Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=C(C=CC=1)C=O>>[CH3:20][O:21][C:6]1[CH:5]=[C:4]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:3]=[CH:8][CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 95 %

Procedure:
According to the preparation of 42, 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) was used to afford 43 (1.7 g, 95.0%) as pale yellow needles.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C@H:14]2[OH:46])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:60]1[C:65](=[O:66])[CH2:64][CH2:63][C:61]1=[O:62])=[N+](C)C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[O:62]=[C:61]1[CH2:63][CH2:64][C:65](=[O:66])[N:60]1[O:43][C:42](=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][C:37]([NH:36][CH2:35][CH2:34][O:33][C@H:15]1[O:16][C@H:17]([CH2:20][O:21][C@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]2[OH:24])[C@@H:18]([OH:19])[C@H:13]([O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C@@H:14]1[OH:46])=[O:45]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)CCCCC(=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC(=O)ON1C(=O)CCC1=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoic acid (1.55 g, 2.294 mmol) in DMF (22 mL) at 0° C. was added TSTU (760 mg, 2.52 mmol) and DIPEA (0.52 mL, 2.98 mmol). After stirring at 0° C. for 1 hr, the reaction was quenched by the addition of TFA (371 μL, 4.82 mmol) and the resulting mixture was concentrated down to about 3 mL. The residue was transferred dropwise, via autopipette, to a tube containing anhydrous acetonitrile (45 mL). The white precipitate was collected through centrifugation (3000 rpm, 15 min, at 4° C.), washed with anhydrous AcCN (1 mL) and dried to yield the title compound. UPLC Method B: calculated for C30H48N2O21 772.27, observed m/e: 773.23 [M+1]; Rt=3.65 min. 1H NMR (D2O) δ 5.07-5.06 (1H, m), 4.84-4.83 (1H, m), 4.79-4.78 (1H, m), 4.06-4.01 (2H, m), 3.96-3.93 (2H, m), 3.87-3.83 (5H, m), 3.80-3.78 (1H, m), 3.75-3.69 (5H, m), 3.67-3.61 (4H, m), 3.57-3.52 (1H, m), 3.41-3.38 (2H, m), 2.91 (4H, s), 2.75-2.71 (2H, m), 2.29-2.25 (2H, m), 1.75-1.58 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([CH2:12]SC)[C:3]=1[NH2:4]>[Ni].C(O)C>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([CH3:12])[C:3]=1[NH2:4]
Reactant: CSCc1c(N)c(F)c(C)c(F)c1F
Agent: [Ni]
Solvent: CCO
Product: Cc1c(N)c(F)c(C)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To 2,4,5-trifluoro-3-methyl-6-methylthiomethylaniline (10.67 g) are added ethanol (300 ml) and Raney nickel (100 g, wet) and the mixture is stirred at room temperature for 30 minutes. After Raney nickel is filtered off, the filtrate is concentrated, diluted with water, extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane: n-hexane =1:1) to give 2,4,5-trifluoro-3,6-dimethylaniline (5.89 g), as yellow crystals.
Reaction SMILES: [OH:1][C:2]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22](/[CH:27]=[CH:28]/[O:29]C)=[CH:21][C:20]=2[Cl:31])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4].Cl>>[OH:1][C:2]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH2:27][CH:28]=[O:29])=[CH:21][C:20]=2[Cl:31])=[O:17])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: CO/C=C/c1cc(Cl)c(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)cc1OC
Agent: Cl
Product: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CC=O
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To a solution of trans-4-[[3-({2-chloro-5-methoxy-4-[(E)-2-methoxyvinyl]phenyl}amino)-3-oxopropyl](methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 122; 0.36 g, 0.17 mmol) in anhydride tetrahydrofurane (0.5 mL) was added dropwise hydrochloric acid 2M (0.34 mL, 0.7 mmol). The mixture was stirred at 65° C. for 5 hours and a half. A mixture of water/ice was poured into the reaction and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was removed under reduced pressure. The crude obtained was purified by column chromatography with silica gel, eluting with methylen chloride/methanol (95:5) to give the title compound as an oil (90%).
Reaction SMILES: [CH:1](/[C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][C:15](=O)[NH:16][C:17]=2[N:18]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.CCOCC>[CH:1](/[C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][CH2:15][NH:16][C:17]=2[N:18]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C(=C/c1ccc2c(n1)NCCO2)\c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (30d) (350 mg, 1.54 mmole), was dissolved in anhydrous THF (10 mL) and the solution was cooled to 0° C. A solution of LiAlH4 in THF (1.0 M, 1.54 mL, 1.54 mmole) was added dropwise at 0° C. The reaction was then warmed to room temperature and stirred for 2 hr. H2O (0.06 mL) was added dropwise and mixture was stirred for 5 min, then 15% sodium hydroxide (0.06 mL) was added followed by H2O (0.18 mL). The mixture was stirred overnight, then was diluted with Et2O and filtered through celite®. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (5% EtOAc/CHCl3) to afford the product (200 mg, 55%).
Reaction SMILES: NC(N)=[S:3].CO.Cl.[CH2:8]([O:15][C:16]1[C:17]([CH3:26])=[N:18][CH:19]=[C:20]([CH:24]=[CH2:25])[C:21]=1[CH2:22]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH3:26][C:17]1[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:21]([CH2:22][SH:3])[C:20]([CH:24]=[CH2:25])=[CH:19][N:18]=1
Reactant: NC(N)=S
Reactant: C=Cc1cnc(C)c(OCc2ccccc2)c1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CS

