Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:19]2[CH2:18][C@@:17]([OH:24])([C:20](=[O:23])[CH2:21][OH:22])[CH2:16][C@H:15]([O:25][C@@H:26]3[O:40][C@@H:39]([CH3:41])[C@H:29]4[O:30][C@H:31]5[N:36]([C@H:28]4[CH2:27]3)[CH2:35][CH2:34][O:33][C@@H:32]5[O:37][CH3:38])[C:14]=2[C:13]([OH:42])=[C:12]2[C:3]=1[C:4](=[O:46])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:44][CH3:45])[C:10]=1[C:11]2=[O:43].[CH2:47]([O:49][C:50](=[O:59])[CH2:51][O:52][C:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]=1)[CH3:48].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[O:23]=[C:20]([C@@:17]1([OH:24])[CH2:16][C@H:15]([O:25][C@@H:26]2[O:40][C@@H:39]([CH3:41])[C@H:29]3[O:30][C@H:31]4[N:36]([C@H:28]3[CH2:27]2)[CH2:35][CH2:34][O:33][C@@H:32]4[O:37][CH3:38])[C:14]2[C:19](=[C:2]([OH:1])[C:3]3[C:4](=[O:46])[C:5]4[C:10]([C:11](=[O:43])[C:12]=3[C:13]=2[OH:42])=[C:9]([O:44][CH3:45])[CH:8]=[CH:7][CH:6]=4)[CH2:18]1)[CH2:21][O:22][C:53]1([O:52][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:59])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: CCOC(=O)COC1=CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COC1(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione (50 mg, 0.078 mmol) [PNU-159682, compound IIA, prepared as reported in WO 9802446] in 2 ml of dry dimethylformamide kept under argon, (Cyclohex-1-enyloxy)-acetic acid ethyl ester (0.5 mL, [prepared as reported in J. Org. Chem. (1978) 43:1244-1245] and p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) were added. The reaction mixture was stirred overnight at room temperature, sodium bicarbonate saturated solution was added (20 mL) and the product extracted with dichloromethane (2×20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent removed under vacuum and the residue partially purified by flash chromatography (DCM/MeOH 97.5:2.5) to give 30 mg (37%) of the ester intermediate that was used as such in step 2. MS (ESI): 826 [M+H]+. Retention time=7.48 min. method 2
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:40]([OH:42])=O)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].Cl.[CH2:44]([NH:50][CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:40](=[O:42])[N:50]([CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[CH3:51])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reactant: C=CCCCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 3 h
Yield: 76 %

Procedure:
Compound 156 (0.81 g, 1.40 mmol) and hex-5-enyl-methyl-amine hydrochloride (272 mg, 1.82 mmol) was dissolved in dry DMF (50 mL). DIEA (975 μL, 5.6 mmol) was added and the reaction flask was placed in an ice bath. After 10 minutes HATU (559 mg, 1.47 mmol) was added to the solution. The reaction flask was allowed to reach room temperature and the stirring was continued for 3 hrs before the solvent was removed by evaporation. The crude product was extracted with CHCl3 and washed with saturated NaHCO3 (aq). The organic phase was dried (Na2SO4), evaporated on silica and purified to by flash chromatography (heptane:ethyl acetate 1:1) to give the title compound (0.716 g, 76%), LRMS (M+H) 673.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[CH:26][CH:25]=2)=[N:19][C:18]=1[CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CCCOC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 66.5 %

