Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[C:18]4[C:22](=[CH:23][C:14]=3[N:13]=2)[C:21]([CH3:25])([CH3:24])[C:20](=O)[C:19]4([CH3:28])[CH3:27])[C:4]=1[CH3:29].Cl.[CH3:31][O:32][NH2:33]>CO>[CH3:31][O:32][N:33]=[C:20]1[C:21]([CH3:25])([CH3:24])[C:22]2[C:18](=[CH:17][C:15]3[N:16]=[C:12]([S:11][CH2:10][C:5]4[C:4]([CH3:29])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[NH:13][C:14]=3[CH:23]=2)[C:19]1([CH3:28])[CH3:27]
Reactant: CON
Reactant: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Agent: Cl
Solvent: CO
Product: CON=C1C(C)(C)c2cc3nc(SCc4ncc(C)c(OC)c4C)[nH]c3cc2C1(C)C

Procedure:
5 g of 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one and 40 g of O-methylhydroxylamine hydrochloride in 250 ml of methanol were boiled at reflux for 16 hours under argon. After removing the solvent in vacuo the residue was partitioned between methylene chloride and water and the aqueous phase was extracted three times with methylene chloride. The combined organic extracts were made neutral with saturated sodium bicarbonate solution in the presence of ice and under argon gasification. After repeated extraction with methylene chloride the organic phases were dried over sodium sulfate and evaporated in vacuo. A red impurity was removed by chromatography on silica gel with ethyl acetate. The separation of the reaction product from starting material was carried out on silica gel using toluene/methyl isobutyl ketone/pyridine (80:18:2) as the elution agent. The purity of the fractions was assayed by thin-layer chromatography using the system ethyl acetate/methyl isobutyl ketone/pyridine (80:18:2). By crystallization from acetone/water there was obtained 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one O-methyl oxime of melting point 110°-112°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](O)(=[O:30])/[C:24](=[C:26](\[CH:28]=O)/[Cl:27])/[Cl:25]>C(O)(=O)C>[Cl:25][C:24]1[C:23](=[O:30])[N:21]([C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:14]=3)[CH:20]=[CH:19][N:18]=2)[N:22]=[CH:28][C:26]=1[Cl:27]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Solvent: CC(=O)O
Product: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 125 °C
Yield: 43.6 %

Procedure:
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (5 g) in acetic acid (80 mL) was added 2.8 g of Mucochloric acid. The mixture was heated at 125° C. for 4 h. The solvent was concentrated and the crude was poured into water (500 mL). The suspension was neutralised by addition of solid potassium carbonate until pH 7. The aqueous phase was extracted with ethyl acetate (3×200 mL). The organic phases were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (1-0 to 1-1), afforded the title compound as a solid (3.11 g, 44%). Mp 238–240° C., 1H NMR (DMSO-d6) 10.3 (1H, s, NH), 8.84 (1H, d, 5 Hz), 8.76 (1H, d, 5 Hz), 8.42 (1H, s), 8.38 (1H, s), 8.28 (1H, 2 Hz, 5 Hz), 8.04 (1H, t, 2 Hz), 7.74 (1H, dd), 7.62 (1H, d, 5 Hz), 7.32 (1H, t, 8 Hz), 7.02 (1H, dd, 2 Hz, 8 Hz). 13CNMR DMSO-d6) 160.3, 160.2, 159.9, 155.5, 153.5, 150.2, 146.6, 141.7, 136.7, 136.6, 134.0, 132.9, 130.1, 121.9, 121.1, 118.7, 118.2, 117.3, 109.3.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccnc3)C2=O)CC1
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride (2.4 equivalents) and 3-(chloromethyl)pyridine hydrochloride, to give the desired product as a white solid (78%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:3]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]2[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]2)[N:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[NH:7]2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Agent: Cl
Product: Cc1cc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc2c1CCC(=O)N2

