 cc) of absolute ethanol and distilled water (50:50 by volume). 2-Imino-3-methyl-6-trifluoromethoxybenzothiazoline (2.1 g), m.p. 60°-62° C., is obtained.
Reaction SMILES: [C:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:4][CH2:5][C:6]([O:8]CC)=O)#[N:2].[BH4-].[Na+].C(OCC)(=O)C.CCCCCC>CO.ClCCl.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([C:3]2([CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[CH2:4][CH2:5][C:6](=[O:8])[NH:2][CH2:1]2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CCOC(=O)CCC(C#N)(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1
Reaction time: 18 h

Procedure:
Combine ethyl 4-cyano-4-(3,4-dichlorophenyl)-6-(t-butyldimethylsilyloxy)hexanoate (9.58 g, 21.55 mmol) and cobalt(II)chloride hexahydrate (10.25 g, 43.1 mmol) in methanol (200 mL). Cool in an ice-bath, add portionwise sodium borohydride (8.15 g, 215.5 mmol). After 18 hours, concentrate the reaction mixture in vacuo to obtain a residue. Dissolve the residue in dichloromethane and extract with 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound: Rf=0.46 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C)C=O>[F:29][C:2]([F:28])([F:1])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:27])=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(c2ccc(C(=O)CCc3ccc(NC(=O)C(F)(F)F)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of 2,2,2-trifluoro-N-{4-[3-oxo-3-(4-piperazin-1-ylphenyl)propyl]-phenyl}acetamide (0.45 g, 1.1 mmol) was treated with methanesulfonyl chloride (0.15 g, 1.32 mmol) and triethylamine (0.28 g, 2.75 mmol) in N,N-dimethyl-formamide (5 mL). The reaction mixture was stirred for 15 minutes at 0° C., diluted with ice water, and extracted with ethyl acetate. The organic extract was washed with water and brine, dried, and concentrated in vacuo to give the title compound as a white solid (0.45 g, 85%).
Reaction SMILES: [S-2:1].[Na+].[Na+].[O-]CC.[Na+].[C:8]1([C:14]#[C:15][C:16](=[O:30])[C:17]#[C:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:8]1([C:14]2[S:1][C:18]([C:19]3[N:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:22]=[CH:21][CH:20]=3)=[CH:17][C:16](=[O:30])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(C#Cc1ccccc1)C#Cc1ccnn1-c1ccccc1
Reactant: [S-2]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(-c2ccccc2)sc(-c2ccnn2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To sodium sulfide (0.079 g) was added 0.25 M sodium ethoxide in ethanol solution (20.0 mL), and the mixture was stirred at room temperature for 10 min. To a solution of 1-phenyl-5-(1-phenyl-1H-pyrazol-5-yl)penta-1,4-diyn-3-one (0.25 g) in ethanol (10.0 mL) was added the above-mentioned solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (80.0 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([Cl:25])([Cl:24])[C:21]([OH:23])=[O:22].C(O)C.C(N(CC)CC)C>CN(C)C=O.ClCCl.O>[CH2:1]([O:22][C:21](=[O:23])[C:20]([Cl:24])([Cl:25])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCCCBr
Reaction time: 0.5 h