Procedure:
A solution of 4-[4-[3-([1-[(tert-butoxy)carbonyl]piperidin-4-yl]oxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoic acid (1.0 g, 2.25 mmol, 1.00 equiv), EDCI (560 mg, 2.92 mmol, 1.30 equiv), HOBt (400 mg, 2.96 mmol, 1.32 equiv), triethylamine (800 mg, 7.91 mmol, 3.51 equiv) and pyridin-3-ylmethanamine (480 mg, 4.44 mmol, 1.97 equiv) in N,N-dimethylformamide (30 mL) was stirred at 35° C. overnight. The product was precipitated by the addition of 50 mL of ice/water. The solid was collected by filtration, washed with 3×30 mL of water and dried in a vacuum oven to give 0.8 g (67%) of tert-butyl 4-[3-(5-methyl-2-[4-[(pyridin-3-ylmethyl)carbamoyl]phenyl]-1,3-oxazol-4-yl)propoxy]piperidine-1-carboxylate as a white solid LC-MS-PH: (ES, m/z): 535 [M+H]+, 435, 367, 352, 239, 102.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]=O)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].B.CSC.CO>O1CCCC1>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(NC=O)cc1)NC(C)=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CNc1ccc(C[C@H](NC(C)=O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100.0 g of methyl (2S)-2-ethanamido-3-(4-methanamidophenyl)propanoate in 3000 cm3 of tetrahydrofuran at 20° C. with stirring are added, under nitrogen, 378 cm3 of a 2 M solution of borane/methyl sulphide in tetrahydrofuran such that the temperature of the reaction mixture is maintained below 25° C. At the end of the addition, the reaction mixture is kept stirring for 1 hour at 25° C. and 1000 cm3 of methanol are then added dropwise. At the end of the addition of the methanol, the mixture is stirred at 25° C. under nitrogen for 16 hours and then concentrated under reduced pressure (20 kPa) at a temperature of 40° C. At the end of the concentration, the mixture is allowed to return to 25° C. under nitrogen and 1000 cm3 of dichloromethane and 1000 cm3 of saturated aqueous sodium chloride solution are then added. The mixture is stirred for 30 minutes at 25° C. and is then separated by settling of the phases. The lower organic phase is removed and dried over anhydrous sodium sulphate. After filtration of the sodium sulphate, the solution is concentrated at 30° C. under reduced pressure (20 kPa).
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2.C(#N)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O.C(Cl)(Cl)Cl>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][N:9]2[CH:6]3[CH2:7][CH2:8][CH:2]2[CH2:3][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]3)=[CH:25][CH:26]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: N#Cc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2CCOc1ccc(C#N)cc1

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate hydrochloride (1.36 g, 5.5 mmol; see Preparation A) was dissolved in H2O/CHCl3/saturated K2CO3 solution (40:40:5) and the resulting mixture was shaken. The phases were separated, dried and evaporated giving 1.1 g (100%), of the free base. Acetonitrile (100 mL), 4-(2-bromoethoxy)benzonitrile (1.49 g, 6.6 mmol; from step (a) above) and K2CO3 (2.4 g, 17.5 mmol) were added. The mixture was stirred at 70° C. for 24 h, the solids were filtered off and the residue evaporated and purified by chromatography on silica, eluting with CHCl3:MeOH (95:5), to give 1.5 g (4.3 mmol) of the sub-title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]=O)=[C:6]2Cl)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]3[CH:14]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:6]2=3)[CH2:2][CH2:3]1
Reactant: O=Cc1c(Cl)n(CC2CC2)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(CC3CC3)c2s1

Procedure:
Prepared from (4) (6.5 g) , K2CO3 (10 g) and methyl 2-mercaptoacetate (3.2 ml) yielding (7) (6 g), m.p. 110°-111° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29](CO)[CH2:30][OH:31])CCCC.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]3[O:31][CH2:30][CH2:29][CH2:24][O:21]3)=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(CO)CO
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(C=O)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(C3OCCCO3)cc2)CC1
Reaction time: 2 h

