Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@H:13]([CH2:15][C@H:16]([S:18][CH3:19])[CH3:17])[NH:12][CH2:11][C@@H:10]2[O:20][CH:21]([C:32]2[CH:33]=[CH:34][C:35]3[O:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:36]=3[CH:46]=2)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1.[Na]>C(COC)OC.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@H:13]([CH2:15][C@H:16]([S:18][CH3:19])[CH3:17])[NH:12][CH2:11][C@@H:10]2[O:20][CH2:21][C:32]2[CH:33]=[CH:34][C:35]3[O:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:36]=3[CH:46]=2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@@H](C[C@@H](C)SC)C[C@@H]3c3ccc(OC)cc3)S(=O)(=O)c3ccc(C)cc3)cc21
Agent: [Na]
Solvent: O
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN[C@@H](C[C@@H](C)SC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 92 mg of 6-[(3R,4R,6R)-4-(4-methoxy-phenyl)-6-((R)-2-methylsulfanyl-propyl)-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine (diastereomer 1) in 2.0 ml of dimethoxyethane are added 100 mg of naphthalene and 20 mg of sodium. The reaction mixture is sonicated for 10 minutes, diluted with water and extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound.
Reaction SMILES: Cl.C(O)C.COC[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[C:10]=1[CH3:36].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[C:10]=1[CH3:36]
Reactant: COCOc1c(C)c(N2CCN(c3ccc(OC)cc3)CC2)c(C)c2c1OC(C)(C)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
Concentrated hydrochloric acid (0.1 mL) was added to a solution of ethanol (16 mL) containing 7-(methoxymethoxy)-5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (800 mg, 1.82 mmol) synthesized in Reference Example 72 and the mixture was stirred under heated reflux for 24 hours. After that, concentrated hydrochloric acid (0.1 mL) was further added thereto, and the mixture was stirred under heated reflux for 24 hours. The reaction solution was cooled to room temperature and poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was crystallized using ethyl acetate and hexane to give 630 mg of the title compound (yield: 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=O)[CH2:6][CH2:5]2.[H-].COCCO[Al+]OCCOC.[Na+].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([OH:13])[CH:7]([CH2:14][CH2:15][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C)C(=O)C(CC(=O)N1CCCC1)CC2
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C)C(O)C(CCN1CCCC1)CC2
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 1-[(1,2,3,4-tetrahydro-6,7-dimethyl-1-oxo-2-naphthalenyl)acetyl]pyrrolidine (9.5 g) in toluene (100 ml) was added dropwise with stirring a 70% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (29.0 g) under ice-cooling, and the mixture was stirred at the same temperature for one hour, and stirred at 25° C. for three hours. The reaction mixture was cooled again with ice, and thereto was added dropwise a saturated aqueous sodium potassium tartrate solution (30 ml), and the mixture was stirred at the same temperature for 30 minutes in order to decompose the excess amount of the reducing agent. The organic layer was separated, washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (8.5 g) as an oily product.
