Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(F)ccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccc(F)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
The crude methyl 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 1) was dissolved in a solution THF: MeOH (1:1) (0.02 M) and to that solution 7 eq of an aqueous solution of NaOH (1N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (12%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=2)=[CH:8][CH:7]=1.[CH2:20]([Mg]Br)[CH3:21].C(OCC)C.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:19])[CH2:20][CH3:21])=[N:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COCOCc1ccc(-c2ccc(C=O)nc2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC(O)c1ccc(-c2ccc(COCOC)cc2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 5-(4-((methoxymethoxy)methyl)phenyl)picolinaldehyde (0.36 g, 1.4 mmol) in THF (15 mL) at 0° C. was slowly added 3.0-M ethyl magnesium bromide in diethyl ether (1.4 mL, 4.2 mmol) was added. The reaction mixture was stirred at 0° C. for 3 h. After completion of the reaction by monitoring with TLC (50% EtOAc\hexane), the reaction mixture was quenched with sat'd. NH4Cl (50 mL) solution. The reaction mixture was extracted with EtOAc (3×50 mL), washed with water (2×50 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by a Biotage Isolera® One column purifier (silica gel 230-400μ) using 33% ethyl acetate in hexane and the product isolated as a yellow solid (0.15 g, 37% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (d, 1H), 8.04 (dd, 1H), 7.69 (d, 2H), 7.53 (d, 1H), 7.44 (d, 2H), 4.66 (s, 2H), 4.57 (s, 2H), 3.30 (s, 3H), 1.79 (m, 1H), 1.65 (m, 1H), 0.862 (t, 3H); LC-MS: m/z 288.5 [M+H]+.
Reaction SMILES: NC1C=C([C:8]2C3C(=CC(OC)=C(OC)C=3)N=[C:10](CN)[N:9]=2)C=CC=1.Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[C:32]([NH:39][CH3:40])[N:31]=[C:30]2[C:41]1[CH:42]=[C:43]([NH:47][C:48](=[O:58])[C:49]2[CH:57]=[CH:56][C:52]([C:53]([OH:55])=O)=[CH:51][CH:50]=2)[CH:44]=[CH:45][CH:46]=1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[C:32]([NH:39][CH3:40])[N:31]=[C:30]2[C:41]1[CH:42]=[C:43]([NH:47][C:48](=[O:58])[C:49]2[CH:57]=[CH:56][C:52]([C:53]([N:9]([CH3:10])[CH3:8])=[O:55])=[CH:51][CH:50]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)cc3)c2)c2cc(OC)c(OC)cc2n1
Reactant: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Agent: Cl
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)N(C)C)cc3)c2)c2cc(OC)c(OC)cc2n1

Procedure:
The following compounds of Examples 4 to 10 were synthesized by methods similar to Example 3, using the compound of Example 2 as a starting substance, and also using the corresponding alcohol or amine.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10](Cl)=[CH:11][C:12]=1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].CCO>COCCOC.[NH4+].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=2[CH3:16])[C:21]([OH:23])=[O:22])=[CH:11][C:12]=1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1sc(Cl)cc1C=O
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Temperature: 25 °C

