Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][NH2:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Na].[CH3:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17].C1(OC2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[CH3:12][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][CH2:10][NH2:11])[CH:7]=[C:2]([O:17][CH2:16][CH:15]([CH3:14])[CH2:18][CH3:19])[N:3]=1
Reactant: CCC(C)CO
Reactant: Cc1cc(NCCN)cc(Cl)n1
Agent: [Na]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CS(C)=O
Product: CCC(C)COc1cc(NCCN)cc(C)n1
Temperature: 160 °C
Yield: 70 %

Procedure:
N-(2-Chloro-6-methyl-4-pyridyl)ethane-1,2-diamine (0.205 g, 1.2 mmol) was combined with the sodium salt of 2-methylbutan-1-ol (0.66 g, 6 mmol, that had been obtained by treating 2-methylbutan-1-ol with sodium hydride dispersion in THF), diphenylether (2.2 g) and DMSO (0.75 ml). The mixture was heated at 160° C. for 16 hours and purified by column chromatography (silica, ethyl acetate/methanol, 1% concentrated NH3) to yield 200 mg of a brown oil (0.84 mmol, 70%). MS (APCI) m/z=237.9 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C@:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C@@:5]12[C:21]([F:23])([F:22])[CH2:20][O:19][C:18]([NH2:24])=[N:17]1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)[OH:33])[CH:29]=[N:30][CH:31]=1>>[CH:20]([OH:19])=[O:33].[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C@:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C@@:5]23[C:21]([F:23])([F:22])[CH2:20][O:19][C:18]([NH2:24])=[N:17]2)[CH:29]=[N:30][CH:31]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(C[C@@]3(CCCOC3)Oc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(C[C@@]3(CCCOC3)Oc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Product: O=CO
Yield: 66 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2′R,4R)-6′-bromo-5,5-difluoro-5,5″,6,6″-tetrahydro-4″H-dispiro[1,3-oxazine-4,4′-chromene-2′,3″-pyran]-2-amine (intermediate B6.7) with 5-chloropyridin-3-ylboronic acid and chromatography on preparative HPLC yielded the title compound (66% yield) as an off-white, amorphous material. MS (ISP): m/z=436 [M+H]+ and 438 [M+2+H]+.
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].C([Li])CCC.CCCCCC.[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]>C1COCC1>[F:18][C:19]1[CH:26]=[C:25]([CH:4]([S:2]([CH3:1])=[O:3])[S:5][CH3:6])[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CSCS(C)=O
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(Methylsulfinyl)(methylthio)methane (3.16 g, 0.0255 mol) was dissolved in 50 mL of dry THF under argon and then cooled to −78° C. Butyllithium in hexane (16 mL 1.6M, 0.0256 mol) was added dropwise with stirring. The mixture was stirred for 15 min. Meanwhile a solution of 2,4,5-trifluorobenzonitrile (2.0 g; 0.013 mol) in 50 mL of dry THF was cooled to −78° C. under argon and the former solution was added through a cannula to the latter solution over a period of 3-5 min. After 30 min, the cooling bath was removed and when the reaction had reached room temperature it was poured into 200 mL of water. The THF was evaporated and the remaining aqueous layer was extracted three times with diethyl ether. The combined ether phase washed with water, dried (Na2SO4) and evaporated. The crude product started to crystallise and could be used as such in the next step. Yield: 2.8 g (84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:11]=2[CH3:28])[CH2:4][O:3]1.C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.C(=O)([O-])[OH:51].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:51])[C:11]=2[CH3:28])[CH2:6][O:7]1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reactant: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 63 %

Procedure:
A toluene (4 ml) solution of 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (500 mg, 1.21 mmol), zirconium(IV) isopropoxide isopropanol complex (295 mg, 0.76 mmol) and N,N,N′,N′-(−)-tetramethyl-(D)-tartaramide (396 mg, 1.94 mmol) was stirred in a nitrogen atmosphere at 40° C. for one hour. After the solution was cooled to room temperature, N,N-diisopropylethylamine (91 μl, 0.52 mmol) was added and subsequently, cumene hydroperoxide (243 μl, 1.32 mmol as the content was regarded as 80%) was added dropwise to the mixture and then the mixture was stirred at room temperature for 22 hours. After a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution were added, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 30 g, elution solvent: ethyl acetate, ethyl acetate/methanol 7:3, 1;1 gradient). The fractions containing the title compound were collected with ethyl acetate and concentrated to obtain the title compound (328 mg, yield: 63%) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.C(C(CC)[C:32]([N:34]([C:41]1[CH:46]=[CH:45]C=[CH:43][CH:42]=1)C1CCNCC1)=[O:33])C.C([O-])([O-])=O.[K+].[K+].FC1C=CC([N+:62]([O-])=[O:63])=CC=1F>CN(C=O)C.O>[CH3:45][C:46]1[C:41]([NH:34][C:32](=[O:33])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:10][CH2:9]3)=[C:4]([F:28])[CH:3]=2)=[C:42]([CH3:43])[O:63][N:62]=1