Reaction SMILES: ClC(OC(Cl)=O)C.COC1C=C(OC)C=CC=1C[N:13]1[CH2:26][CH:25]([CH3:27])[N:16]2[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@@H:15]2[CH2:14]1.C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:27][CH:25]1[N:16]2[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@@H:15]2[CH2:14][NH:13][CH2:26]1
Reactant: COc1ccc(CN2CC(C)N3Cc4ccccc4C[C@@H]3C2)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CNC[C@H]2Cc3ccccc3CN12
Temperature: 0 °C
Yield: 56 %

Procedure:
1-Chloroethylchloroformate (0.050 ml, 0.47 mmol) was added to a solution of (11aR)-2,3,4,6, 11,11a-hexahydro-2-(2,4-dimethoxybenzyl)-4-methyl-1H-pyrazino[1,2-b]isoquinoline (53 mg, 0.15 mmol) in 1,2-dichloroethane (1 ml) stirring at 0° C. The ice bath was removed and the reaction stirred at ambient temperature for 30 min. After refluxing an additional 2 h, the reaction was evaporated in vacuo. Methanol (1.0 ml) was added to the residue and the reaction refluxed under nitrogen for 1 h. Evaporation in vacuo afforded 75 mg of crude product. This crude product was transferred to a separatory funnel with CH2Cl2 and saturated NaHCO3. Extraction with CH2Cl2 (2×) and drying of the combined organic layers over MgSO4 afforded 42 mg which was further purified by flash chromatography (SiO2, 0.2 to 10% 2N NH3 in MeOH/CH2Cl2) to give pure product (17 mg, 55%). MS (ESI) 203 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@H:54]2[NH:58][CH2:57][C@H:56]([OH:59])[CH2:55]2)[CH2:51][CH2:50]1>CN(C=O)C.C(Cl)Cl>[CH:49]1([NH:52][CH2:53][C@@H:54]2[CH2:55][C@@H:56]([OH:59])[CH2:57][N:58]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: O[C@H]1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
To a mixture of {5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (238 mg, 0.46 mmol), HOBt (69 mg, 1.2 eq.) and EDC (105 mg, 1.2 eq.) in DMF (8 mL) was added TEA (69 mg, 2.5 eq.) and (3R,5S)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.). After stirring at rt for 1 day, the reaction was diluted with DCM (200 mL), washed with ammonium chloride solution, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 52 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:28][CH:29]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: N12CCCCC1C=NCCC2.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:27]([O:30][C:31]([C@@H:33]1[C:39](=O)[CH2:38][C@H:37]2[N:34]1[C:35](=[O:51])[C@H:36]2[C@H:41]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:42][O:43][SiH:44]([CH3:46])[CH3:45])=[O:32])[CH:28]=[CH2:29].C(N(C(C)C)C(C)C)C.[SH:61][C:62]1[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[N:65]1[CH:66]=[CH:67][C:62]([S:61][C:39]2[CH2:38][C@@H:37]3[C@H:36]([C@H:41]([C:47]([CH3:50])([CH3:48])[CH3:49])[CH2:42][O:43][SiH:44]([CH3:46])[CH3:45])[C:35](=[O:51])[N:34]3[C:33]=2[C:31]([O:30][CH2:27][CH:28]=[CH2:29])=[O:32])=[CH:63][CH:64]=1
Reactant: Sc1ccncc1
Reactant: C=CCOC(=O)[C@@H]1C(=O)C[C@@H]2[C@H]([C@@H](CO[SiH](C)C)C(C)(C)C)C(=O)N12
Agent: C1=NCCCN2CCCCC12
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(Sc2ccncc2)C[C@@H]2[C@H]([C@@H](CO[SiH](C)C)C(C)(C)C)C(=O)N12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
1.94 ml (13 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) and, after 20 minutes, 2.2 ml (13 mmol) of trifluoromethanesulphonic anhydride were added dropwise to a solution, which had been cooled to -78° C., of 3.68 g (10 mmol) of (2S,5R,6S)-2-allyloxycarbonyl-3,7-dioxo-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]-1-azabicyclo[3.2.0]heptane in 100 ml of anhydrous THF. The mixture was then stirred at -78° C. for 30 minutes and the solution was concentrated in vacuo to about 40 ml without the temperature rising above -20° C. Then, successively 20 ml of DMF, 2.1 ml (12 mmol) of ethyl diisopropylamine and 1.33 g (12 mmol) of 4-mercaptopyridine were added and the mixture was stirred at -20° C. for 1 h. The mixture was then diluted with ethyl acetate and poured into cold, saturated NaHCO3 solution. Extraction was carried out with ethyl acetate, followed by washing with saturated NaCl solution and drying with MgSO4. After evaporation of the solvent in vacuo and chromatography of the residue on 600 g of silica gel (toluene:ethyl acetate), 3.1 g (66%) of the title compound were obtained as a viscous oil, Rf: 0.30 (toluene:ethyl acetate 7:3).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:17]3[N:16]([C:17]4[CH2:18][CH2:19][CH2:20][N:16]=4)[CH2:20][CH2:19][CH:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: Clc1cccc2c1Sc1ccccc1N2