Procedure:
A mixture of N-tert-butyl-5-chloro-3-formylthiophene-2-carboxamide (2.40 g, 9.77 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (3.07 g, 11.7 mmol), Pd(PPh3)2Cl2 (0.343 g, 0.488 mmol, Strem), and sodium carbonate (3.11 g, 29.3 mmol) in DME:EtOH:H2O=7:2:3 (36 ml) was heated to 80° C. for 8 hrs. After cooling to RT, the mixture was diluted with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered and concentrated over SiO2. Column chromatography (MeOH/CH2Cl2=0→2%) gave the desired product. Yield: 2.31 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se][N:8]=[C:4]2[C:3]=1[N+:11]([O-:13])=[O:12].[OH-].[Na+].[C:16]([O-])([O-])=[O:17].[Na+].[Na+]>Cl.I.OS([O-])(=O)=O.[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][C:16](=[O:17])[NH:8][C:4]=2[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c(Cl)ccc2n[se]nc12
Agent: Cl
Agent: I
Agent: O=S(=O)([O-])O
Product: O=c1[nH]c2ccc(Cl)c([N+](=O)[O-])c2[nH]1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-4-nitro-2,1,3-benzoselenadiazole from Step B (650 mg, 2.47 mmol) in conc. HCl (4 mL) and 48% aqueous HI (2 mL) was stirred at ambient temperature for 2 h. The reaction was diluted with a 1:1 saturated aqueous solution of NaHSO4 and Na2CO3 (20 mL) and then adjusted to pH 10 using 10 M aqueous NaOH. The mixture was extracted with EtOAc (3×10 mL) and the organic extracts dried over Na2SO4, filtered, and concentrated in vacuo. The resulting dark red solid was dissolved in CH3CN (4 mL) and phosgene was added (20% solution in toluene, 1.5 mL, 3.2 mmol). The reaction mixture was stirred for 1 h, then diluted with toluene. Filtration of the resultant solid gave the title compound. MS: m/z=214 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:7]2.[CH:52](=O)[CH3:53].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:52]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:7]2)[CH3:53]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cccc(N)c4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNc1cccc2c1C(=O)N(c1c[nH]c3ncc(-c4ccc(S(=O)(=O)C(C)C)cc4)nc13)C2
Reaction time: 48 h

Procedure:
7-amino-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (63 mg, 0.09133 mmol) dissolved in DCE (5 mL) and acetaldehyde (5.6 μL, 0.10 mmol) then Na(OAc)3BH (38.72 mg, 0.1827 mmol) added at RT under N2. Reaction mixture stirred for 48 h then quenched by the addition of water. DCM added and layers separated. Organic phase dried and concentrated. Residue taken up in DCM (2 mL) under N2 and treated with triethylsilane (73 μL, 0.4566 mmol) then TFA (300 μL). Reaction mixture stirred overnight then concentrated. Residue purified by hplc to give the title compound; 1H NMR (400 MHz, DMSO) δ 1.20-1.26 (9H, m), 3.50 (1H, partly obsc sep), 5.38 (2H, s), 6.64-6.68 (2H, m), 6.85 (1H, d), 7.42 (1H, d), 8.00 (2H, d), 8.44 (1H, d), 8.51 (2H, d), 9.08 (1H, s), 12.31 (1H, s) ppm; MS (ES+) 476.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.Br[CH2:35][F:36].[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:35][F:36])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: FCBr
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
0.76 g (2.0 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide and 8ml of anhydrous N,N-dimethylformamide were mixed and 0.5 ml of bromofluoromethane was added thereto at −15° C. 88 mg (2.2 mmol) of 60% sodium hydride was added and stirred at −15° C. for 30 minutes and then stirred at approximately 0° C. for 1.5 hours. Water was added to the reaction mixture, followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=1:1) to give 0.68 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide(the present compound 1103).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[CH3:6][N:7]([CH3:34])[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:34][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:4][CH2:3][O:2][CH3:1])=[CH:29][CH:30]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)cc1
Temperature: 25 °C

