Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH2:6][C:7]2[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=2)[N:24]=1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Cc2cccnc2NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (19.2 ml of a 2.5M solution in hexane) was added dropwise to a stirred suspension of the product of stage (a) above (5.0 g) in dry tetrahydrofuran (100 ml) under nitrogen at -70° C. The mixture was stirred at -70° C. for 20 minutes and then at 5° C. for 3 hours. It was then cooled to -70° C. and treated with 4,6-dimethoxy-2-methylsulfonylpyrimidine (5.42 g), and the mixture was stirred at -70° C. for 1 hour, then at room temperature overnight. Saturated ammonium chloride solution (500 ml) was added, and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml), dried and evaporated to give an orange oil which was triturated with hexane to give 5.35 g of the desired product as a pale yellow solid, mp 89°-92° C.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][CH:6]([CH2:10][CH:11]=[CH2:12])[C:7]([OH:9])=O)=[O:4].[C:15](OC(=O)CC)(=O)[CH2:16]C.O>N1C=CC=CC=1>[CH3:13][C:2]([CH3:1])([CH3:14])[C:3]([NH:5][CH:6]([C:7](=[O:9])[CH2:15][CH3:16])[CH2:10][CH:11]=[CH2:12])=[O:4]
Reactant: CCC(=O)OC(=O)CC
Reactant: C=CCC(NC(=O)C(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: C=CCC(NC(=O)C(C)(C)C)C(=O)CC

Procedure:
4.27 g of the above synthesized 2-(2,2-dimethyl-propionylamino)-pent-4-enoic acid (21.43 mmol) were dissolved in 13.5 ml of pyridine, treated with 132.81 ml of propionic anhydride (5 eq.), and heated to 100° for 15 h. After cooling, 10.04 ml of water were added and the mixture kept for 45 Min. at 90°. Careful pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing twice with Na2CO3 and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=8/2) left finally 2.10 g of the title compound as yellowish oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[C:13]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)=[N:14][C:15]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:16][C:17]=3[O:18]C)=[N:9][C:8]=2[CH:40]=1)(=[O:3])[NH2:2].Cl>>[N:20]1([C:15]2[NH:16][C:17](=[O:18])[C:12]([C:10]3[S:11][C:7]4[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:40][C:8]=4[N:9]=3)=[C:13]([NH:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[N:14]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C(N)=O)ccc2s1
Agent: Cl
Product: NC(=O)c1ccc2sc(-c3c(N[C@@H]4CCCNC4)nc(N4CCOCC4)[nH]c3=O)nc2c1
Reaction time: 0.12 h

Procedure:
Following the same procedure as in step 4 of Example 337 using tert-butyl (3R)-3-[[5-(5-carbamoyl-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (70.0 mg, 0.12 mmol, 1.00 equiv) and cone. hydrochloric acid (4.0 mL). The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm,; mobile phase, water 0.03% NH3H2O and CH3CN (14% CH3CN up to 27% in 7 min, up to 100% in 2 min, down to 14% in 1 min); Detector, Waters 2489 254&220 nm to afford the title compound as a white solid. 1H-NMR(400 MHz, DMSO-d6) δ ppm 1.54-1.66(m, 2H), 1.75(m, 1H), 1.99(m, 1H), 2.61-2.73(m, 2H), 2.80-2.85(m, 1H), 3.14-3.16(m, 1H), 3.69(m, 8H), 4.15-4.16(m, 1H), 7.38(s, 1H), 7.75-7.77(m, 1H), 7.97-8.00(m, 1H), 8.08(s, 1H), 8.26(s, 1H), 10.77-10.79(d, J=7.6 Hz, 1H). MS m/z [M+H]+ (ESI): 456. IRAK4 IC50=10 nM
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 12.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenyl)amino-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.249 g, 0.520 mmol) obtained in Example 106, step 2 and ethanesulfonamide (0.238 g, 2.60 mmol), the title compound (0.036 g, 11%) was obtained.
Reaction SMILES: [C:1](/[C:9](=[C:12](/OC)\[CH3:13])/[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[C:1](/[C:9](=[C:12](/[NH:20][CH2:16][CH2:17][CH2:18][CH3:19])\[CH3:13])/[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Product: CCCCN/C(C)=C(\C#N)C(=O)c1ccccc1