Procedure:
The title compound was prepared by reductive amination of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-naphthalen-1-yl-piperazine hydrochloride according to the above procedure. MS: APCI: M+1: 445.2 (Exact Mass: 444.25).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[N+:35]([O-:37])=[O:36].Cl.[C:39]([C:42]1[O:43][CH:44]=[CH:45][CH:46]=1)(=[NH:41])[NH2:40].N1CCOCC1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[O:43]1[CH:44]=[CH:45][CH:46]=[C:42]1[C:39]1[NH:41][C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH:31]([C:30]2[CH:33]=[CH:34][C:27]([CH3:26])=[C:28]([N+:35]([O-:37])=[O:36])[CH:29]=2)[N:40]=1
Reactant: N=C(N)c1ccco1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCN1
Solvent: CC(=O)O
Product: Cc1ccc(C2N=C(c3ccco3)NC(COCCN3CCCCC3)=C2C(=O)OCCCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 0.9 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (10.0 g, 28.78 mmol), 4-methyl-3-nitrobenzaldehyde (4.75 g, 28.78 mmol), 2-amidinofuran hydrochloride (4.20 g, 28.78 mmol), morpholine (3.75 ml, 43.17 mmol), acetic acid (3.29 ml, 57.56 mmol), and sodium sulfate (8.17 g, 57.56 mmol) was stirred in ethanol (50 ml) for 1 hour at room temperature and then heated to 50° C. for 7 days. The ethanol was removed in vacuo and ethyl acetate was added to the residue. The mixture was filtered and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC (twice) to give the title compound (150 mg) as an oil. Electrospray MS m/z 587 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].[O-]CCCC.[CH3:20][N:21]=[C:22]=[S:23]>O1CCCC1.C(Cl)(Cl)Cl.O>[CH3:20][NH:21][C:22]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])=[S:23]
Reactant: CN=C=S
Reactant: O=C1CCCCC1c1ccccc1
Agent: CCCC[O-]
Agent: [K]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=S)C1(c2ccccc2)CCCCC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
A solution of (±)-2-phenylcyclohexanone (3.0 g, 17.2 mmol) at -15° C. in tetrahydrofuran (40 ml) was treated with potassium t.-butoxide (1.9 g, 17.2 mmol) during 2 minutes. After 15 minutes at -15° C., a solution of methyl isothiocyanate (1.38 g, 19 mmol) in tetrahydrofuran (20 ml) was added dropwise during 2 minutes and the resulting solution was stirred for 3 hours at 0° C. Water (200 ml) followed by chloroform (200 ml) were added to the reaction mixture and the aqueous layer was extracted with chloroform (200 ml). The combined organic extracts were washed with brine (150 ml) then dried over sodium sulphate. Concentration in vacuo (30° C.; 14 mm Hg) afforded a crude oil (4.2 g) which was purified by flash chromatography over silica gel eluting with a 1:1 mixture of diethyl ether and hexane to give (±)-N-methyl-2-oxo-1-phenylcyclohexanecarbothioamide (1.5 g, 6.1 mmol) m.p. 86° C. N.M.R. (CDCl3) 1.62-2.05 (c, 4H), 2.42-2.56 (m, 2H), 2.64-2.84 (ddd, 1H), 3.0-3.18 (c, 4H), 7.23-7.45 (c, 5H) 8.72-9.06 (broad singlet, 1H). Found C, 68.3; H, 7.2; N, 5.8; S, 13 0%, C14H17NOS requires C, 68.0; H, 6.9; N, 5.7; S, 13.0%.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C(O)=O>[Pt]=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][CH:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Nc1nc(O)c2c(n1)NCC(CCC1CCC(C(=O)O)CC1)C2
Reaction time: 24 h