Procedure:
A solution of 3 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzaldehyde and 1.7 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol.) sulfuric acid. The mixture was heated to boiling for 2 hours, whereby the resulting water was distilled off simultaneously. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 50 ml of 1N sodium hydrogen carbonate solution and twice with 50 ml of water each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from acetone gave 1.2 g of trans-5-pentyl-2-(4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenyl-1,3-dioxane with m.p. (C-N) 73° C. and clop. (N-Z) 106° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1.Cl.[F:17][C:18]([F:24])([F:23])[CH2:19][N:20]=[C:21]=[S:22]>C(#N)C>[F:17][C:18]([F:24])([F:23])[CH2:19][NH:20][C:21](=[S:22])[NH:8][C:9]1[N:10]=[C:11]([O:6][CH2:5][CH2:4][CH2:3][OH:7])[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc(Br)n1
Reactant: FC(F)(F)CN=C=S
Reactant: OCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OCCCOc1cccc(NC(=S)NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50% w/w dispersion of sodium hydride in oil (0.5 g.) was added in portions to propane-1,3-diol (5 ml.) and the mixture stirred at room temperature for 1 hour. 2-Amino-6-bromopyridine (0.85 g.) was added and the mixture stirred at 150° for 4 hours and then cooled to room temperature. The mixture was taken up in N aqueous HCl and washed with EtOAc and the aqueous phase basified with 10 N aqueous NaOH. The mixture was extracted three times with EtOAc and the combined extracts dried and evaporated to dryness to give a brown oil (1.6 g.). A portion of the oil (0.67 g.) was dissolved in acetonitrile (5 ml.) and the solution treated with 2,2,2-trifluoroethylisothiocyanate (0.3 g.). The mixture was kept at room temperature for 18 hours and then evaporated to dryness and the residue recrystallised from EtOH to give 6-[3-(2,2,2-trifluoroethyl)thioureido]-2-(3-hydroxypropoxy)pyridine (0.18 g.), m.p. 123°-124°.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([CH2:32][CH2:33][NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.[Cl-].[NH4+]>[CH2:25]([CH2:32][CH2:33][NH:34][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)c(-c2c3nc(C)nc(Cl)c3n3ccccc23)c(C)c1
Reactant: NCCCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(-c2c3nc(C)nc(NCCCc4ccccc4)c3n3ccccc23)c(C)c1
Temperature: 110 °C

Procedure:
A mixture of 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine (15 mg) and N-benzylethylamine (0.04 mL) in DMSO (0.4 mL) is heated to 110° C. for 2 hours. The mixture is allowed to cool, diluted with aqueous ammonium chloride, and extracted twice with 50% ethyl ether in hexane. The combined extracts are washed with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (10% to 20% ethyl acetate in hexane) gives 22 mg of the title compound (compound 5, Table 1) as a yellow oil: 1H nmr (400 MHz, CDCl3) d 1.17 (t, 3 H), 2.00 (s, 6 H), 2.38 (s, 3 H), 2.70 (s, 3 H), 3.40 (q, 2 H), 4.72 (s, 2 H), 6.68 (t, 1 H) 7.00 (s, 2 H), 7.03 (d, 1 H), 7.13 (d, 1 H), 7.29 (d, 1 H), 7.35 (t, 2 H), 7.41 (d, 2 H), 8.61 (d, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:5][CH:6]=1)[CH2:9][CH3:10]
Reactant: CCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.468 g (1.58 mmol) of the above prepared [rac]-1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-propan-1-ol was dissolved in 7.6 ml of CH2Cl2 and treated dropwise at 0° C. with 0.23 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents yielded 0.496 g of pure title compound as light yellow oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[C:9]1(C)C=CC=CC=1.C(OC)(OC)OC.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:9][O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: CO
Product: COC1=CC(=O)CCC1

Procedure:
In a 21 three-necked flask, 100 g (0.89 mol) of cyclohexane-1,3-dione are initially charged and dissolved in 300 ml of methanol, 1000 ml of toluene and 97.6 ml of trimethyl orthoformate, 5 g of p-toluenesulphonic acid dihydrate are added and the mixture is heated under reflux for 2 h. After cooling, the mixture is washed 4× with in each case 200 ml of 10% strength NaOH and the organic phase is dried over sodium sulphate and concentrated on a rotary evaporator. This gives 73.4 g of a light-brown oil which is used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:32])[C:15]([CH2:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:35](Cl)([CH3:38])(=[O:37])=[O:36].N1C=CC=CC=1>CC(C)=O>[CH:26]1([CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:33]=[CH:34][C:3]([NH:2][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 76.4 %