Procedure:
A sample of 2.5 g. of 2-benzoyl-3-methoxycrotononitrile is dissolved in 10 ml. of n-butylamine. The solution is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then opened and the solvent evaporated under reduced pressure. A greenish oil is obtained which is distilled on a Kugelrohr apparatus at 200° C./0.1 mm. to obtain the yellow oily product.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:19]=[CH:18][C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[C:11]=1[N+:20]([O-:22])=[O:21])C(=O)OC(C)(C)C>Cl.CCOCC>[CH3:1][NH:2][C:10]1[CH:19]=[CH:18][C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[C:11]=1[N+:20]([O-:22])=[O:21]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(c1[N+](=O)[O-])OCCO2
Agent: Cl
Solvent: CCOCC
Product: CNc1ccc2c(c1[N+](=O)[O-])OCCO2
Yield: 95.2 %

Procedure:
tert-Butyl methyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate (2.2 g, 7.1 mmol) in 2.0 M hydrochloric acid in Et2O (30 mL) was stirred at room temperature for 3 h. The volatiles were removed to give N-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (1.42 g, 95% yield). ESI MS: m/z 211 [M+H]+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH3:20]>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH3:20]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CCBr
Product: CCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-Ethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and ethyl bromide.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.N#N.[H-].[Na+:15].[CH2:16]1[S:21](=[O:23])(=[O:22])[O:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Na+:15].[O:1]1[CH:6]([CH2:7][O:8][CH2:19][CH2:18][CH2:17][CH2:16][S:21]([O-:23])(=[O:22])=[O:20])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12
Reactant: O=S1(=O)CCCCO1
Reactant: OCC1COc2cscc2O1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCCOCC1COc2cscc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (6.9 g, 40 mmol) was dissolved into tetrahydrofuran (100 mL) and blanketed by N2. NaH (1.76 g) was added and stirring was continued for 30 min. Then butanesultone (6.0 g) was added dropwise after which the reaction mixture was brought to reflux for 3 h. Then it was cooled to 25° C. again, the solvent was removed, methanol was added, the mixture was stirred, filtered and the filtrate was concentrated. The remaining oil was solidified by addition of hexane and ethanol, followed by stirring. Final filtration and drying resulted in pure 4-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-butane-1-sulphonic acid sodium salt as was demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[C:17]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.NN>CO.[Ni]>[N:25]1([CH2:24][CH2:23][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[N:14][N:13]3[S:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:11])=[O:12])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ncc3c(OCCN4CCCCC4)cccc32)cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: Nc1ccc(S(=O)(=O)n2ncc3c(OCCN4CCCCC4)cccc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]1H-indazole (0.39 g, 0.91 mol) in methanol is treated with Raney Nickel followed by hydrazine (0.2 ml, 6.3 mmol), stirred at 0° C. for 2 hr and decanted. The catalyst is washed with a methanol: methylene chloride 3:7 mixture. The washes and supernatant are combined and concentrated in vacuo. The resultant residue is purified by flash chromatography (silicagel, EtOAc/2M NH3 in methanol 8:2) to give the title product as a white solid, 0.15 g, mp 149-150° C. (dec), identified by NMR and mass spectral analyses.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[C:15]([F:37])=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=5)=[CH:22]4)[C:18]=3[CH:36]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O>[F:37][C:15]1[C:14]([S:13][CH:10]2[CH2:11][CH2:12][N:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:38])=[O:2])[CH2:8][CH2:9]2)=[CH:36][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=1)[N:20]=3
Reactant: COC(=O)C(C)(C)N1CCC(Sc2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)C(=O)O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C

Procedure:
To a solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (0.394 mmol) in MeOH (3 mL) was added 2.0M NaOH in water (1 mL). The reaction mixture was heated at 100° C. for 1 h using microwave irradiation. The crude mixture was purified by column chromatography (C18, gradient 20-60% MeOH in 0.003M HCl/H2O) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid as a yellow solid (177 mg, 85% over two steps). LCMS: RT 2.32, 2.37, 2.44 min [M−H]− 526.8
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([OH:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])C.[F:26][C:27]([F:34])([CH3:33])[CH2:28][NH:29][CH2:30][CH2:31][OH:32]>C(OCC)(=O)C>[F:26][C:27]([F:34])([CH3:33])[CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:4]([C:6]1[C:10]([OH:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5]
Reactant: CC(F)(F)CNCCO
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Solvent: CCOC(C)=O
Product: CC(F)(F)CN(CCO)C(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Temperature: 125 °C

Procedure:
A stirred mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-3c (15 g, 40 mmol) and 2-(2,2-difluoro-propylamino)-ethanol (16.5 g, 120 mmol) were heated at 125° C. for 18 hours. The reaction solution was cooled, diluted into ethyl acetate, washed with 1 N aq. HCl, brine, dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes) to afford the title compound (I-3d) as an oil, 10 g.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].C[O-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CO>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:3][C:2]1[NH:1][CH2:7][C:5](=[O:6])[N:4]=1
Reactant: O=C1CNC(=S)N1
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CNC(SCc2ccccn2)=N1

