Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([OH:31])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C@@H:36]1[O:38][CH2:37]1)Cl>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:31][CH2:34][C@H:36]5[CH2:37][O:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC[C@H]1CO1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC[C@H]1CO1
Yield: 8.9 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (320 mg, 0.712 mol) and (R)(−)epichlorohydrin (288 μL, 3.56 mmol) were reacted using the same procedure as described before from Example 111A to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (160 mg, 44%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][N:22]([C:25]4([CH2:29][C:30]#[N:31])[CH2:28][NH:27][CH2:26]4)[CH:21]=3)[N:17]3[CH:32]=[CH:33][N:34]=[C:16]3[CH:15]=2)[CH:11]=[N:10]1.CCN(C(C)C)C(C)C.FC(F)(F)S(OCC(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[N:19]=[C:18]([C:20]3[CH:24]=[CH:23][N:22]([C:25]4([CH2:29][C:30]#[N:31])[CH2:28][N:27]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:26]4)[CH:21]=3)[N:17]3[CH:32]=[CH:33][N:34]=[C:16]3[CH:15]=2)[CH:11]=[N:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)c3)n2)cn1
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.2 %

Procedure:
A solution of 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrrol-1-yl)azetidin-3-yl)acetonitrile trifluoroacetate (Example 127, 100 mg, 0.182 mmol) in dry DMF (1.0 mL) was cooled on an ice bath and DIEA (191 μL, 1.09 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (63.5 mg, 0.273 mmol) were added sequentially. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 17 hours. The mixture was added to H2O (5 mL), mixed and extracted with DCM. The combined organic extracts were washed with 0.5M Na2CO3 and H2O, and dried over Na2SO4. The crude material was eluted through a SiO2 plug eluting first with DCM then 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated to give a colorless glass. The glass was dissolved in minimal DCM and treated with hexanes to afford a white suspension. The suspension was concentrated providing the title compound (25 mg, 31% yield) as a white solid. MS (apci) m/z=441.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH:24]1[CH2:27][O:26][CH2:25]1>C(O)(C)C.C(O)C.I[Ni]I.Cl.N[C@H]1CCCC[C@@H]1O>[CH3:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH:24]1[CH2:27][O:26][CH2:25]1)[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1B(O)O
Reactant: IC1COC1
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Cc1cc(C#N)ccc1C1COC1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
(4-Cyano-2-methyl-phenyl)boronic acid (1.75 g, 10.87 mmol), diiodonickel (102 mg, 0.326 mmol), (1S,2S)-2-aminocyclohexan-1-ol hydrochloride (50 mg, 0.33 mmol) and NaHMDS (2.01 g, 11.0 mmol) were combined in isopropanol (10 mL) under N2 in a pressure vial. A solution of 3-iodooxetane (1.00 g, 5.44 mmol) in isopropanol (1 mL) was added. The vial was immersed in a pre-heated 90° C. oil bath and stirred for 2 h, then cooled, diluted with ethanol (20 mL), filtered over Celite, concentrated, then absorbed onto Celite and purified by silica gel column chromatography (0-60% EtOAc/hexane) to give 3-methyl-4-(oxetan-3-yl)benzonitrile (616 mg, 3.556 mmol, 65.42%) as a white solid. ESI-MS m/z calc. 173.1, found 174.3 (M+1)+; Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>O>[C:25]([NH:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1)(=[O:27])[CH3:26]
Reactant: CC(c1c[nH]c2ccccc12)C1OC(N)=NC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1=NC(=O)C(C(C)c2c[nH]c3ccccc23)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-amino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one (100 mg) was dissolved into pyridine (0.5 ml). Acetic anhydride (117 μl) was added. The mixture was stirred for 2 hours at 80° C. To the reaction mixture was added water. The mixture was made acidic using 4N hydrochloric acid. The whole was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to the silica gel chromatography. The eluent with hexane-acetone (1:1) was collected and concentrated to provide the titled compound (16 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.424 g. of pelargonic acid chloride as in Example 1. The 0.722 g. of yellow crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.617 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl nonanoate obtained melts at 43.2°-43.6° and has a clearing point of 74.0°. The compound is smectic up to 61.3°. UV (EtOH): ε 272 = 26900.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[O:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][O:31][CH2:30][C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:35][CH2:36]1
Reactant: Brc1cncc(COCCN2CCOCC2)c1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(COCCN4CCOCC4)c3)cnc21
Temperature: 90 °C

Procedure:
To a sealed tube which contained the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-[2-(5-bromo-pyridin-3-ylmethoxy)-ethyl]-morpholine (282 mg, 0.937 mmol), Na2CO3 (166 mg, 1.56 mmol) and Water (0.5 ml). The mixture is bubbled with Ar for 5 min. Then PdCl2(DPPF) (57.1 mg, 0.078 mmol) is added. The mixture is then bubbled with Ar for 5 min. The cap is sealed and the mixture is heated at 90° C. for 1 h, and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is separated by flash silica gel column (MeOH/DCM 0 to 10% gradient, then 10%). The fractions which contained the desired product are combined, concentrated and then further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=11, and is extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 89 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CN(C=O)C>[F:10][C:4]1[CH:3]=[C:2]([CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 110 °C
Reaction time: 21 h