Procedure:
To a well stirred solution of 0.11 mole of thiourea in 250 ml. methanol, under M2 is added 0.1 mole of 3-benzyloxy-4-chloromethyl-2-methyl-5-vinylpyridine hydrochloride. The mixture is refluxed for 1 hour and then cooled. A solution of 0.4 mole of sodium hydroxide in 50 ml. of water is added, and the resulting mixture refluxed for 30 minutes. After concentration in vacuo the reaction mixture is taken up between benzene and water and enough acetic acid added to neutralize the mixture. The organic layer is separated, washed well with water, dried, and concentrated to give 2-methyl-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:57])[C:31]([CH3:56])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][CH2:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:57])[C:31]([CH3:56])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][CH2:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.3 %

Procedure:
4-Acetylaniline (0.128 g, 0.946 mmol), triethylamine (0.096 g, 0.946 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.160 g, 0.946 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.080 g, 0.148 mmol, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][N:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(Br)cc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccnc(-c2nc(=O)c3ccc(Br)cc3s2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
tert-Butyl 3-[2-(7-bromo-4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.49 g, 1.1 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether-tetrahydrofuran to give the titled compound (0.38 g, 89%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pt]=O>[NH2:12][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CO
Product: Cc1ccc(S(N)(=O)=O)cc1N
Yield: 68 %

Procedure:
A solution of 4-methyl-3-nitrobenzenesulfonamide (2.1 g) and platinum oxide (210 mg) in methanol (50 ml) was stirred under hydrogen atmosphere at room temperature for 6 hours. The insoluble compound was filtered out, then the filtrate was concentrated. The residue was recrystallized from hexane/acetone to obtain the title compound (1.23 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][NH:22][CH2:20][C:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:28][CH:27]=2)[CH:19]=[CH:18][N:17]=1
Reactant: [H][H]
Reactant: COCCNC(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
A solution of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl) amino]phenoxy}-N-(2-methoxyethyl)pyridine-2-carboxamide from Example 23 (50 mmol) in anhydrous THF (50 mL) is added in portions to a pre-cooled in ice-bath solution of lithium aluminum hydride (100 mmol, 1.0 M in THF) in anhydrous THF (150 mL). The reaction is stirred at 0° C. for 30 min until evolution of hydrogen subsides. The reaction mixture is refluxed under nitrogen for 48 h. The mixture is brought to 5-10° C. and carefully quenched with water (3.8 mL), 15% NaOH (3.8 mL) and water (12 ruL). The mixture is extracted with EtOAc and the organic layer is dried and concentrated to give a crude product which is purified by chromatography on a silica column to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](N)=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[I:17]I.CCCCCON=O>C(Cl)(Cl)Cl>[I:17][C:12]1[N:13]=[C:14]([CH3:15])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: II
Reactant: COc1ccc(-c2ccc(N)nc2C)cc1
Agent: CCCCCON=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(I)nc2C)cc1
Temperature: 82 °C