Procedure:
Initially, 1 g of 2-thiohydantoin and 2.5 g of sodium methylate were dissolved in 50 mL of methanol (MeoH), and 1.5 g of 2-chloromethylpyridine hydrochloride was added to the solution. The reaction mixture was stirred under reflux for one and a half hour and concentrated in vacuo. To the residue, there was added 50 mL of chloroform (CHCl3), and the mixture was washed with 50 mL of water. Then, the CHCL3 layer was dried over magnesium sulfate (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [using a developing solvent consisting of CHCl3 :MeOH=50:1 (volume ratio, v/v)]. Recrystallization from diethylether gave the desired compound in the form of a needle-like crystal. The yield of this compound was 1.2 g with a yield ratio of 67.2%, and its melting point was 105°-107° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:45])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[N:25]=[CH:26][N:27]([C:29]5[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=5[F:36])[CH:28]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].C1OCCOCCOCCOCCOCCOC1.[F-].[Cs+]>C(#N)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:45])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[N:25]=[CH:26][N:27]([C:29]5[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=5[F:36])[CH:28]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:10][CH2:11]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(-c5cc(F)ccc5F)cn4)nc23)C2CC2)C1
Reaction time: 2 h
Yield: 18.9 %

Procedure:
A solution of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.037 g, 0.058 mmol), 18-crown-6 (0.016 g, 0.058 mmol) and cesium fluoride (0.093 g, 0.58 mmol) in 1 mL of acetonitrile was stirred at 75° C. for 5 d, then concentrated. The resulting residue was partitioned between 5 mL of a 1 M citric acid solution and 5 mL of dichloromethane. The aqueous layer was extracted with two 5 mL portions of dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. Dichloromethane (1 mL) and 1 mL of trifluoroacetic acid were added, and the yellow solution was stirred 2 h, then concentrated. Dichloromethane (0.5 mL) and 0.5 mL of ethylene diamine were added, and the yellow-orange solution was stirred 1 h. The solution was partitioned between 10 mL of ethyl acetate and 5 mL of water, and the aqueous layer was extracted with 10 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. Column chromatography (0->10% MeOH/EtOAc) afforded 0.0055 g (19%) of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a pale yellow solid. MS: (M−H)−=501.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.S(Cl)(Cl)=O.[CH3:18][C:19]1[O:20][CH2:21][CH2:22][N:23]=1>C(Cl)(Cl)Cl>[CH3:18][C:19]12[O:20][CH2:21][CH2:22][N:23]1[C:7](=[O:9])[C:6]1[CH:10]=[C:11]3[O:12][CH2:1][O:2][C:3]3=[CH:4][C:5]=1[O:13]2
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Reactant: CC1=NCCO1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC12OCCN1C(=O)c1cc3c(cc1O2)OCO3
Reaction time: 1 h
Yield: 60.7 %

Procedure:
4,5-Methylenedioxysalicylic acid (0.472 g; 2.59 mmol) was suspended in 8 mL dry chloroform to which was added 0.476 g (4.00 mmol) thionyl chloride. The reaction mixture was heated at reflux for 3 h, during which time the suspension turned into a dark solution. The solution was allowed to cool to ambient and the solvent and excess thionyl chloride were removed in vacuo. The residue was dissolved in 8 mL methylene chloride and 0.392 g (4.60 mmol) 2-methyl-2-oxazoline was added dropwise. The solution was stirred for 1 h and then concentrated onto silica gel for subsequent purification by column chromatography (hexane/ethyl acetate=2:1) to yield 0.500 g of crude product. The product was recrystallized from ethyl acetate/hexane (1:10) to give 0.392 g (64% yield) of white crystalline solid with mp 132-133° C. IR (thin film): 1659, 1629, 1454, 1376, and 1267 cm-1. 1H NMR (500 MHz; CDCl3) δ 7.28 (1H, s), 6.48 (1H, s), 6.00 (2H, AB quartet), 4.27 (1H, dd, J=10.5 & 5.6 Hz), 4.17-4.23 (1H, m), 4.05-4.13 (1H, m), 3.55 (1H, td, J=10.6 & 6.5 Hz), and 1.59 ppm (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)=[O:15])[CH2:10][C:9]1([CH2:25][O:26][CH3:27])[CH3:24])C1C=CC=CC=1>[Pd].CO>[CH3:27][O:26][CH2:25][C:9]1([CH3:24])[NH:8][CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)=[O:15])[CH2:10]1
Reactant: COCC1(C)CN(C(=O)c2cccc(OC)n2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCC1(C)CN(C(=O)c2cccc(OC)n2)CCN1
Reaction time: 12 h