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc2c1Sc1ccccc1N2C1=CCCN1C1=NCCC1
Yield: 17.1 %

Procedure:
A solution of 4-chlorophenothiazine (32.3 g., 0.134 mole) and 2-pyrrolidinone (23 g., 0.27 mole) in 125 ml. of 1,2-dichloroethane is added dropwise to a solution of phosphorus oxychloride (20.5 g., 0.134 mole) in 50 ml. of 1,2-dichloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provides 7.5 g., (17.1% yield) of 4-CHLORO-10-[1-(1-PYRROLIN-2YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE free base, m.p. 195°-197° C. Analytically pure 4-CHLORO-10-[1(1-PYRROLIN-2-YL)-2PYRROLIN-2-YL]PHENOTHIAZINE HYDROCHLORIDE obtained by crystallization from ethanol-ether has a melting point of 232°-234° C. (corr.). Analysis. Calcd. for C20H18ClN3S.HCl (percent): C, 59.41; H, 4.74; N, 10.39; Cl, 17.53. Found (percent): C, 59.20; H, 4.74; N, 10.59; Cl, 17.46.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[C:18]2[C:14]=1[CH2:15][C:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17]2.C(N(CC)CC)C>C1COCC1.O>[CH3:27][O:26][C:19]1[C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:13]([O:12][CH3:11])=[C:14]2[C:18]=1[CH2:17][C:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[O:42])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:15]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)(c1ccccc1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC=O)(c1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of oxalyl chloride (0.394 ml) in THF (36 ml) was dropwise added a solution of dimethylsulfoxide (468 mg) in THF (2.4 ml) at −70° C. or under nitrogen atmosphere. After the reaction mixture was stirred for 10 min, a solution of 8-(4,5,6,7-tetramethoxy-2-phenylindan-2-yl)octanol (1.00 g) in THF (12 ml) was dropwise added to the reaction mixture at −70° C. or under. After being stirred for 15 min, the reaction mixture was stirred at between −60° C. and −50° C. for 1 hr, to which triethylamine (2.30 ml) was dropwise added. The reaction mixture was allowed to warm to 0° C. and stirred for 20 min, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=4:1) to yield the entitled compound (985 mg) as an oil.
Reaction SMILES: C1(C)C(S(O[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=O)=O)=CC=CC=1.[F-:26].[Cs+].C(O)(CC)(C)C.C(OCC)C>CCCCCC.C(OCC)(=O)C>[F:26][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: Cc1ccccc1S(=O)(=O)OCCCOc1ccc2ccccc2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCC(C)(C)O
Product: FCCCOc1ccc2ccccc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
356 mg (1.0 mmol) of 2-(3-toluenesulfonyloxypropoxy)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to 4.0 mL of t-amyl alcohol in a reaction vessel. The reaction mixture is stirred for 2 hrs at 90° C. 7 mL of ethyl ether is added to remove metal salt. After filtration, the filtrate is concentrated by a reduced pressure distiller. 190 mg (93% yield) of 2-(3-fluoropropoxy)naphthalene is obtained by column chromatography (ethyl acetate:n-hexane=1:20).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24]CCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCC1CC[N:67]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:66][CH2:65]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:19][CH2:24][N:67]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:66][CH2:65]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 11 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetic acid salt (for example, as prepared for Intermediate 6) and phenylmethyl 4-(2-bromoethyl)-1-piperidinecarboxylate (for a preparation, see J. Med. Chem., 2003, 46(13), 2606).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH:21]1[CH2:24]C[O:22]1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(OCC)C.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:24][CH:21]([OH:22])[CH2:20][O:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: C1CCC(OCC2CCO2)OC1
Reactant: Brc1ccccn1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(COC1CCCCO1)Cc1ccccn1
Reaction time: 0.08 h
Yield: 27.6 %

Procedure:
