Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[OH:42][CH:43]1[CH2:46][NH:45][CH2:44]1>>[OH:42][CH:43]1[CH2:46][N:45]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH2:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: OC1CNC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CC(O)C4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 3-hydroxyazetidine. MS (ES+): m/z 651.24 (100) [MH+]; HPLC: tR=0.91 min (UPLC, purity).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2.[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(O)CCC.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH:14][C:25]2[N:24]=[C:23]([NH2:22])[N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][NH:29]3)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2
Reactant: CC(N)c1cc(F)c2ccnnc2c1-c1cccc(F)c1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1cc(F)c2ccnnc2c1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A solution of 1-[5-fluoro-8-(3-fluorophenyl)cinnolin-7-yl]ethanamine (73 mg, 0.26 mmol) [from peak 1 of Examples 20 and 21, step B] and 2-amino-6-bromopurine (82 mg, 0.38 mmol) in 1-butanol (0.51 mL, 5.6 mmol) was treated with N,N-diisopropylethylamine (67 μL, 0.38 mmol), degassed with nitrogen for 5 minutes and stirred at 120° C. for 18 hours. The reaction mixture was diluted with methanol (10 mL), stirred and filtered. The filtrate was purified first by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/minute) and then by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/minute) to give the desired product in 26%. LCMS for C21H17F2N8 (M+H)+: m/z=419.2; Found: 418.9. 1H NMR (300 MHz, DMSO-d6): δ 12.1 (br s, 1H), 9.44 (d, J=5.9 Hz, 1H), 8.25-8.22 (m, 1H), 8.13-8.01 (m, 1H), 7.94-7.83 (m, 1H), 7.72-7.53 (m, 3H), 7.40-7.29 (m, 1H), 7.28-7.22 (m, 1H), 5.45-5.21 (m, 3H), 1.42-1.38 (m, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][C:18]([C:27]2[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=2)=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:12]=1.C1C(=O)N([Br:50])C(=O)C1.O>CN(C=O)C>[Br:50][C:20]1[C:21]2[C:26]3=[C:25]4[C:24](=[CH:23][CH:22]=2)[C:11]([C:2]2[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=2)=[CH:12][C:13]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:14]4[CH:15]=[CH:16][C:17]3=[C:18]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:19]=1
Reactant: c1ccc(-c2cc(-c3ccc4ccccc4c3)c3ccc4ccc(-c5ccc6ccccc6c5)c5ccc2c3c45)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc(-c2ccc3ccccc3c2)c2ccc3c(-c4ccccc4)cc(-c4ccc5ccccc5c4)c4ccc1c2c34

Procedure:
5.4 g of 1,6-dinaphthalene-2-yl-3-phenylpyrene was dispersed into 60 ml of DMF, and 1.9 g NBS in DMF solution was dropped therein at room temperature. After 3 days reaction, 150 ml of water was added to it and the deposited crystal was filtrated, followed by water and ethanol washing of the crystal.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([O-:10])=O)([O-:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>N1C=CC=CC=1.C1COCC1>[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:10])([O-:4])=[O:3]
Reactant: NCCCCCC(=O)OCc1ccccc1
Reactant: O=C([O-])c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(CCCCCNC(=O)c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1)OCc1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
14.6 g of 3-nitro-5-sulfobenzoic acid monosodium salt were dissolved in 300 ml of pyridine and stirred for 2 hours, after which 2.2 ml of oxalyl chloride were added dropwise. After 1 hour, 16.6 g of benzyl ε-aminocaproate as a solution in 100 ml of THF were added dropwise and the mixture was stirred overnight. The mixture was concentrated on a rotary evaporator and then stirred with 100 g of strongly acid ion exchanger in 100 ml water for 50 hours. The mixture was filtered and washed with water, and the filtrate was concentrated. The residue was dissolved in 30% methanol/water, treated with 21 g of tetraethylammonium bromide and adjusted to pH 6.5 with sodium hydroxide solution. The resulting solution was chromatographed on 500 g of silanized silica gel (RP2) with 30% methanol. 8.6 g of benzyl ε-(3-nitro-5-sulfobenzoylamino)caproate were obtained in the form of the tetraethylammonium salt, which was stirred with 100 g of cation exchanger in water, filtered off and washed with water. The filtrate was concentrated and gave the corresponding free sulfonic acid. TLC (silica gel: HOAc/EtOAc=20%) Rf=0.7 (educt=0.4); TLC (silica gel: NH3/EtOH=1%) Rf=0.8 (educt=0.7); TLC (RP18: EtOH/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=60% Rf=0.4 (educt=0.8). HPLC (RP18: MeCN/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=30%) tR =5.9 min. (educt=1.3 min). 1.32 g of benzyl 6-(3-nitro-5-sulfobenzoylamino)hexanoate were dissolved in 30 ml ethanol/water=60%, 100 mg of Pd/C 10% were added and the mixture was hydrogenated while stirring (magnetic stirrer). The total absorption of hydrogen (1.5 hours) was 235 ml. TLC control showed that starting material was no longer present. In the TLC the amine is present practically at the start. The catalyst was filtered off and the solution was concentrated to dryness on a rotary evaporator. The IR control of the substance showed the complete absence of the original nitro group and of the benzyl group. The resulting 6-(3-amino-5-sulfobenzoylamino)hexanoic acid was used directly for the preparation of the azide.
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[CH:10][CH:9]=1)=[O:5])[CH3:2].[N:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>C(OCC)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:17]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(CCBr)cc1
Reactant: C1CN2CCCN2C1
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(CCN2CCCNCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.2 %

