Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:22]([O:29][CH2:30][CH3:31])(=[O:28])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH3:27].[NH4+].[Cl-]>C1COCC1>[CH2:30]([O:29][C:22](=[O:28])[CH2:23][C@@H:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[CH2:25][CH2:26][CH3:27])[CH3:31]
Reactant: CCC/C=C/C(=O)OCC
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][C:31]1[N:32]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:34][C:35]=1[C:36](Cl)=[O:37]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([C:35]3[S:34][C:33]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[N:32][C:31]=3[CH3:30])=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)sc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.45 g, 4.5 mmol) in CH3CN (25 ml), were added triethyl amine (1.56 mL, 11.22 mmol) and 4-methyl-2-phenyl-1,3-thiazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL) to afford 4-methyl-2-phenyl-thiazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (1.45 g, 66%): mp, 277-279° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.96 min. (99%); 1H NMR (DMSO-d6): δ 2.08-2.10 (m, 1H), 2.55-2.59 (m, 2H), 2.66 (s, 3H), 2.86-2.98 (m, 1H), 4.91 (d, J=5.6 Hz, 2H), 5.18 (dd, J=6, 12 Hz, 1H), 7.53-7.98 (m, 8H), 8.91 (t, J=5.6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 17.20, 30.92, 38.56, 48.87, 121.98, 125.65, 126.65, 126.25, 127.18, 129.37, 130.95, 131.57, 132.36, 133.15, 134.85, 138.83, 155.65, 161.37, 166.14, 166.93, 167.51, 169.82, 172.75. Anal Calcd for C25H20N4O5S: C, 61.47; H, 4.13; N, 11.47; S: 6.56. Found: C, 61.44; H, 4.04; N, 11.63; S: 6.49.
Reaction SMILES: [CH2:1]([C@H:8]([NH:45]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C@@H:9]([OH:44])[CH2:10][C@@H:11]([NH:19][C:20](=[O:43])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=[CH:34][CH:33]=2)[C:27]1=[O:42])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C>CN(C=O)C>[NH2:45][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:44])[CH2:10][C@@H:11]([NH:19][C:20](=[O:43])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=[CH:34][CH:33]=2)[C:27]1=[O:42])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)N1CCN(Cc2ccnc3ccccc23)C1=O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 134A (0.122 g, 0.147 mmol) in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compounds.
Reaction SMILES: C1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])C=CC=CC=1.C=CC=C.C(O)(=[O:22])C=C>C1C=CC=CC=1>[CH:9]1([C:7]([OH:22])=[O:8])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1
Reactant: C=CC(=O)O
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: C=CC=C
Solvent: c1ccccc1
Product: O=C(O)C1CC=CCC1

Procedure:
The present invention relates to a method for preparing a cyclohexyl phenyl ketone from a 1,3 butadiene and acrylic acid without a purification or separation step and, more particularly, to a synthesis method of cyclohexyl phenyl ketone that includes carrying out a [2+4] Diels-Alder reaction of 1,3-butadiene and acrylic acid in the presence or absence of benzene or a non-aromatic organic solvent to yield 3-cyclohexene-1-carboxylic acid, a hydrogenation reaction to yield cyclohexanecarboxylic acid, a chlorination reaction to prepare a cyclohexanecarbonyl chloride; and a Friedel-Crafts reaction in the same reactor without purifying or separating the cyclohexanecarboxylic acid to prepare a cyclohexyl phenyl ketone with a high yield.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[C:28]([CH3:33])=[N:29][O:30][C:31]=1[CH3:32])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1noc(C)c1N=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3c(C)noc3C)c(=O)n(C3CCCC3)c12
Yield: 83.7 %