Procedure:
A mixture of 170 mg (414 μmol, purity: 90%) (4-benzyl-3-methoxymethyl-3-methyl-piperazin-1-yl)-(6-methoxy-pyridin-2-yl)-methanone and 20 mg palladium on carbon in 10 mL methanol was hydrogenated at 50° C. for 12 h at 50 psi. The catalyst was removed by filtration and the solvent was evaporated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:42])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:41])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[CH:30]=[C:31](/[CH:33]=[CH:34]/[C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[O:36])\[CH3:32])\[CH3:27])\[CH3:22].[Na].S(=O)(=O)(O)O>C(Cl)Cl.CO>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:42])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:41])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[CH:30]=[C:31](/[CH:33]=[CH:34]/[C@@H:35]([OH:36])[C:37]([OH:40])([CH3:39])[CH3:38])\[CH3:32])\[CH3:27])\[CH3:22]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)C(C)(C)O)C(C)(C)CCC1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(C)/C=C/[C@@H](O)C(C)(C)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17.4 %

Procedure:
70.0 g (123 mmol) of 2'-dehydroplectaniaxanthin are dissolved in 2000 ml of methylene chloride and 500 ml of methanol. At 16-18° C. 4.70 g (123 mmol) of sodium borohyride are added in portions, and the mixture is stirred for 1.5 hours at room temperature. The resulting solution is then cooled to 10° C., and approx. 150 ml of 1N sulphuric acid are added at such a rate that the temperature is maintained between 10° and 15° C. until a pH between 7 and 8 is obtained. The resulting mixture is then extracted three times with 500 ml of methylene chloride in each case. The organic layer is washed several times with 500 ml of ice-water, then dried over anhydrous sodium sulphate and evaporated at 35° C. using a water jet vacuum. The resulting crystalline mass is stirred with 1500 ml of diethyl ether and the resulting suspension filtered. In this way there are obtained 12.2 g (HPLC purity 97%) of racemic plectaniaxanthin crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].I[CH2:18][CH3:19].ClCCl.CO>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH3:19]
Reactant: CCI
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: CCOc1ccc2[nH]ccc2c1
Temperature: 50 °C
Yield: 90 %

Procedure:
A mixture of commercially available 5-hydroxy-indole (18 g, 13.5 mmol), anhydrous K2CO3 (93.5 g, 5 equiv) and iodoethane (40.5 ml, 3.75 equiv) in acetone (180 mL) is stirred at 50° C. under argon. When TLC (dichloromethane-methanol, 95:5) indicates the disappearance of 5-hydroxy-indole (4 days), the mixture is filtered, the solid is washed with acetone, then the filtrate is concentrated to give 17.67 g (90%) of the title compound, which is sufficiently pure to be used in the next step. M.p. 144-146° C. (from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](N)=[C:7](N)[CH:6]=1)C.[B:14]1(B2OC(C)(C)C(C)(C)O2)[O:18]C(C)(C)C(C)(C)[O:15]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([B:14]([OH:18])[OH:15])=[CH:7][CH:6]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(B(O)O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 228.9 %

Procedure:
Referring to Scheme 11-1, to a solution of the bromide 1 (2.0 g, 4.2 mmol, prepared according to published conditions) in dioxane (60 mL) was added bis(pinacolato)diboron (4.32 g, 17 mmol), Pd(PPh3)4 (0.49 g, 0.42 mmol) and potassium acetate (2.06 g, 21 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 5 h, and then diluted with ethyl acetate (150 mL). The organic phase was washed with H2O (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was further purified by silica gel column chromatography (haxanes/ethyl acetate=1/4 to 0/1 (v/v)) to give 2 (1.73 g, 79% yield). LC-MS (ESI): m/z 523.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(O[CH2:16][CH2:17][CH:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH3:19])(=O)=O>>[N:20]1([CH:18]([CH3:19])[CH2:17][CH2:16][NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC(CCOS(C)(=O)=O)N1CCOCC1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: CC(CCNc1ccc([N+](=O)[O-])cc1)N1CCOCC1

Procedure:
In a manner similar to Preparation 2, react 4-nitrobenzenamine with 3-(morpholin-4-yl)-1-butanol methanesulfonate to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]O)=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:31]>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][Cl:31])=[CH2:2]
Reactant: C=Cc1cccc(CO)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cccc(CCl)c1

Procedure:
3-Ethenylbenzyl alcohol (5.26 g) was dissolved in carbon tetrachloride (100 ml) and triphenylphosphine (10.2 g) added. The solution was refluxed overnight and then left to cool. A white precipitate formed which was filtered through celite. The filtrate was evaporated in vacuo to yield a crude product. The residue was purified by gravity chromatography on silica using 5% dichloromethane in petrol (60-80) as eluant. This yielded the pure product.