Procedure:
Five grams of 2-pivaloylamino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine described in European Pat. Application No. 87308921.3) and 1.60 g. of platinum oxide in 200mL. of trifluoroacetic acid were hydrogenated in a Parr apparatus at ambient temperature and 60 psi for 24 hours. Removal of the catalyst by filtration and concentration of the filtrate yielded 2-pivaloylamino-4-hydroxy-6-[2-(4-carboxycyclohex-1-yl)ethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine as a white solid which was further purified by column chromatography (Waters 200) eluting with 1:9 methanol:dichloromethane. m.p. 218°-234° C. Anal. Calc. for C21H32N4O4 : C, 63.35; H, 7.97; N, 13.85. Found: C, 63.30; H, 7.48; N, 13.57.
Reaction SMILES: [NH:1]1[C@H:3]([C:4](OCC)=[O:5])[C@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CCO.[BH4-].[Na+]>CCOC(C)=O>[CH2:12]([O:11][C:9]([C@@H:2]1[C@@H:3]([CH2:4][OH:5])[NH:1]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1N[C@@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1N[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In a round bottom flask equipped with a magnetic stirring bar and a septum was placed (S,S) diethyl aziridine-2,3-dicarboxylate (1.87 g, 10 mmol) dissolved into 30 ml of EtOH. The vessel was cooled to 0° C. and NaBH4 (302.6 mg, 8 mmol) was added slowly. The reaction mixture was allowed to stir at 0° C. until the reaction was complete according to TLC (EtOAc, Rf=0.66), which was approximately 2 hours. The reaction was quenched by the addition of pH 7 phosphate buffer, and extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient 8:2 EtOAc/hexanes—100% EtOAc) to afford the title compound in 84% yield as a pale yellow oil. 1H NMR (CDCl3, 200 MHz) δ: 4.22 (q, J=7.0 Hz, 2H), 3.82 (dd, J=12.4 Hz, 2.8 Hz, 1H), 3.48 (dd, J=12 Hz, 4.8 Hz, 1H), 2.46 (m, 2H), 1.50 (bs, 1H), 1.31 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 50 MHz) δ: 172.2, 62.0, 61.5, 39.8, 32.7, 14.3 ppm. HRMS (ESI) [M+H]+ calcd. for C6H12NO3 146.0817, found 146.0820.
Reaction SMILES: N[C:2]1[C:3]2[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[NH:25][C:4]=2[N:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:7]=1.N(OCCC(C)C)=O.[I:39]CI>CN1C(=O)CCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:10]1[N:9]=[C:8]([C:6]2[N:7]=[C:2]([I:39])[C:3]3[C:27]([CH3:28])([CH3:29])[C:26](=[O:30])[NH:25][C:4]=3[N:5]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]=12
Reactant: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(N)c21
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(I)c21
Temperature: 85 °C
Reaction time: 4 h

Procedure:
1.500 g (3.35 mmol) of 4-amino-2-[8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one was suspended in 6.00 ml (44.56 mmol) of isopentyl nitrite and 4.00 ml (49.66 mmol) of diiodomethane and it was stirred for 2d at 85° C. 4.00 ml isopentyl nitrite and 5 ml NMP were added and the solution was stirred for 4 h at 85° C. The mixture was concentrated by evaporation in the rotary evaporator except the NMP and was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 928 mg (purity 69%, 37% of theor.) of the target compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Sc3ccc(F)cc3)cn2)CC1
Temperature: 110 °C
Yield: 44 %

Procedure:
A stirred solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.924 mmol), 4-fluorobenzenethiol (561 mg, 4.386 mmol), Pd2(dba)3 (267 mg, 0.292 mmol), Xantphos (169 mg, 0.292 mmol) and DIPEA (754 mg, 5.848 mmol) in dioxane (50 mL) was degassed with nitrogen for three times, and then heated at 110° C. for 16 hrs. The reaction mixture was cooled to RT and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (silica gel, 0-20% EtOAc/PE) to afford the title compound as a white solid. (500 mg, yield 44%, purity: 99%). MS (ES+) C19H23FN4O2S requires: 390. found 391 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[O:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[N:1]=2)[CH:14]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Cc1cccc(O)c1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nc3c(C)cccc3o2)c1