Procedure:
5-(4-methoxyphenyl)-6-methylpyridin-2-amine (500 mg, 2.33 mmol) and iodine (710 mg, 2.8 mmol) were stirred in chloroform (10 mL) at room temperature for 12 minutes followed by addition of n-amyl nitrite (545.9 mg, 4.66 mmol). The resulting mixture was heated in a 82° C. oil bath for 1.5 hours to finish the transformation. The reaction was quenched by addition of saturated NaS2O3 aqueous solution. The reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4 followed by filtration and concentration. The resulting crude was purified by flash column chromatography on SiO2 (Biotage 40+M cartridge, dichloromethane/hexanes, gradient) to afford a yellow oil. The oil was further purified by preparative TLC on SiO2 (eluted with 80% dichloromethane in hexanes) to afford 6-iodo-3-(4-methoxyphenyl)-2-methylpyridine. LCMS calc.=325.00; found=326.06 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])[CH2:23][NH:22][C:21]1=[S:26])[CH3:16].N1CCCCC1>ClCCl>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])/[C:23](=[CH:13]/[C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)=[CH:9][CH:10]=2)/[NH:22][C:21]1=[S:26])[CH3:16]
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Reactant: CCOC(=O)CN1C(=O)CNC1=S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(=O)CN1C(=O)/C(=C/c2ccc(-c3cccc(I)c3)o2)NC1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) synthesized by the same method as in Example 1 and ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate (20 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give compound 2 in a yield of 21 mg (yield 43.6%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([O:26][CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1)[C:24]#[CH:25]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:27]1([O:26][CH2:23][C:24]#[C:25][C:2]2[C:10]3[C:5](=[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])[CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1I
Reactant: C#CCOC1CCCc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1C#CCOC1CCCc2ccccc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 564B (180 mg) and 1-(prop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalene (165 mg) in triethylamine (5 ml) was added bis(triphenylphosphine)palladium(II) dichloride (18.71 mg) and copper(I) iodide (4.23 mg). The reaction mixture was stirred at 70° C. for 3 hours, cooled and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with dichloromethane, to provide ethyl 3-(3-(1,2,3,4-tetrahydronaphthalen-1-yloxy)prop-1-ynyl)-7-o-tolyl-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, methanol-d4) 7.76 (dd, J=7.98, 1.23 Hz, 1 H), 7.52 (dd, J=6.75, 2.46 Hz, 1 H), 7.34-7.40 (m, 2 H), 7.27-7.31 (m, 2 H), 7.26 (d, J=7.98 Hz, 1 H), 7.13-7.19 (m, 3 H), 7.07-7.12 (m, 1 H), 4.97 (t, J=3.99 Hz, 1 H), 4.52-4.71 (m, 2 H), 2.79-2.90 (m, 1 H), 2.68-2.78 (m, 1 H), 2.14-2.21 (m, 1 H), 2.12 (s, 3 H), 1.91-2.06 (m, 2 H), 1.73-1.84 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccc(O)c(CO)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccc(OCc2ccccc2)c(CO)n1