Reactant: CCC(CC)C(=O)N(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCC(CC)C(=O)N(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)N(c1ccccc1)C1CCN(c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
N-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-2-ethyl-N-phenyl-butyramide. To a mixture of 2-ethyl-N-phenyl-N-piperidin-4-yl-butyramide (10 mmol) and K2CO3 (40 mmol) in DMF (30 mL) was added 1,2-difluoro-4-nitro-benzene (1.6 g, 10 mmol). The reaction mixture was stirred at 50° C. for 3 h, then was diluted with H2O (500 mL). The solution was decanted, leaving a semi-solid, which was collected and re-dissolved into 1:1 EtOH/EtOAc (100 mL). The mixture was treated with SnCl2.2H2O (10 g) and was heated at 100° C. for 16 h. The mixture was cooled to rt, diluted with ice water (100 mL), basified to pH=9 with NaHCO3, and extracted with EtOAc (3×200 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give the crude title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:30])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.ClC1C=CC(OCC(N2C3C=CC=CC=3CN3C(C(NCC4C=NC=CC=4)=O)=CC=C3C2)=O)=CC=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:30])=[C:23]([CH3:29])[CH:24]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Product: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)NCc3cccnc3)n2Cc2ccccc21

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step C (0.34 mmol), and 3-aminomethylpyridine (0.71 mmol), in a manner similar to the synthesis of 10-[(4-chlorophenoxy)acetyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 179 (0.126 g; 74%), m.p. 168° C.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].FC(F)(F)C(O)=O>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)(C)N1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4.8 parts of 1-(tert.-butyl)-3-azetidinol, 6.1 parts of 2,3-xylenol and 1.4 parts of trifluoroacetic acid was heated at 130° C. for 12 hours. The reaction mixture was cooled and dissolved in 100 parts of ether, and the solution was washed three times with 50 parts of 2N-sodium hydroxide aqueous solution and extracted three times with 2N-hydrochloric acid aqueous solution. The extract was washed twice with 50 parts of ether and made alkaline by addition of 2N-sodium hydroxide solution. The extraction was conducted three times with 50 parts of ether, and the extract was condensed and distilled under reduced pressure to yield 3.2 parts of 1-(2',3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C. and a boiling point of 134°-136° C. under 0.7 mm Hg.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[O:32][CH3:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.CCCCC>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:26][C:25]=1[O:32][CH3:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: BrCCCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: COc1cc(C(O)CCCc2ccccc2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 20.0 g of 3-phenylpropyl bromide in 300 ml of ether is treated at -60° while stirring within 15 minutes with a solution of 71.8 ml of tert.butyllithium (1.4 molar) in pentane. After 10 minutes there is added dropwise at this temperature within 15 minutes a solution of 22.14 g of vanillin benzyl ether in 200 ml of ether, whereupon the mixture is stirred for an additional 2 hours. The mixture is poured into 1 l of ice-water and extracted three times with 500 ml of ethyl acetate each time. The organic phase is washed twice with 200 ml of water each time, dried over sodium sulfate and evaporated. The oil obtained is chromatographed on 1 kg of silica gel with methylene chloride. The crystals obtained are recrystallized from ether/pentane. There is obtained 4-(benzyloxy)-3-methoxy-α-(3-phenylpropyl)benzyl alcohol in the form of colorless crystals of m.p. 71°-73°.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[CH:35][N:36]=[C:6]12.Cl.[NH2:41][O:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:43][O:42]/[N:41]=[C:3](/[C:2]([CH3:1])([CH3:39])[CH3:38])\[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:17][CH:18]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[CH:35][N:36]=[C:6]12
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OC)C(C)(C)C)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
A mixture of 4-(3,3-dimethyl-2-oxobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.1 g), (aminooxy)methane hydrochloride (0.32 g) and pyridine (5 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.022 g, 21%).