Procedure:
To a solution of 2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl bromide (2.10 g) in diethyl ether (20 ml) was added 1,5-diazabicyclo[3,3,0]octane (0.89 g), and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. To a solution of the residue in ethanol (30 ml) was added a 10% palladium on activated carbon (0.44 g), and the mixture was stirred at room temperature for 5 hours under an atmosphere of hydrogen. The catalyst was removed by filtration through a celite column, and the filtrate was concentrated under reduced pressure. The residue was quenched with an aqueous 1N-NaOH solution (20 ml), and the mixture was extracted with methylene chloride (30 ml). The extract was dried over anhydrous MgSO4, and concentrated to dryness under reduced pressure to give 1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (2.46 g) as a colorless oily liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>Cl(O)(=O)(=O)=O>[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:1]=[C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:17]=1[NH:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: O=Cc1ccc[nH]1
Reactant: Nc1ncccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc[nH]2)nc2ncccn12

Procedure:
Compound (19) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, MC), 0.500 ml pyrrole-2-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=O.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1/[CH:11]=[CH:21]/[CH:22]=[O:23]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cnc2ccccc2n1
Product: O=C/C=C/c1cnc2ccccc2n1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 2-quinoxalinecarboxaldehyde (prepared as described in J. Chem. Soc. 1956, 2052) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 185 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C@@H:12]2[O:14][CH2:13]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].N(C[C@@H](C1C=CC([N+]([O-])=O)=CC=1)O)=[N+]=[N-]>C1N(CCCS(O)(=O)=O)CCOC1.C(OCC)C>[N:1]([CH:12]([C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=1)[CH2:13][OH:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc([C@H]2CO2)cc1
Agent: O=S(=O)(O)CCCN1CCOCC1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CCOCC
Product: [N-]=[N+]=NC(CO)c1ccc([N+](=O)[O-])cc1

Procedure:
To 60 ml of MOPS buffer (50 mM, pH=7.0), 0.47 gram (3.2 mmol) of racemic para-nitro styrene oxide was added and the suspension was stirred for 60 min. The halohydrin dehalogenase, obtained as described in Example 1, (29 mg in 6 ml buffer) was added. A prepared stock solution of 0.12 gram (1.6 mmol) NaN3 in 5 ml MOPS buffer was slowly added over a period of 24 hours. The reaction was stopped and the suspension was three times extracted with diethylether. After separating, the organic phase was dried with MgSO4, and removed by rotary evaporator yielding an orange oil. This mixture was redissolved in diethylether and the composition and e.e. of the products were determined by chiral HPLC. The mixture mainly consisted of (S)-para-nitro styrene oxide in 46% yield (98% e.e.) and (R)-2-azido-1-(para-nitrophenyl)ethanol in 47% yield (97% e.e.). The chemical side product 2-azido-2-(para-nitrophenyl)ethanol was formed to a total of 4% of the reaction mixture. The product of chemical hydrolysis of the epoxide, para-nitrophenyl ethanediol was formed in 3%. All the mentioned yields are calculated yields. Flash chromatography on silica 60H using heptane/ethylacetate (ratio 7:3) as eluent yielded pure epoxide and azido alcohols. The NMR data were identical with synthesized racemic reference compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1>>[F:30][C:24]1[CH:23]=[C:22]([N:17]2[CH2:18][CH2:19][N:14]([C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[C:11]4[O:10][CH:9]([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:13])[CH2:15][CH2:16]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: COc1ccc(Br)cc1F
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1F
Yield: 38.6 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 4-bromo-2-fluoro-1-methoxybenzene (720 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 309 mg (yield 39%). Melting point was 120 to 122° C. (ethanol-water).
Reaction SMILES: [CH:1]1[C:14]2NC3C(=CC=CC=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(S[CH:22]([OH:24])[CH3:23])C=CC=CC=1>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[C:5]1([SH:6])[CH:14]=[CH:1][CH:2]=[CH:3][CH:4]=1.[CH2:22]1[O:24][CH2:23]1
Reactant: CC(O)Sc1ccccc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C1CO1
Product: Sc1ccccc1