Procedure:
1-Cyclopentyl-3-(3,5-dimethyl-isoxazol-4-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (17 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (0.05 mmol) following general procedure C. LCMS: m/z 407 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CC(C)=O>[N:20]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (2.1 equivalents). FAB-MS: (M+H)+ =372 (corresponds to C21H17N5O2); Rf value (toluene-acetone--4:6)=0.36.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:14]1[CH2:16][CH2:15]1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].CO>CCOCC>[CH:14]1([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][OH:11])[CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)C1CC1
Temperature: 40 °C
Yield: 88.6 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-2-cyclopropylacetate (5.35 g, 23.33 mmol) in Et2O (100 ml) was added LiBH4 (0.762 g, 35.0 mmol), followed by drop wise addition of methanol (1.420 ml, 35.0 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×100 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (4.16 g). LCMS m/z 224.1 (M+Na)+, Rt 0.62 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=2[CH3:24])O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[OH:30][C@H:31]1[C@H:38]2[C@H:34]([O:35][C:36]([CH3:40])([CH3:39])[O:37]2)[O:33][C@H:32]1[C:41](N1CCOCC1)=[O:42].C([Mg]Cl)(C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:17]2[CH:22]=[C:21]([C:41]([C@@H:32]3[O:33][C@H:34]4[O:35][C:36]([CH3:40])([CH3:39])[O:37][C@H:38]4[C@@H:31]3[OH:30])=[O:42])[CH:20]=[CH:19][C:18]=2[CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a solution of 2-(4-(benzyloxy)benzyl)-4-bromo-1-methylbenzene (34, 2.71 g, 7.4 mmol) in THF (37 mL) under nitrogen at −78° C. was slowly added n-butyllithium (3.3 mL of 2.5 M solution in hexanes, 8.1 mmol), and the reaction was stirred for 30 min. Meanwhile, to a solution of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (2.02 g, 7.4 mmol) in THF (37 mL) under nitrogen at 0° C. was added tert-butylmagnesium chloride (8.1 mL of 1 M solution in THF, 8.1 mmol). The reaction was stirred for 20 min, then added slowly by cannula to the aryl lithium solution at −78° C. The reaction was allowed to gradually warm to room temperature over 3 hours, then quenched with saturated aqueous NH4Cl, diluted with EtOAc, washed with H2O and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient 0-50% EtOAc/hexanes) to give 2.44 g (70% yield) of the product 35 as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (dd, J=7.8, 1.8 Hz, 1 H), 7.75-7.80 (m, 1 H), 7.27-7.49 (m, 6 H), 7.04 (d, J=8.6 Hz, 2 H), 6.86-6.96 (m, 2 H), 6.09 (d, J=3.5 Hz, 1 H), 5.32 (d, J=2.8 Hz, 1 H), 5.04 (s, 2 H), 4.60 (d, J=3.5 Hz, 1H), 4.53-4.58 (m, 1 H), 3.98 (s, 2 H), 3.03 (d, J=4.3 Hz, 1 H), 2.31 (s, 3 H), 1.56 (s, 3 H), 1.36 (s, 3 H); MS (ES+) [M+H]+=475.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][NH:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: CNC1CNC1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4C)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 68.2 %

Procedure:
To 90 mg of N,N-dimethylformamide were added 25 mg of 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25 mg of 3-(methylamino)azetidine dihydrochloride, and 70 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 20 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S([O-])([O-])(=O)=O.[Mg+2]>CN(C=O)C>[CH2:17]([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: COC(=O)CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNCC(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
Under argon condition, glycine methyl ester (358 mg, 2.85 mmol) was dissolved in 2 mL of dry DMF, and then DIPEA (620 μL, 3.56 mmol) and 1-bromooctane (123 μL, 0.712 mmol) were added, and the reaction mixture was stirred for one day at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water, and the reaction mixture was extracted with diethyl ether (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 31.6 mg (0.157 mmol, 22%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7](Br)=[CH:8][N:9]=1)[C:5]#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[CH:3]=[C:4]([C:7]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][C:16]=2[Cl:18])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(N)ncc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinonitrile (1.0 g, 5.1 mmol, prepared according to Example 3, Step 2.1), 2,4-dichloro-benzeneboronic acid (1.45 g, 7.6 mmol), Pd(PPh3)4 (292 mg, 0.25 mmol) and Na2CO3 (2.0 M solution in water, 8.8 mL) in DME (10 mL) was refluxed for 2 h under an inert atmosphere of argon. The reaction mixture was cooled to RT, diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (880 mg, 3.3 mmol, 66%). MS: 264 [M+1]+; HPLC: AtRet=1.73; TLC: RF 0.31 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCI
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Yield: 56 %

Procedure:
7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.61 g, 3.2 mmol), sodium carbonate (0.60 g, 5.7 mmol) and pentyl iodide (0.64 g, 3.2 mmol) were stirred in DMF (5 ml) at 50° C. for 18 h. The solution was cooled, separated between ethyl acetate and brine and the organics isolated, dried (MgSO4) and concentrated. Chromatography over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) provided the title compound as a pale yellow solid (0.47 g, 56%). m/z 263[MH+]
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[C:20]([F:31])([F:30])[C:21]([NH:23][CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22]>CC(C)=O.C(OCC)(=O)C>[F:31][C:20]([F:30])([O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[F:1])[C:21]([NH:23][CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: Oc1ccc2ccccc2c1F
Reactant: O=C(NCc1ccco1)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccco1)C(F)(F)Oc1ccc2ccccc2c1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 112.1 %