Procedure:
One drop of dimethylformamide and 1.34 g (10.5 mmol) oxalyl chloride was added to a solution of 3.30 g (8.77 mmol) 2 in 40 ml dichloromethane. After 30 minutes excess oxalyl chloride was removed in a stream of nitrogen. Subsequently a mixture of 0.97 g (21.1 mmol) ethanol and 2.13 g (21.1 mmol) triethylamine was added dropwise at 0° C. It was allowed to reach room temperature and it was stirred for a further 30 minutes. After adding 60 ml water it was extracted with methylene chloride, washed with 0.5 N HCl and water, dried over sodium sulfate and the solvent was removed. Yield 3.38 g (95%) colourless oil.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35]([SH:37])=[N:34][N:33]=2)=[CH:28][CH:27]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:35]3[O:36][C:32]([C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)=[N:33][N:34]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1nnc(-c2ccncc2)o1
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4ccncc4)o3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.53-1.70 (m, 8H) 2.09 (m, 2H, overlap) 2.82 (d, J=18.1 Hz, 1H) 3.00 (d, J=18.1 Hz, 1H) 3.78 (s, 3H) 6.97 (d, J=8.5 Hz, 1H) 7.13 (dd, J=8.4, 2.1 Hz, 1H) 7.27 (d, J=1.9 Hz, 1H) 7.73 (d, J=5.5 Hz, 2H) 8.71 (d, J=5.8 Hz, 2H). MS (APCI) calcd C26H26ClN3O5S: 528.03; found M=528.1.
Reaction SMILES: [S:1]([CH2:11][N:12]=[C:13]=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:15](=O)[CH2:16][CH3:17].[Na].O1CCN=C1>C(O)C>[CH2:16]([CH:17]1[O:14][CH:13]=[N:12][CH:11]1[S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: CCC=O
Agent: C1=NCCO1
Agent: [Na]
Solvent: CCO
Product: CCC1OC=NC1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred suspension of tosylmethylisocyanate (TosMIC, 3.90 g, 20 mmol) and propionaldehyde (1.5 mL 20.4 mmol) in 60 mL dry ethanol, finely powdered sodium cyamide (0.098 g, 2 mmol) was added. The reaction mixture became clear and white crystals of oxazoline began to precipitate in 15 min. The reaction was continuously stirred for an additional 30 min. The mixture was filtered and the crystals were washed with ether-hexane (1:1) before drying. Compound 15 was attained in 81% yield (4.1 g). The structure was confirmed by 1H NMR in CDCl3. LC-MS: [M+1]=254. Purity was >98%.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.[CH3:17][C:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][NH:20][N:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>CCOC(C)=O.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.CO>[CH3:16][N:14]1[CH:15]=[C:11]([C:4]2[N:3]=[C:2]([C:22]3[C:18]([CH3:17])=[N:19][NH:20][CH:21]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:12]=[N:13]1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CO
Product: Cc1n[nH]cc1-c1nc(-c2cnn(C)c2)cc2nccn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a flask charged with 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J; 0.650 g, 2.78 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.868 g, 4.17 mmol), and 2 M K3PO4 (4.17 mL, 8.35 mmol) was added 20 mL of DME and argon was bubbled through for 15 minutes before tetrakis(triphenylphosphine)palladium (0) (0.321 g, 0.278 mmol) was added. The flask was sealed and the reaction was heated to 100° C. for 4 hours, then allowed to cool to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (300 mL) and washed with aqueous saturated sodium bicarbonate (50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was taken up in DCM in preparation for chromatography when a precipitate began to form and continued to thicken over time. The addition of minimal MeOH (0.5 mL) did not dissolve the precipitate. The solid was collected by vacuum filtration and retained. The rinse was purified by means of silica gel chromatography eluting with a gradient of 5-10% MeOH in EtOAc containing 1% NH4OH. This was successful at generating material that was combined with the solid above to afford 7-(1-methyl-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.215 g, 0.770 mmol, 27.7% yield). MS (apci) m/z=280.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1CBr
Yield: 85.4 %

Procedure:
A mixture of (R)-5-bromo-2-methyl-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (3.32 g, 9.5 mmol), N-bromosuccinimide (1.86 g, 10.4 mmol), and benzoyl peroxide (0.23 g, 0.95 mmol) in CCl4 (100 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 3.48 g of the title compound as a white solid. MS: (+) m/z 452.06 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(O)C>[OH:15][C:8]1[CH:9]=[CH:10][C:11]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCC(=O)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccc(Nc2ccccc2)cc1
Yield: 27 %

Procedure:
0.93 g of aniline, 2.24 g of 1,4-cyclohexanedione and 1.4 ml of triethylamine were heated with stirring in 15 ml of ethanol at 50° C. to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After concentrating the reaction mixture under reduced pressure, the resultant was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 0.50 g of N-(4-hydroxyphenyl)aniline was obtained (yield 27.4%).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23](=O)[CH2:24][C:25](OC)=[O:26])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>CO.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:23]3[N:5]=[C:2]([CH3:3])[N:4]=[C:25]([OH:26])[CH:24]=3)[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: COC(=O)CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC(=N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc(O)cc(C2(c3ccc(Cl)cc3)CCC2)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of acetamidine hydrochloride (0.617 g, 6.53 mmol) in methanol (10 mL) was added potassium tert.-butoxide (0.80 g, 6.54 mmol) followed by methyl 3-[1-(4-chlorophenyl)cyclobutyl]-3-oxopropionate (1.34 g, 5.02 mmol). The mixture was stirred at 20° C. for 16 h, then refluxed for 2 h. The reaction mixture was cooled, diluted with water, made alkaline by the addition of 10 mL of 10% aqueous sodium hydroxide solution, and then washed with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid, and then extracted with diethyl ether. This ether extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.04 g, 75%) as a solid foam. Mp 130-140° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[Cl:12].CCN(C(C)C)C(C)C.[O:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:28]([CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)=[O:29]
Reactant: Nc1c(Cl)cc(O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOCC1
Reaction time: 2 h