Procedure:
One mole of phenothiazine is placed in a one liter, round bottom flask with 300 ml of toluene. The reaction is maintained under a nitrogen blanket. To the mixture of the phenothiazine and toluene is added 0.05 mole of sulfuric acid as a catalyst. The mixture is then heated to reflux temperature and 1.1 moles of phenylthioethanol is added dropwise over a period of approximately 90 minutes. The phenylthiothethanol is obtained from the reaction of thiophenol and ethylene oxide with a basic catalyst. Water is continuously removed as it is formed in the reaction process.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([C:9]([CH3:19])=[C:10]3[C:15]=1[CH:14]=[C:13](C(=O)C)[CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl([O-])(=O)(=O)=[O:21].[Na+].Cl.[O:27]1[CH2:32]COCC1>>[CH3:1][C:2]1[C:3]2[C:8]([C:9]([CH3:19])=[C:10]3[C:15]=1[CH:14]=[C:13]([C:32]([OH:27])=[O:21])[CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: C1COCCO1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CC(=O)c1ccc2c(C)c3ccccc3c(C)c2c1
Agent: Cl
Agent: [Na+]
Product: Cc1c2ccccc2c(C)c2cc(C(=O)O)ccc12
Temperature: 85 °C
Reaction time: 8 h

Procedure:
9,10-Dimethyl-2-acetylanthracene (1.2 g) was dissolved in dioxane (24 mL). An aqueous solution of sodium perchlorate (10 mL; effective chlorine concentration: 10 wt %) was then added, followed by reaction under stirring at 85° C. for 8 hours. The reaction mixture was chilled, and then rendered acidic with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed with a small amount of water, and then dried in vacuo to afford the target compound (1.16 g).
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:33]=4[N:34]=3)=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:40])=[O:5]
Reactant: Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.2 %

Procedure:
To (S)-3-methyl-2-{4′-[(4-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester (135 mg) was added 4 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 140 mg of (S)-3-methyl-2-{4′-[(4-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.4 (d, J=8.3 Hz, 1 H) 7.5 (m, 1 H) 7.7 (d, J=8.3 Hz, 1 H) 7.8 (m, 6 H) 8.1 (t, J=8.8 Hz, 3 H) 11.3 (s, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][N:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
0.62 g (25.88 mmol) of sodium hydride was added in portions at 60° C. to a suspension of 3.9 g (23.5 mmol) of 3-methylxanthine in 85 ml of dimethylformamide, and the mixture was stirred at this temperature for 1.5 hours and heated to 90° C. 6.6 g (23.67 mmol) of trityl chloride in 30 ml of dimethylformamide were then added and the mixture was stirred at 90° C. for 3 hours. The solid was then filtered off hot with suction and the filtrate was concentrated under reduced pressure, the residue was taken up in 1 N sodium hydroxide solution, the mixture was heated to 80° C. and the solid was filtered off with suction. The filtrate was brought to pH 4-5 using 2 N hydrochloric acid. The precipitate formed in this way was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.2). Yield:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N+:32]([O-])=[C:31]([CH3:36])[CH:30]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH2:37]([OH:39])[CH3:38].ClCCl.C(=O)(O)[O-:44].[Na+]>C(OC(=O)C)(=O)C>[ClH:1].[C:37]([O:44][CH2:36][C:31]1[CH:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]([N:18]3[CH2:17][CH2:16][N:15]([S:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[CH:8]=4)(=[O:14])=[O:13])[CH2:20][CH2:19]3)=[O:22])=[CH:28][CH:27]=2)[CH:34]=[CH:33][N:32]=1)(=[O:39])[CH3:38]
Reactant: Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cc[n+]1[O-]
Reactant: CCO
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)ccn1
Product: Cl
Yield: 87 %