Procedure:
A solution of Example 41H (1.17 g, 2.33 mmol), mesyl chloride (0.720 mL, 9.31 mmol), and pyridine (1.51 mL, 18.61 mmol) in acetone (30 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.968 g, 42%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.84 m, 7 H) 1.34 m, 4 H) 1.53 (m, 3 H) 2.20 m, 2 H) 3.07 m, 3 H) 7.57 m, 3 H) 7.76 m, 3 H) 8.17 m, 1 H) 10.28 m, 1 H) 13.83 m, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1>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.COCCOC>[N:14]1([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=3)[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 83 %

Procedure:
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite™. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C[SiH](C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(O)C(C)(C)C)cc1
Agent: C[SiH](C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1ccc(CC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
1-(4-Allyloxyphenyl)-2,2-dimethylpropan-1-ol (1.2 g, 6.1 mmol) and trimethylsilane (mL, 61.0 mmol) were dissolved in dichloromethane (5.0 mL) and trifluoroacetic acid (2.1 g, 18.3 mmol) was added at 0° C. After 30 min, the reaction mixture was concentrated to give esentially pure 1-allyloxy-4-neopentylbenzene. The crude product was dissolved in 1,2,4-trichlorobenzene (5.0 mL) and the solution was heated to reflux for 4 hrs. Removal of solvent and chromatography of the residue on silica gel eluting with 9:1 hexane:ethyl acetate gave 0.70 g 2-allyl-4-(2,2-dimethyl-propyl)phenol.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:13]([C:14]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([CH2:23][CH3:24])[C:16]=2[C:18](=[O:22])[C:19]([NH2:21])=[O:20])[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CCCCCC.C[CH2:39][O:40][C:41]([CH3:43])=[O:42]>>[C:41]([CH2:43][O:8][C:9]1[C:17]2[N:13]([C:14]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([CH2:23][CH3:24])[C:16]=2[C:18](=[O:22])[C:19]([NH2:21])=[O:20])[CH:12]=[CH:11][CH:10]=1)([O:40][CH3:39])=[O:42]
Reactant: CCOC(C)=O
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCc3ccccc3)cccn2c1CC1CCCCC1
Solvent: CCCCCC
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccn2c1CC1CCCCC1
Yield: 19 %

Procedure:
Mp, 149-150 C, (Hexane-EtOAc). 19% Yield from 49b.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>ClCCCl>[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][I:20])[CH:33]=1
Reactant: II
Reactant: COC(=O)CCc1cccc(CO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCc1cccc(CI)c1
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
A mixture of Ph3P (36 mg, 0.14 mmol), I2 (41 mg, 0.16 mmol) and imidazole (10.5 mg, 0.15 mmol) in 0.40 mL 1,2-dichloroethane was stirred for 15 min. and then a solution of 18 (20.5 mg, 0.11 mmol) in 0.1 mL 1,2-dichloroethane was added by cannula. The resulting mixture was stirred for 1 h and then was filtered through basic alumina, washing with ethyl acetate. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel to give compound 19 (26 mg, 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].C(=O)(O)[O-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C=O)C>[OH:21][CH2:20][CH:19]1[O:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=2[O:8][CH2:17]1
Reactant: BrCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Temperature: 90 °C
Reaction time: 17 h
Yield: 3.5 %

Procedure:
17.6 g 4-nitrocatechol and 11.0 g potassium bicarbonate were stirred in 200 ml DMF at 10° C. 13.99 g epibromohydrin in 10 ml DMF were added dropwise and stirring was continued at 60° C. for another 17 hrs. DMF was evaporated and the residue diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with caustic soda and water., dried and evaporated. The crude oily product was heated to 90° C. with 200 ml toluene and the supernatant decanted from insoluble parts. After cooling to RT the solution is again decanted from insoluble oils and left at RT for 3 d. A first crop of 0.75 g crystalline title product was obtained. The mother liquor was evaporated and the residue dissolved in 20 dichloromethane at RT. Seeding and chilling to 0° C. yielded another 2.78 g crystalline title product.