Procedure:
0.40 g (2.12 mmol) 4-amino-3-chloro-5-nitrophenol were placed in 5 mL DCM. 0.44 mL (2.54 mmol) DIPEA and 0.26 mL (2.54 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and at RT the mixture was stirred for 2 h. A further 0.26 mL (2.54 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)[CH:2]=[CH2:3].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1NCC2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: C=CCc1cccc2c1N(C(=O)OCC)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
The product from Example 113 (0.8 g) was dissolved in pyridine (3 ml), cooled to 0° C. and ethyl chloroformate (0.77 ml) was added. After 10 minutes, the reaction was quenched with water and extracted with diethylether. The organic layer was separated and washed with cold 2% hydrochloric acid, 5% sodium bicarbonate, brine and dried. The solvent was evaporated in vacuo affording the desired compound in 90% yield as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:15][CH:16]=3)[C:11](=[O:34])[C:10]=2[C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC1C=C(C2C3C(=CC(OCCCN4CCN(C(OC(C)(C)C)=O)CC4)=CC=3)C(=O)C=2C2C=NC=CC=2)C=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:15][CH:16]=3)[C:11](=[O:34])[C:10]=2[C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCNCC3)cc21
Reaction time: 0.5 h

Procedure:
The procedure of Step 1 of Example 66 was repeated except for using tert-butyl 4-(2-(3-(3,5-difluorophenyl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yloxy)ethyl)piperidine-1-carboxylate obtained in Example 69 as a starting material instead of tert-butyl 4-(3-(3-(3,5-difluorophenyl)-1-oxo-2-(pyridin-3-yl)-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate and being stirred for 30 min to provide the title compound.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[CH:6][CH:5]=1)#[N:3].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(#N)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([Cl:16])(=[O:14])=[O:12])=[CH:6][CH:5]=1)#[N:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1ccc(CS(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC#N
Product: N#Cc1ccc(CS(=O)(=O)Cl)cc1

Procedure:
A suspension of 1.1 g (5.02 mMol) of the sodium salt of 4-cyanobenzenemethanesulphonic acid in 20 ml of acetonitrile was mixed with 1.2 g (5.76 mMol) of phosphorus-(V)-chloride and then refluxed for 24 hours. The insoluble matter was filtered off and the filtrate was evaporated down in vacuo. Yield; 0.8 g (74% of theory). The product was used in the next step without purification.
Reaction SMILES: CSC.C([O:11][C@H:12]1[C@@H:17]([O:18]CC2C=CC=CC=2)[C@@H:16]([O:26]CC2C=CC=CC=2)[C@@H:15]([CH2:34][O:35]CC2C=CC=CC=2)[O:14][CH:13]1[C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45]([CH2:53][C:54]2[S:58][C:57]3[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:56]=3[CH:55]=2)[CH:44]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:63][C:61]1[CH:60]=[CH:59][C:57]2[S:58][C:54]([CH2:53][C:45]3[CH:44]=[C:43]([C@H:13]4[C@H:12]([OH:11])[C@@H:17]([OH:18])[C@H:16]([OH:26])[C@@H:15]([CH2:34][OH:35])[O:14]4)[C:52]4[C:47]([CH:46]=3)=[CH:48][CH:49]=[CH:50][CH:51]=4)=[CH:55][C:56]=2[CH:62]=1
Reactant: Fc1ccc2sc(Cc3cc(C4O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2cc(Cc3cc4cc(F)ccc4s3)cc3ccccc23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 45.3 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (1.72 ml) and a boron trifluoride-diethyl ether complex (0.86 ml, 6.8 mmol) were added to a solution of (3R,4R,5S,6R)-3,4,5-trisbenzyloxy-6-benzyloxymethyl-2-[3-(5-fluorobenzo[b]-thiophen-2-ylmethyl)naphthalen-1-yl]tetrahydropyran (550 mg, 0.68 mmol) in methylene chloride (15 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 2.5 days, then a saturated sodium hydrogen carbonate aqueous solution was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate, and thereafter the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (40:1)] to obtain the title compound (140 mg, 46%).