Procedure:
2-Bromoethyl methyl ether (0.033 ml) was added to a stirred suspension of N-(3-dimethylaminophenyl)-3-(4-hydroxybenzamido)4-methylbenzamide (0.9 g) and anhydrous potassium carbonate (0.064 g) in DMF (10 ml) and the resultant mixture was stirred at 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.073 g); NMR Spectrum: (DMSOd6) 2.28 (s, 3H), 2.87 (s, 6H), 3.31 (s, 3H), 3.67 (m, 2H), 4.18 (m, 2H), 6.43, (d, 1H) 7.12 (m, 5H), 7.37 (d, 1H), 7.78 (d, 1H), 7.97 (m, 3H), 9.87 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester, which was directly subjected to the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:20]1[CH:21]=[CH:22][C:23]([Cl:28])=[C:24]([O:26][CH3:27])[CH:25]=1.CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:28][C:23]1[CH:22]=[CH:21][C:20]([N:16]2[CH2:15][CH2:14][N:13]([C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:12])[CH2:18][CH2:17]2)=[CH:25][C:24]=1[O:26][CH3:27]
Reactant: COc1ccc([C@@H](C)N2CCNCC2)cc1OC
Reactant: COc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN([C@H](C)c3ccc(OC)c(OC)c3)CC2)ccc1Cl
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A quantity of 4.2 g (17 mmoles, 1 eq) of (R)-1-[1-(3,4-dimethoxy-phenyl)-ethyl]-piperazine and 4.4 g (20 mmoles, 1.2 eq) of 5-Bromo-2-chloro-anisole was dissolved in 110 mL of anhydrous toluene, and the solution is purged with N2 for 20 minutes. To the solution was added 0.33 g (0.5 mmoles, 0.03 eq) of rac-2,2′-Bis(diphenyl-phosphino)-1,1′-binapphtyl, 0.031 g (0.34 mmole, 0.02 eq) of tris(dibenzylideneacetone)-dipalladium(0) and 2.4 g (22 mmoles, 1.3 eq) of potassium tert-butoxide in order. The mixture was heated at 80° C. under N2 overnight. After cooled down, the reaction was filtered through Celite. The organic solution is washed with 1N NaOH and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel eluted with 1:1 ethyl acetate:hexanes to afford brownish oil. The product (compound 4) was converted to its HCl salt, giving yellowish solid (4.1 g, 53%). Mp: 172–6° C. Analysis: 1H NMR (300 MHz, DMSO): 11.8 (1H, s), 9.2 (1H, s), 7.48 (1H, s), 7.21(1H, d), 7.12 (1H, dd), 6.99 (1H, d), 6.68 (1h, d), 6.59 (1H, dd), 4.42 (1H, t), 3.80 (12H, m), 3.39 (1H, t), 3.19 (1H, t), 2.99 (3H, m), 1.73 (3H, d). MS (LC-MS): Calculated for C21H27ClN2O3 390.90. Found 391.38 (M+).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=CC=1)[CH3:2].N1CC[S:17]CC1.C1(C(Cl)=O)CCC1>>[CH:5]1([C:4]([N:3]2[CH2:1][CH2:2][S:17][CH2:13][CH2:12]2)=[O:11])[CH2:10][CH2:9][CH2:8]1
Reactant: C1CSCCN1
Reactant: CCN(CC)C(=O)c1ccccc1
Agent: O=C(Cl)C1CCC1
Product: O=C(C1CCC1)N1CCSCC1

Procedure:
The product of Example 42 was followed using thiomorpholine and cyclobutanecarbonyl chloride giving the desired product as a solid, mp 39°-40° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:12]=[C:11]2[N:21]([CH2:30][C:31]([OH:33])=[O:32])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=12.[CH2:34](OC(Cl)=O)[CH:35]([CH3:37])[CH3:36].[BH4-].[Na+]>C1COCC1.Cl>[Cl:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][N:12]=[C:11]2[N:21]([CH2:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[N:22]=[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10]=12
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 1 h
Yield: 6.2 %

Procedure:
Triethylamine (535 μL, 3.8 mmol) was added to 2-(4-chloro-3,5-diphenyl-1Hpyrazolo[3,4-c]pyridazin-1-yl)acetic acid (700 mg, 1.92 mmol) in THF (20 mL) at 0° C., followed by the addition of isobutylchloroformate (342 mg, 2.9 mmol). The reaction mixture was stirred for 1 h. Sodium borohydride (220 mg, 5.8 mmol) was then added portionwise and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with 0.5 M HCl and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried (phase separator), and concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate/isohexane 0:1 to 1:0), to provide Compound 12 as a solid (50 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:20]=[C:19]([C:21]#[N:22])[C:18]3[C:13](=[CH:14][C:15]([O:23]CC4C=CC=CC=4)=[CH:16][CH:17]=3)[CH:12]=2)=[N:8][C:7]=1[CH3:31])=[O:5])[CH3:2]>O1CCCC1.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:20]=[C:19]([C:21]#[N:22])[C:18]3[C:13](=[CH:14][C:15]([OH:23])=[CH:16][CH:17]=3)[CH:12]=2)=[N:8][C:7]=1[CH3:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2cc(C#N)c3ccc(OCc4ccccc4)cc3c2)nc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2cc(C#N)c3ccc(O)cc3c2)nc1C
Reaction time: 1.5 h
Yield: 31.4 %