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:47]3[C:43]([S:44][CH:45]=[CH:46]3)=[CH:42][N:41]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([O:65][Si](C(C)(C)C)(C)C)[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]>C1COCC1.C(OCC)(=O)C>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:47]3[C:43]([S:44][CH:45]=[CH:46]3)=[CH:42][N:41]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 39 h

Procedure:
Acetic acid (0.19 ml) and 1.1 ml of a 1 M tetra-n-butylammonium fluoride/THF are added to a solution of 155 mg of the high polar component (stereoisomer A) of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate in 3.3 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 39 hr. The reaction solution is diluted with 30 ml of ethyl acetate, and the diluted solution is washed with semi-saturated saline and dried over anhydrous magnesium sulfate, followed by filtration and the removal of the solvent by evaporation to give a slightly yellow oil. This oil is successively purified by column chromatography on silica gel (ethyl acetate:methanol=95:5) and on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 117 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) as a yellow viscous material.
Reaction SMILES: [CH2:1]([C:3]([CH:17]([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)[CH3:2].C(OO)(=[O:26])C>>[O:26]1[C:20]([CH3:21])([CH3:22])[CH:19]1[CH2:18][CH:17]([CH3:23])[C:3]([CH2:1][CH3:2])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)OO
Reactant: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC=C(C)C
Product: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC1OC1(C)C

Procedure:
Following the procedure of Example 17, 7-(3-ethyl-4,7-dimethyl-2,6-octadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-ethyl-4,7-dimethyl-2-octenyloxy)-chromane, nD20 = 1.5287.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]([CH3:20])[CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([F:23])[CH:4]=1)#[N:2].[NH2:24][OH:25]>C(O)C.O>[NH2:2][C:1](=[N:24][OH:25])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]([CH3:20])[C@H:9]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH:17]([CH3:19])[CH3:18])=[C:5]([F:23])[CH:4]=1
Reactant: NO
Reactant: CC(C)C(C(=O)OC(C)(C)C)N(C)Cc1ccc(C#N)cc1F
Solvent: O
Solvent: CCO
Product: CC(C)[C@@H](C(=O)OC(C)(C)C)N(C)Cc1ccc(C(N)=NO)cc1F
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl 2-[(4-cyano-2-fluorobenzyl)(methyl)amino]-3-methylbutanoate (3.4 g, 0.011 mol), in ethanol (30 mL), was added 50% aqueous. hydroxylamine (1.4 mL, 0.021 mol). The mixture was stirred at −20° C., for 12 h. The reaction mixture was diluted with water and extracted in dichloromethane (100 mL), dried over Na2SO4 and concentrated under reduce pressure. The solid was recrystallised with ethyl acetate (5 mL), filtered and dried under vacuum, affording the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.73 (s, 1H), 7.49 (m, 1H), 7.38 (m, 2H), 5.85 (s, 2H), 3.71 (d, J=14.2 Hz, 1H), 3.57 (d, J=14.2 Hz, 1H), 2.66 (d, J=10.7 Hz, 1H), 2.18 (s, 3H), 1.99-1.93 (m, 1H), 1.45 (s, 9H), 0.91-0.81 (m, 6H). LC/MS (Method B) 354.3 (M+H)+. HPLC (Method A) Rt: 2.66 min (Purity 98.6%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([Br:14])[CH:13]=1)[NH:10][CH:9]=[CH:8]2.[CH3:15]I>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][C:12]=2[Br:14])[CH:8]=[CH:9]1