Procedure:
In acetic anhydride (25 ml), 4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-2-methylpyridine N-oxide (900 mg) was dissolved, followed by heating under reflux for 15 minutes. Ethanol (25 ml) was added to the reaction mixture and the resulting mixture was heated under reflux for further 1 hour. To the reaction mixture, dichloromethane and an aqueous solution of sodium bicarbonate were added to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate and 775 concentrated under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (dichloromethane˜1.5% methanol—dichloromethane), followed by crystallization from ethanol. The crystals were dissolved in dichloromethane and the resulting solution was made acidic by the addition of hydrochloric acid in ethanol. The resulting acidic mixture was concentrated, whereby the title compound (842 mg, 87%, pale yellow powder) was obtained.
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:16]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:15]=[CH2:14]
Reactant: OC1(c2ccccc2)CCCCO1
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC1(c2ccccc2)CCCCO1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-phenyltetrahydro-2H-pyran-2-ol (1.066 g, 5.98 mmol) and allyltrimethylsilane (1.901 mL, 11.96 mmol) in CH2Cl2 (25 mL) at 0° C. was added BF3.OEt2 (0.758 mL, 5.98 mmol) dropwise, and the mixture was stirred at the same temperature for 1 hr. Then the reaction was quenched with saturated NaHCO3 and the product was extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with 1:9 followed by 4:6 EtOAc-hexane to give 2-allyl-2-phenyltetrahydro-2H-pyran as oil (0.954 g). 1H NMR (400 MHz, CCl3D) δ ppm 7.10-7.45 (5H, m), 5.47-5.65 (1H, m, J=17.19, 10.11, 7.33, 7.33 Hz), 4.84-5.00 (2H, m), 3.64-3.78 (1H, m), 3.41-3.57 (1H, m), 2.35-2.48 (1H, m), 2.20-2.35 (1H, m), 1.55-1.81 (4H, m), 1.35-1.54 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]#[CH:15])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:16]=O.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl.[OH-].[Na+]>O1CCOCC1.CCOCC.O>[ClH:1].[CH:20]1([N:19]([CH2:16][C:15]#[C:14][C:4]2[CH:5]=[CH:6][C:7]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[C:2]([Cl:1])[CH:3]=2)[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNC1CCCCC1
Reactant: C#Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CN(CC#Cc1ccc(C2CCCCC2)c(Cl)c1)C1CCCCC1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A solution containing 16.4 g of 3-chloro-4-cyclohexyl-1-ethynylbenzene, prepared above, in 30 ml of dioxane, 4.5 g of paraformaldehyde and 0.15 g of cuprous chloride is heated to 60° C. and 9.3 g of N-methyl-N-cyclohexylamine are then added over half an hour. The temperature is kept at 60° C. for 1 hour. When the reaction is complete, the cooled mixture is diluted with ether and treated with water and then with a dilute solution of hydrochloric acid. The acid solution is then rendered alkaline with a dilute solution of sodium hydroxide and extracted with ether. The organic phase is dried over sodium sulfate and then concentrated. The hydrochloride is prepared from the crude base, washed with water and then crystallized twice from acetonitrile to give 8.4 g of the expected compound.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][S:9]([O:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature (r.t.) to a solution of cyclopentanemethanol (0.2 g, 2 mmol, Aldrich, Cat. No. 103985) in methylene chloride (5 mL, 80 mmol) was added methanesulfonyl chloride (180 uL, 2.4 mmol), followed by triethylamine (330 uL, 2.4 mmol), and 4-dimethylaminopyridine (24 mg, 0.20 mmol). The mixture was stirred at r.t. overnight. It was diluted with methylene chloride, washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.39 g of the product which was directly used in the next step reaction without further purification.