Procedure:
47 g (0.3 mol) of 3-hydroxy-2,6-bis(hydroxymethyl)pyridine are dissolved in 800 ml of acetonitrile. 104 g of K2CO3 (0.753 mol) and 55 ml of benzyl bromide (0.45 mol) are added. The combined mixture is brought to reflux for 12 h. After having filtered off the insoluble material, the solution is concentrated and the residue is hardened in isopropyl ether. w=39 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@H:5]([NH:6][C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=[C:9](SC)[N:8]=2)[CH2:4][C@@H:3]1[OH:19].ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].CC1(C)[C@H](NC2C(C(F)(F)F)=CN=C(S(C)(=O)=O)N=2)C[C@@H]1O.CCN(C(C)C)C(C)C.Cl.Cl.[CH:71]([C:74]1[C:79]([CH2:80][NH2:81])=[CH:78][N:77]=[CH:76][N:75]=1)([CH3:73])[CH3:72]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH:71]([C:74]1[C:79]([CH2:80][NH:81][C:9]2[N:8]=[C:7]([NH:6][C@@H:5]3[CH2:4][C@H:3]([OH:19])[C:2]3([CH3:20])[CH3:1])[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=2)=[CH:78][N:77]=[CH:76][N:75]=1)([CH3:73])[CH3:72]
Reactant: CSc1ncc(C(F)(F)F)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Reactant: CC(C)c1ncncc1CN
Agent: CC1(C)[C@@H](O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ncncc1CNc1ncc(C(F)(F)F)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
In a round-bottomed flask, (1S,3R)-2,2-dimethyl-3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol (1.0 equiv.) and 3-chlorobenzoperoxoic acid (2.0 equiv.) were combined in THF (0.5 M). The reaction was stirred at 25° C. for 45 min. The mixture was diluted with ethyl acetate. To this solution was added potassium carbonate (4.0 equiv.). The mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated to afford the crude product. A solution of (1S,3R)-2,2-dimethyl-3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol (1.0 equiv.), DIEA (3.0 equiv.) and (4-isopropylpyrimidin-5-yl)methanamine dihydrochloride (1.5 equiv.) were combined in dioxane (0.4 M) and stirred at ambient temperature. Additional dioxane was added to ensure solubility. After 1 h at room temperature, LCMS indicated the presence of some product. After 12 h, the reaction was heated to 75° C. for 6 h. Standard work-up afforded the title compound (39% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.97 (s, 1H) 8.32-8.68 (m, 1H) 8.03 (s, 1H) 7.26-7.93 (m, 1H) 6.07 (d, J=7.03 Hz, 1H) 4.79 (m, 1H) 4.54 (br. s., 2H) 3.80-3.96 (m, 1H) 3.37-3.59 (m, 1H) 2.15-2.41 (m, 1H) 2.05 (m, 1H) 1.06-1.24 (m, 6H) 0.67-0.92 (m, 6H); MS(ESI) m/z 411.3[M+1]+.
Reaction SMILES: C1(=O)CCCCCCCCCCCCCC1.[C:17]1(=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCCCCCC=CCCCCCCCCC1
Agent: O=C1CCCCCCCCCCCCCC1
Product: OC1CCCCCCCCC=CCCCCCCCCC1

Procedure:
Cyclopentadecanone of Synthesis Example 3 was replaced by 10-cycloeicosenone, and the ketone group was reduced under the same conditions as in Synthesis Example 3, whereby 10-cycloeicosenol was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15]2)=[CH:7][CH:6]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:15]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:18])[C:9]=2[C:8]2[C:16]1=[CH:17][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2c3c([nH]c2c1)CCCC3=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(n(Cc4ccccc4)c2c1)CCCC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a slurry of sodium hydride (0.26 g, 11 mmol) in dry DMF (50 mL) is added 7-methoxy-1,2,3,9-tetrahydro-4H-carbazol-4-one (2.2 g, 10.2 mmol). The mixture is stirred at room temperature for 30 min. To this is added benzyl bromide (1.3 mL, 11 mmol). The mixture is stirred at room temperature overnight. The mixture is partitioned between water and Et2O. The layers are separated and the organic layer washed twice with water (200 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (200 mL) silica gel using CH3OH/CH2Cl2 (2/98) gave 1.7 g (55%) of the title compound; IR (drift) 1638, 1628, 1578, 1535, 1497, 1461, 1449, 1357, 1266, 1200, 1149, 1105, 834, 807, 700 cm−1. 1H NMR (CDCl3) δ2.2, 2.6, 2.8, 3.8, 6.7, 6.9, 7.0, 7.3, 8.1; Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.29; H, 6.39; N, 4.53.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[O:12][CH3:13]
Reactant: COc1ccncc1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1c(C)cncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 30 %

Procedure:
30 ml of 100% nitric acid is added to 150 ml of 98% sulphuric acid with stirring and cooling. To this solution is added dropwise 3.2 g (26 mmol) of 3-methyl-4-methoxy pyridine. The mixture is stirred at 80° C. for 2.5 hours, cooled down and added cautiously to a mixture of 400 g of crushed ice and 300 g of potassium carbonate with external cooling. 125 g more of potassium carbonate is added, and the suspension is filtered. The cake is washed with around 11 of diethyl ether. The filtrate layers are separated, the ethereal layer is dried, filtered off and concentrated to give 2.9 g (30% yield) of a yellow oil (M+1=169) (purity #80%, used with no further purification).