Reactant: COc1cc(Br)c2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.32 g, 7.96 mmol) in DMF (18 mL) was added a solution of 5-methoxy-7-bromoindole (1.5 g, 6.63 mmol) in DMF (25 mL). The mixture was stirred at room temperature for 1 h, and then methyl iodide (0.62 mL, 9.95 mmol) was added with cooling in an ice-water-bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and concentrated to give a crude product (1.6 g, 100%), which was used without further purification. 1HNMR (400 MHz, CDCl3) 3.82 (s, 3H), 4.10 (s, 3H), 6.36 (d, J=3.13 Hz, 1H), 6.96 (d, J=2.74 Hz, 1H), 7.0 (d, J=2.35 Hz, 1H), 7.03 (d, J=2.35 Hz, 1H); MS (ES, m/z): C10H10BrNO: 240.08 (M+(79Br)+1), 242.1 (M+(81Br)+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:25]3[CH2:26][CH2:27][C:22]([CH3:21])([OH:28])[CH2:23][CH2:24]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC1(O)CCNCC1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: Cn1c(CCN2CCC(C)(O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.8 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (200 mg, 0.68 mmol) in DCE (15 mL) was added 4-methylpiperidin-4-ol (117 mg, 1.01 mmol), trimethyl orthoformate (0.74 mL, 6.76 mmol) and acetic acid (0.04 mL, 0.68 mmol). The reaction mixture was stirred at room temperature for 1.5 h, sodium triacetoxyborohydride (187 mg, 1.35 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-20% 2 M NH3/MeOH in DCM) to give the title compound as a colourless oil (45 mg, 17%). LCMS (Method H): RT=2.24 min, [M+H]+ 395.5
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:14][CH2:15][C:16]#[N:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](O)=[O:25]>>[C:16]([CH2:15][CH2:14][N:13]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:18])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=1)#[N:17]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NCCC#N
Product: Cc1ccccc1-c1ccncc1N(CCC#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 3-(4-o-tolyl-pyridin-3-ylamino)-propionitrile and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 19 hours. The compound was purified by two silica gel chromatographies (10 g and 5 g column, respectively) using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless solid (2%). MS (ESI): m/z=478.13 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To a solution of 2-fluoro-4-hydroxy-benzaldehyde (1.0 g, 7.1 mmol) in DMF (70 mL) was added benzylbromide (0.85 mL, 1.2 g, 7.1 mmol) and K2CO3 (1.1 g, 7.9 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was treated with H2O (50 mL) and filtered to afford the title compound as a colorless solid (1.4 g, 85%). MS (ESI): mass calcd. for C14H11FO2, 230.1; m/z found, 231.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.21 (s, 1H), 7.82 (t, J=8.8, 1H), 7.48-7.32 (m, 5H), 6.85 (dd, J=8.8, 2.3, 1H), 6.71 (dd, J=12.3, 2.3, 1H), 5.11 (d, J=14.8, 2H).
Reaction SMILES: C([NH:11][C@H:12]([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H].O1CCOCC1.Cl>CN(C)C=O.CO.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@H](C)N)C2
Yield: 72.1 %

Procedure:
The compound obtained in Example 224 (3.0 g, 6.9 mmol) was dissolved in dimethylformamide (200 ml). To the obtained solution, 10% palladium-on-carbon (3.0 g) was added, followed by stirring at room temperature overnight in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was dissolved in methanol (20 ml), and 4N-HCl dioxane (4 ml) was added thereto while cooling on ice. The mixture was condensed under reduced pressure. The resultant residue was recrystallized from methanol--ether to obtain 1.5 g of the title compound as pale yellow powdery crystals (64.4%).