Procedure:
To a solution of 1-fluoronaphthalen-2-ol (280 mg, 1.73 mmol) and K2CO3 (1.2 g, 8.65 mmol) in 10 mL of acetone, 2-bromo-2,2-difluoro-N-(furan-2-ylmethyl)acetamide (527 mg, 2.08 mmol) were added. The resulting mixture was stirred at 40° C. overnight. The reaction was cooled at room temperature, diluted with ethyl acetate (30 mL) and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2,2-difluoro-2-[(1-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)acetamide as red oil (650 mg) which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]([CH3:14])[CH2:11]C=O)=[CH:2]1.[CH:15](OC)([O:18][CH3:19])[O:16][CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:17][O:16][CH:15]([O:18][CH3:19])[CH2:14][CH:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:11]
Reactant: COC(OC)OC
Reactant: C[C@H](CC=O)c1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(CC(C)c1c[nH]c2ccccc12)OC
Yield: 92.9 %

Procedure:
(R)-3-(1H-Indol-3-yl)-butanal (236 mg, 1.26 mmol) was dissolved in methanol (15 mL) and treated with trimethyl orthoformate (275 μl, 2.50 mmol) and a catalytic amount of p-TSA. The reaction was stirred at room temperature for 3 hours, at which time H2O (10 mL) was added and the reaction was extracted with ether (3×20 mL). The collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (228 mg, 1.17 mmol). 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (39.9 mg, 0.171 mmol) was dissolved in a KOH (38.4 mg, 0.684 mmol)/DMSO (2 mL) solution and allowed to stir at 0° C. for 10 min, at which time dimethyl sulfate (32.5 μl, 0.340 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was left to stir at room temperature until it appeared done by TLC. The reaction was quenched with H2O (1 mL) and brought to a neutral pH with dropwise addition of 1M HCl. The solution was extracted with Et2O (3×5 mL), and the collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1-methyl-indole. This crude residual material was dissolved in THF (5 mL) and 1M HCl (1 mL) to give (R)-3-(1-methyl-1H-indol-3-yl)-butanal (1.9 mg, 0.0094 mmol) after preparative TLC (25:75 EtOAc/hexanes). [α]D=−4.1 (c=1.0, CHCl3); reported rotation for (R)-3-(1-methyl-1H-indol-3-yl)-butanal [α]D=−4.2 (c=1.0, CHCl3).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=[CH:23][C:24]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])=[CH:25][CH:26]=1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available [1,1′-biphenyl]-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 416.23 g/mol.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][NH2:28].C(O)C>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][NH:28][CH3:27])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CN
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Solvent: CCO
Product: CNCc1cc(-c2ccc(OC)c(F)c2)nn(CC2CC2)c1=O

Procedure:
A solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (160 mg, 0.42 mmol) in 30% methylamine/ethanol (5 mL) was stirred at 80° C. for 4 hours in a sealed tube. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/methanol (10/1)] to yield title compound as a slightly yellow oil (87 mg, 65.5%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].IC.[CH3:26]COC(C)=O>CN(C=O)C>[CH3:26][O:22][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of BOC-5-hydroxy-tryptophan (5.9 g, 18.4 mmol) and iodomethane (3.43 mL) in DMF (80 mL) was added powered KHCO3 (3.68 g). The reaction mixture was stirred at rt for 4 hours. EtOAc (500 mL) was added and the mixture was washed with brine (500 mL) and water (500 mL). The organic phase was concentrated and the residual oil was triturated with CH2Cl2 (20 mL). The formed white solid was collected by filtration, washed with CH2Cl2 (20 mL) and dried to give the desired product (4.48 g, 73%). MS (DCI) m/z 335 (M+1)+.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:33]([F:36])([F:35])[F:34])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=2[F:32])[C:21]([NH:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])=[O:22])([CH2:16][F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:33]([F:36])([F:35])[F:34])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=2[F:32])[C:21]([NH:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])=[O:22])([CH2:16][F:17])[N:15]=1
Reactant: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a solution of 3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamide (0.0591 g, 0.115 mmol) in MeOH (1.15 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.021 ml, 0.138 mmol) and allowed to stir at 65° C. for 15 h. The reaction mixture was concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP Ultra silica gel column (25 g), eluting with a gradient of 20-100% EtOAc in hexane, to provide 3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-N-((S)-1-methoxypropan-2-yl)benzamide (0.0246 g, 0.060 mmol, 52.2% yield). MS m/z=410.0 [M+H]+. Calculated for C17H20F5N3O3: 409.14