Procedure:
2-Amino-3-methyl-phenol (6.09 mmol) is heated with 3-formyl-benzoic acid methyl ester (6.09 mmol) in MeOH (6 mL) at 60° C. for 30 minutes. The solvent is removed from the mixture to obtain a dark red oil which is dissolved in dry CH2Cl2 (6 mL) at room temperature and treated with DDQ (6.4 mmol) for 16 hours. The mixture is diluted with EtOAc and poured onto saturated aqueous NaHCO3. The aqueous phase is further extracted with EtOAc and the combined organic phases are dried over Na2SO4. Filtration and removal of the solvent yields a residue which is purified by silica gel chromatography (5-10% EtOAc/hexane) to yield 3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester as a white solid: 1H NMR (400 MHz, CDCl3) 8.92 (d, J=1.6 Hz, 1H), 8.47 (dt, J1=7.8 Hz, J2=1.5 Hz, 1H), 8.2 (dt, J1=7.8 Hz, J2=1.4 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 3.99 (s, 3H), 2.69 (s, 3H); LC/MS (ES+): (M+1) 268.1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][O:54][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][OH:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 75.7 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 9f (2.9 g, 3.37 mmol) was dissolved in 20 mL methanol, followed by addition of acetyl chloride (38 μL, 0.5 mmol). The reaction mixture was stirred for 2 hours and was partitioned after 30 mL ethyl acetate and 30 mL water were added. The aqueous phase was extracted with ethyl acetate (30 mL×2) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 9g (1.9 g, yellow solid), yield: 76.0%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1.O>CC(C)=O>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:45])([CH3:46])[C:35]=2[CH:34]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCN(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reaction time: 48 h
Yield: 81.9 %

Procedure:
440 mg (2.78 mmol) of 3-dimethylaminopropyl chloride hydrochloride and 970 mg (7 mmol) of potassium carbonate are added to a solution of 1 g (2.33 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetone. The reaction mixture is stirred for 48 hours at reflux. The reaction is stopped by adding water, and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 90/10 ethyl acetate/methanol). 980 mg of ethyl 4′-(3-dimethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellow oil (yield=82%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=4[CH:27]=3)[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:36][C:32]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:38])([CH3:39])[C:28]2[CH:27]=[C:26]([C:23]3[CH:22]=[C:21]([N:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[O:25][N:24]=3)[CH:35]=[CH:34][C:33]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)no2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(N4CCNCC4)on3)ccc21

Procedure:
The protecting group was cleaved off as already described using TFA in DCM starting from 27 mg (0.06 mmol) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperazine-1-carboxylic acid tert-butyl ester from step d. The product is in the form of the TFA salt.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH2:29]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc3ncc(C(C)c4cc5cccnc5cc4F)n3n2)CC1

Procedure:
The title compound was prepared in analogy to Example 38 using (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-7-fluoro-quinoline (Intermediate K, 50 mg, 0.153 mmol) and 1-acetylpiperazine (39.2 mg, 0.306 mmol) (tR 3.33 min (conditions 5), MH+=419, 1H-NMR in DMSO-d6: 8.83 (d, 1H); 8.30 (d, 1H); 7.83 (d, 1H); 7.74 (d, 1H); 7.56 (s, 1H); 7.44 (m, 1H); 7.10 (d, 1H); 4.87 (m, 1H); 3.37 (m, 8H); 1.98 (s, 3H); 1.78 (d, 3H)).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1>>[OH:18][C:15]1([C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(Br)c(CO)c1
Product: Cc1ccc(C2(O)CCN(C)CC2)c(CO)c1

Procedure:
Reaction of 2-bromo-5-methylbenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-hydroxy-4-(α-hydroxy-5-methyl-2-tolyl)-1-methylpiperidine.