Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([F:15])=[C:4]([F:16])[N:3]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[H-].[Na+]>O1CCCC1>[F:16][C:4]1[C:5]([F:15])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:7]([F:8])=[C:2]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: OCCN1CCOCC1
Reactant: Fc1nc(F)c(F)c(N2CCOCC2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Reaction time: 8 h
Yield: 95 %

Procedure:
4-(2,3,5,6-Tetrafluoro-pyridin-4-yl)-morpholine (2.36 g; 10 mmol) was dissolved in tetrahydrofuran (50 mL). To the solution was added 4-(2-hydroxyethyl)-morpholine (1.57 g; 12 mmol) followed by sodium hydride (288 mg; 12 mmol), and it was stirred overnight. The solvent was then evaporated, and the solid was purified by column chromatography to give 4-[2,3,5-trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine (3.3 g).
Reaction SMILES: [C:1]1([N:7]2[C:17](=[O:18])[CH:11]3[CH2:12][C:13](=O)[CH2:14][CH2:15][CH:10]3[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[C:24]([CH3:30])[CH:23]=1>>[C:1]1([N:7]2[C:17](=[O:18])[CH:11]3[CH:10]([CH2:15][CH2:14][C:13]4[NH:28][C:25]5[C:26]([C:12]=43)=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=5[CH3:30])[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC2C(=O)N(c3ccccc3)C(=O)C2C1
Reactant: COc1ccc(NN)c(C)c1
Agent: Cl
Product: COc1cc(C)c2[nH]c3c(c2c1)C1C(=O)N(c2ccccc2)C(=O)C1CC3

Procedure:
Using N-phenyl-4-oxocyclohexane-1,2-dicarboximide instead of the N-benzyl-4-oxocyclohexane-1,2-dicarboximide and using 4-methoxy-2-methylphenyl-hydrazine hydrochloride instead of the phenylhydrazine, the same procedure as in Reference Example 1 (1) was repeated, to obtain N-phenyl-6-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[N:6][C:7]=1[Cl:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 3-nitro-2,5,6-trichloropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59,190.) and 4-aminophenylethyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:11])[O:12][CH2:13][CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
3-Chloroaniline (2.510 g) was dissolved in pyridine (20 ml), and to the solution was added dropwise ethyl chloroformate (2.257 ml) under ice-cooling. After the mixture was stirred for 1 hour, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (3.9287 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:24][CH2:23][CH2:22][NH2:25])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Product: NCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
20 mg (0.063 mmol) of N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are stirred for 26 h at 110° with 1 ml of ethylenediamine. Concentration and chromatography (methylene chloride:methanol:conc. ammonia solution=80:20: 1) give N-(3-chloro-phenyl)-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine; Rf =0.15 (methylene chloride:methanol:conc. ammonia solution=80:20:1), FAB-MS: 341 (M+ +1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2].Br[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=[C:3]([CH2:1][CH3:2])[CH:12]=2)=[CH:16][CH:17]=1)#[N:28]
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cc(OCc2ccc(-c3ccccc3C#N)cc2)c2c(n1)CCCC2
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (40 mg) was added to a suspension of 4-[(2-ethyl-5,6,7,8-tetrahydroquinolin-4-yl)oxymethyl]-phenylboronic acid (200 mg) and 2-bromobenzonitrile (106 mg) in toluene (2 ml) ethanol (0.5 ml) and 2M aqueous sodium carbonate (0.58 ml). The mixture was degassed and placed under an atmosphere of argon, then heated under reflux for 12 hours. The resulting solution was cooled to ambient temperature, and dichloromethane (30 ml) and water (10 ml) were added. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (3:1 v/v), and the product triturated with ether/hexane to give 4-[(2'-cyanobiphenyl-4-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline (106 mg) as a white solid, m.p. 147°-148° C.; NMR (CDCl3): 1.29(t,3H), 1.7-1.95(m,4H), 5.17(s,2H), 6.57(s,1H), 7.4-7.7 (complex m,7 H), 7.78(d,1H); mass spectrum (+ve CI) 369 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[Br:21].N#N>O=[Pt]=O.CCO.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[Br:21]
Reactant: COC(=O)/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1Br
Agent: O=[Pt]=O
Agent: N#N
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of (E)-3-(4-benzenesulfonyl-2-bromo-phenyl)-acrylic acid methyl ester (8.52 g) in a mixture EtOH/THF (2/1, 150 mL) was added under N2 atmosphere PtO2 (0.45 g). A balloon filled with H2 was set up and N2 was replaced with H2, the reaction was then stirred for 4 h 30 min. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 85/15) affording 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionic acid methyl ester (6.73 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@H:13]3[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Compound 32 (0.76 g, 1.2 mmol) was deblocked in the same manner as described for 31 above using sodium methoxide (200 mg, 3.7 mmol) in dry MeOH (50 mL). The title compound (34) was obtained (0.12, 32%) after crystallization from water: mp 248°-250° C.: UV λmax (pH 1) 222 nm (ε 35100), 265 (14,300), 290 (11,400): UV λmax (pH 7, 11) 215 nm (ε 45000), 262 (13,200): 1H NMR (DMSO-d6) δ 5.91 (d, J=5.43 Hz, 1H, C1,H), 7.44 (b, 1H, NH2), 8.22 (s, 1H, C5H), and other sugar protons. Anal. Calcd. for C10H12N4O5S: C, 40.00: H, 4.03: N, 18.66: S, 10.68. Found: C, 39.80: H, 3.99: N, 18.39: S, 10.57.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=1.Cl[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>CN(C)C=O>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[CH:12]([C:13]#[N:14])[C:11]1[CH:15]=[CH:16][C:8]([F:7])=[CH:9][CH:10]=1)#[N:21]
Reactant: N#Cc1ccccc1Cl
Reactant: N#CCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(C#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 700 gr potassium tert-butoxide in 3.6 ltr N,N-dimethylformamide (DMF) is added gradually a solution of 401.4 gr 4-fluorobenzylcyanide and 429.2 gr 2-chlorobenzonitrile in 1.2 ltr DMF, maintaining an internal temperature between 25° C. and 30° C. (ice bath). The reaction mixture is subsequently stirred for one hour at ambient temperature and quenched with dilute hydrochloric acid. Extractive work-up with diethylether gives the product 2-cyano-4'-fluorobenzhydrylcyanide.
Reaction SMILES: CN1[C:11](=[O:12])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=2)[N:4]=C1.C[OH:27]>[OH-].[Na+]>[NH2:4][C:5]1[C:10]([C:11]([OH:27])=[O:12])=[N:9][C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)=[CH:7][N:6]=1
Reactant: CO
Reactant: Cn1cnc2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Yield: 34 %