2-Bromopyridine (9.48 g) was dissolved in diethyl ether (100 ml). To the solution was added dropwise, at −70° C., n-butyl lithium (a 1.6M hexane solution, 37.5 ml). The mixture was stirred for 5 minutes at the same temperature. To the reaction mixture was added a solution of 2-(2-tetrahydropyranyloxymethyl)oxetane (3.13 g) in diethyl ether (10 ml). To the mixture was added boron trifluoride ethyl etherate (7.6 ml), followed by stirring for 20 minutes at the same temperature. To the reaction mixture was added an aqueous solution of sodium hydrogencarbonate (60 ml), followed by extraction with ethyl acetate four times. The organic layer was dried over anhydrous sodium sulfate, which was then concentrated. The concentrate was purified by means of a column chromatography (carrier: silica gel, 200 g, developing solvent: ethyl acetate-hexane, 4:1) to give the title compound (1.19 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[NH:4][N:3]=1.S(Cl)([Cl:13])(=O)=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:13][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[N+:7]([O-:9])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])[nH]n1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1n[nH]c([N+](=O)[O-])c1Cl
Temperature: 115 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
Nitropyrazole 9 (10.0 g, 78.68 mmol) was dissolved in a mixture of chloroform (500 mL) with 1 drop DMF. To this was added sulfuryl chloride (9.60 mL, 14.33 g, 118.0 mmol) and the mixture heated to reflux for 20 hour at 115° C. external temperature. After additional 48 hours stirring at ambient temperature the mixture was evaporated to dryness in vacuo, dichloromethane (250 mL) added and the solution again evaporated in vacuo. Crude 15 was purified by column chromatography (1 kg SiO2, 0-10% methanol in DCM) yielding pure 15 (11.7 g, 72.42 mmol, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)[C:41]([CH2:57][CH3:58])=[N:40]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:45]3[CH:46]=[C:47]4[C:42]([C:41]([CH2:57][CH3:58])=[N:40][NH:39]4)=[CH:43][CH:44]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CCc1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCc1n[nH]c2cc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 14.5 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), N-Boc-3-ethyl-6-indazoleboronic acid pinacol ester 103 (0.423 g, 1.137 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.060 g, 15% yield). MP: 270-273° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.08(s,1H), 8.05(dd, J=7.9,1.4 Hz, 1H),7.88(m, 2H), 7.68(d, J=8.4 Hz, 1H),7.63(s,1H), 7.53(d, J=7.2 Hz, 1H),7.33(d, J=8.3 Hz, 1H),7.29(br s,1H), 7.07(dt, J=8.9,1.4 Hz, 1H), 6.95(br s,2H), 6.07(q, J=6.9 Hz, 1H),2.98(q, J=7.5 Hz, 2H),1.92(d, J=7.1 Hz, 3H),1.34(t, J=7.6 Hz, 3H), Mass: 546.04(M+).
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][OH:14].C(N(CC)CC)C.[CH3:22][O:23][C:24]([CH2:26][CH2:27][C:28](O)=[O:29])=[O:25].OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:14][N:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])[C:28](=[O:29])[CH2:27][CH2:26][C:24]([O:23][CH3:22])=[O:25]
Reactant: COC(=O)CCC(=O)O
Reactant: ONc1ccc2ccccc2c1O
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)N(O)c1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a 1.68 g (ca. 7.9 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride in THF (10 ml) and water (2 ml) was added, 1.7 ml (12 mmol) of triethylamine, followed by addition of a solution of 300 mg (2 mmol) of acid chloride of 3-methoxycarbonylpropionic acid in THF (2 ml). The mixture was stirred at room temperature for 30 minutes, the reaction was completed by an addition of aqueous KHSO4, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH:8](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2/[CH:19]=[CH:18]/[CH:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)Cc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(C#N)cc1
Yield: 92.2 %

Procedure:
A solution of 1.75 g (4.64 mmol) of ethyl E-6-(4-cyanobenzyl)-8-(2-hydroxyphenyl)oct-7-enoate from Example 112A in 50 ml of dry acetonitrile is mixed with 1579 mg (6.95 mmol) of 4-(tert-butyl)benzyl bromide and 961 mg (6.95 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→4:1). 2.24 g (4.28 mmol, 92% yield) of a solid are obtained.