Procedure:
To a suspension of 2-(7-benzyloxy-4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.27 g) in tetrahydrofuran (20 mL) was added palladium-carbon (100 mg) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours under a hydrogen atmosphere. The mixture was stirred at 50° C. overnight. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=95/5-40/60) to give 2-(4-cyano-7-hydroxynaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.067 g). The title compound (0.019 g) was prepared by deprotecting this compound (0.030 g) in a similar manner to that described in Example 47.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[CH2:18]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCCCc1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-hydroxypropyl)phenol (1.27 g) in MeCN (12.7 mL) were added K2CO3 (1.73 g) and benzyl bromide (1.05 mL) at ambient temperature and the mixture was stirred at 60° C. for 16 hours. Water (15 mL) was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc (20 mL, two times). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=3:1) to afford 3-[3-(benzyloxy)phenyl]-1-propanol (1.77 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17]O)([O-:3])=[O:2].C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:17][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl

Procedure:
To a round bottom flask equipped with a nitrogen inlet and a water cooled condenser, 2-nitro-5-phenoxy-phenyl-methanol (2.7 g, 11.1 mmol) and triethylamine (4.7 mL, 33.9 mmol) were dissolved in dichloromethane (100 mL). Methane sulfonyl chloride (2.6 mL, 33.3 mmol) was added to the reaction mixture which was subsequently heated to reflux for 16 h. The next day the reaction was removed from the heating source, allowed to cool and poured into a separatory funnel which contained a water solution of 1N HCl. The organic phase washed 2 times with 1N HCl and one time with saturated brine solution. The phases were separated and the ethyl acetate layer was dried with sodium sulfate, filtered and the solvent removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes:ethyl acetate as the mobile phase (9:1) to yield a residue.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]3[N:23]([CH3:24])[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])=[N:21][N:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(Cl)(=O)OC(Cl)C>C(Cl)Cl>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[N:23]([CH3:24])[C:19]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:20][N:21]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C1(C2CCN(Cc3ccccc3)CC2)CCCC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cn1c(-c2ccccc2Cl)nnc1C1(C2CCNCC2)CCCC1
Yield: 80.2 %

Procedure:
1-Benzyl-4-{1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclopentyl}piperidine (0.87 g) and 1-chloroethyl chlorocarbonate (0.24 ml) were reacted in methylene chloride (20 ml) at room temperature for 2.5 hours. The residue obtained by subjecting the reaction solution to evaporation under reduced pressure was heated and refluxed in methanol (20 ml). After concentration, dil. hydrochloric acid (30 ml) was added thereto and the whole washed with diethyl ether. After neutralization, the product was extracted with chloroform (20 ml×2) and the concentration residue was purified by silica gel column chromatography (methanol:chloroform=4:96) to obtain 4-{1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclopentyl}piperidine (0.553 g).
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH2:2]1.[Br:16]Br.O>C(O)(=O)C>[Br:16][CH:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12]3)[C:1]1=[O:15]
Reactant: O=C1CC=Cc2ncc3ccccc3c21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2c(ncc3ccccc23)C=CC1Br
Yield: 91.4 %

Procedure:
99.8 g (511 mmol) phenanthridinone was added to a 3 L multi-neck flask equipped with a stir arm and condenser. 1.2 L glacial acetic acid was added and the mixture was allowed to stir at 150 rpm and heated to reflux. 90 g (562 mmol) Br2 suspended in 100 ml acetic acid was added to the refluxing solution dropwise over a period of 3 hours. After addition, the mixture was assayed and revealed to be ˜80% complete. Based on this assay, an additional 20 g of Br2 (in 30 mL acetic acid) was added dropwise to the mixture at reflux. After this addition, the assay was >90% complete. A final 20 g Br2 (in 30 mL acetic acid) was added dropwise and the mixture allowed to stir for 1 hour after addition. The final assay was >97%. The mixture was cooled and 1 L of water was added and the mixture filtered. The wet solids were then stirred in aqueous sodium thiosulfate to destroy residual bromine and refiltered. These solids were rinsed with H2O and allowed to dry in vacuo to remove residual water. The solids were then recrystalllized from nitrobenzene (>2 liters) and collected on a funnel to give 128 g 2-bromophenanthridinone (90.8% yield).