Procedure:
Tert-butyl 4-(3-methyl-4-oxo-pteridin-6-yl)piperazine-1-carboxylate (25 g, 72.17 mmol) was stirred in NaOH (250 mL of 10% w/w,) and MeOH (250 mL) overnight at RT. The resulting suspension was concentrated and then acidified with formic acid followed by extraction of the aqueous with DCM. The mixture was treated with water, taken to pH 10 and filtered. The aqueous layer was reacidified and the resulting precipitated product was extracted into DCM and concentrated to give the product as a yellow solid (8 g, 24.74 mmol, 34% Yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](F)(F)F)[CH:15]=3)[N:10]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][NH:31][C:30]4=[O:34])[CH2:23][CH2:22]3)[CH:9]=2)=[CH:4][CH:3]=1.N1(CCN2CCC(N3C4C(=CC=CC=4)C(C4C=CC=CC=4)=C3C)CC2)CCN[C:36]1=O>>[CH3:36][C:9]1[N:10]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][NH:31][C:30]3=[O:34])[CH2:23][CH2:22]2)[C:11]2[C:16]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: O=C1NCCN1CCN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C(F)(F)F)ccc32)CC1
Reactant: Cc1c(-c2ccccc2)c2ccccc2n1C1CCN(CCN2CCNC2=O)CC1
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C1CCN(CCN2CCNC2=O)CC1

Procedure:
In a corresponding manner the following indole derivatives were prepared: 3-(4-Fluorophenyl)-1-[1-[2-(imidazolidin-2-on-1-yl)ethyl]-4-piperidyl]-5-trifluoromethyl-1H-indole 7b, mp 182°-186° C 1-[1-[2-(Imidazolidin-2-on-1-yl)ethyl]-4-piperidyl]-2-methyl-3-phenyl-1H-indole 7c, mp 179°-183° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[N:9]=[CH:10][N:11]=[C:12](O)[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:5]1[N:6]=[CH:7][C:8]2[N:9]=[CH:10][N:11]=[C:12]([Cl:18])[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ncc2ncnc(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1ncc2ncnc(Cl)c2n1
Reaction time: 0.17 h

Procedure:
6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol (210 mg, 1.03 mmol) was dissolved in phosphorous oxychloride (10 mL), and the mixture was heated at reflux for 4 hours. The solution was concentrated in-vacuo, then concentrated from methylene chloride (3×50 mL) to remove excess phosphorous oxychloride. The residue was stirred for 10 minutes in saturated sodium bicarbonate (50 mL), then extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (30 mL), followed by brine (30 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 50% ethyl acetate/heptane, to yield 150 mg of a white solid as product. NMR (500 MHz, CDCl3) δ 9.61 (s, 1H), 9.15 (S, 1H), 1.52 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]([F:36])([F:35])[C:4]1[CH:34]=[CH:33][C:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49](=[O:53])[C:50](Cl)=[O:51])[CH3:47]>C(Cl)Cl>[O:51]=[C:50]([N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:35])[F:36])=[CH:34][CH:33]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=2)=[CH:15][CH:16]=1)[C:49]([O:48][CH2:46][CH3:47])=[O:53]
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a cold (0° C.) solution of N-[4-(trifluoromethyl)benzyl]-N-[4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzyl]amine hydrochloride (45 mg, 0.09 mmol) and DIEA (24 mg, 0.19 mmol) in anhydrous DCM (1 mL) was added dropwise the chloro-oxo-acetic acid ethyl ester (24 mg, 0.19 mmol). The reaction mixture was stirred at 0° C. for 3 h. Evaporation of the solvents under vacuum gave an orange oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/9) to give the title compound as a colorless oil (38 mg, 75%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, J=8.3 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.39-7.21 (m, 4H), 4.50 (s, 2H), 4.37 (s, 2H), 4.29 (dq, J1=7.1 Hz, J2=2.3 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 1.85-1.65 (m, 2H), 1.41-1.05 (m, 19H), 0.89 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 7.5 min (HPLC purity: 88.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33](=[O:38])[CH2:34][C:35](O)=[O:36])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([O:32][C:33](=[O:38])[CH2:34][C:35]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:36])([CH3:31])([CH3:30])[CH3:29]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1 g, 2.380 mmol), 3-tert-butoxy-3-oxopropanoic acid (0.457 g, 2.86 mmol), EDC (1.369 g, 7.14 mmol), and DMAP (0.291 g, 2.380 mmol) in DCM (50 ml) was stirred at RT overnight. The reaction mixture was washed with HCl 1N, NaHCO3 5% and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM:EtOAc=40:60) affording (S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.1303 g, 2.010 mmol, 84% yield, MS/ESI+ 562.0 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Cn1cc(CCl)cn1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cn1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (6 mL), sodium tert-butoxide (153 mg, 1.588 mmol) and 4-(chloromethyl)-1-methyl-1H-pyrazole (190 mg, 1.456 mmol) (113 mg, 26%). ESI-MS m/z [M+H]+ calc'd for C41H17ClN6O, 321.12. found 321.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[NH:9]C(=O)C.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:25](OCCC(C)C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:25][NH:9][C:3]=12
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1c(Br)ccnc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccnc2cn[nH]c12
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a solution of N-(4-bromo-2-methylpyridin-3-yl)acetamide (0.6 g, 2.62 mmol) in toluene (26.2 ml) was added potassium acetate (0.308 g, 3.14 mmol) and acetic anhydride (0.743 ml, 7.86 mmol). The mixture was stirred for 15 minutes and isopentyl nitrite (0.806 ml, 6.02 mmol) was added and the reaction was heated at 85° C. for 4 hours. The reaction was cooled and partitioned between ethyl acetate (75 mL) and water (75 mL). The organic layer was separated, dried over MgSO4, and concentrated to a brown oil. The oil was purified on silica column chromatography eluted with methanol:dichloromethane (3:97). Concentration of product fractions afforded 7-bromo-1H-pyrazolo[4,3-b]pyridine (90 mg, 0.454 mmol, 17.35% yield) as an amber solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (1H, d, J=4.80 Hz) 8.32-8.40 (1H, m) 8.40-8.51 (1H, m) 13.89 (1H, br. s.). MS [M+H] found 197.9.
Reaction SMILES: C(C(C)=O)C(C)C.[C:8]1([CH:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N+:39]([O-:41])=[O:40])[CH2:25][CH2:24]1>C(N(CC)CC)C>[C:8]1([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 15 h
Yield: 76 %

Procedure:
Into 270 ml of methyl isobutyl ketone were dissolved 32.1 g of diphenylmethyl bromide, 28.0 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 30.4 g of triethylamine. The resultant solution was heated under reflux with stirring for 15 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with methanol-chloroform (1:50) by silica gel column chromatography to give 33.9 g of oily 4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccccc2)n1
Yield: 69.9 %

Procedure:
2-Amino-6-bromopyridine 10 g (58 mmol), phenylboronic acid 8.5 g (70 mmol) and tetrakis(triphenylphosphine)palladium 1.3 g (1.2 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 6.9 g (yield: 70%) of 2-amino-6-phenylpyridine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[CH:42]=[N:41][N:40]=5)=[O:57])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCCC)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCCC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.00 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.55 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), and was recrystalized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 145) (614.2 mg) as yellow crystals.