Procedure:
In a 350-mL pressure-glass was added 4-bromo-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 mL, 0.39 mol), ethyl acrylate (34.27 g, 0.34 mol), DMF (50 mL), palladium (II) acetate (1.29 g, 5.75 mmol), and followed by tri-o-tolyphosphine (2.34 g, 7.6 mmol) under N2. The mixture in the sealed glass was stirred at 110° C. overnight (21 hours), cooled to room temperature and added EtOAc (150 mL) and stirred for 30 minutes, filtered through celite and rinsed with EtOAc (3×100 mL). The filtrate was acidified with 2N HCl to pH ˜2. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with water (2×100 mL), brine (100 mL) and dried over sodium sulfate. After filtration, heptane (200 mL) was added and the solution was concentrated in vacuo. The resulting precipitate was filtered, washed with heptane (2×50 mL) and dried to afford the desired product as a light-yellow solid. The mother liquor was concentrated in vacuo to obtain additional desired product (10) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J=15.9 Hz, 1H), 7.09 (d, J=8.3 Hz, 2H), 6.29 (d, J=15.9 Hz, 1H), 5.54 (br, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:34])([F:33])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]([O:30]CC)=O)=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>O1CCCC1.CO>[F:3][C:4]([F:33])([F:34])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]([NH:2][CH3:1])=[O:30])=[O:25])[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reaction time: 12 h

Procedure:
7.10 ml (14.15 mmol) of a solution of methylamine (2M) in tetrahydrofuran are added to a solution of 1.60 g (3.54 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{4′-[(trifluoromethyl)oxy]-4-biphenylyl}-1-piperazinecarboxylate, prepared in step 1.3, in 14 ml of methanol. Stirring is continued at room temperature for 12 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. A solid is obtained, and is recrystallized from a mixture of ethyl acetate and diisopropyl ether. 0.86 g of pure product is thus obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Yield: 82 %

Procedure:
4-Bromo-2-fluorobenzonitrile and 4-methoxyphenylboronic acid were processed as described in Example 164A to provide the title compound (82% yield). 1HNMR (300 MHz, CDCl3) δ3.73 (s, 3H); MS (DCI) m/z 228 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[OH2:10].[OH2:11].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH3:9])(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: CSc1ccc(Br)cn1
Reactant: O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Br)cn1
Yield: 92 %

Procedure:
5-bromo-2-methylsulfanyl pyridine (3.47 g) was dissolved in a mixed solvent of dichloromethane and methanol with the ratio of 5:1 (v/v) and magnesium monoperoxyphthalate hexahydrate was slowly added dropwise. After completing the reaction for 3 hours at room temperature, magnesium monoperoxyphthalate hexahydrate was filtered out, sodium bicarbonate and salt water was added to dilute, and extracted with dichloromethane to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 5-bromo-2-methylsulfonyl pyridine (3.7 g, yield: 92%) was obtained as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:53][NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:55]([N:54]([CH3:53])[C:18]([CH:15]1[CH2:14][CH2:13][N:12]([C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[CH2:17][CH2:16]1)=[O:20])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reaction time: 0.17 h

Procedure:
1-(1H-indole-2-carbonyl)piperidine-4-carboxylic acid (1.00 g, 3.67 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.408 g, 7.34 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (1.125 g, 7.34 mmol) were dissolved in DCM (Volume: 10 ml). The reaction was allowed to stir for 10 minutes before adding DIEA (1.283 ml, 7.34 mmol) and N-methyl-1-phenylmethanamine (0.836 ml, 7.34 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, 1N HCl, and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using 30% to 60% ethyl acetate:hexanes to obtain product. (Yield: 1.03 g, white solid) 11.53, 7.59-7.54, 7.41-7.11, 7.01, 6.76-6.70, 4.66, 4.52-4.35, 3.22-2.93, 2.76, 1.84-1.51
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[Cl-].[C:26]([OH:35])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N+:29]([O-:33])[CH:28]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl.C(O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:26]([C:27]2[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=2)=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:26]([C:27]2[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=2)=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(NCCCOc1cccc(CN2CCCC2)c1)c1ccc[n+]([O-])c1
Temperature: 0 °C
Yield: 30 %

Procedure:
To a mixture of 0.03 mol of 3-(3-pyrrolidinomethylphenoxy)propylamine and 0.095 mol of pyridine in 100 ml of methylene chloride, stirred at 0° C., 0.047 mol of nicotinic acid 1-oxide chloride hydrochloride is added portionwise, then the resulting mixture is stirred 1 hour at room temperature and the solvent is evaporated off under reduced pressure. The residue is taken up with N hydrochloric acid and the salts obtained are eliminated by filtration, then the solution is extracted 3 times with 100 ml of ethyl acetate and sodium hydroxide is added thereto up to a basic pH. The solution is extracted 4 times with 100 ml of ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated off under reduced pressure. The oil thus obtained is chromatographied on silica, and eluted with methanol, the fractions of the pure product are collected and the solution thus obtained is treated with a solution of oxalic acid in ethanol; the precipitate which forms is crystallized from ethanol to yield 3.5 g of N-[3-(3-pyrrolidinomethylphenoxy)propyl]3-pyridinecarboxamide 1-oxide sesquioxalate CM 57891A; m.p. 115°-116° C. Yield: 30% of the theoretical value.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]=2[O:15][CH3:16])=[C:4]([Cl:18])[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:29](Br)[C:30]#[CH:31]>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:11](=[O:17])[CH:12]([CH2:31][C:30]#[CH:29])[CH2:13][C:14]=2[O:15][CH3:16])=[C:4]([Cl:18])[CH:3]=1
Reactant: COC1=C(c2c(Cl)cc(Br)cc2OC)C(=O)CC1
Reactant: C#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCC1CC(OC)=C(c2c(Cl)cc(Br)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 45.5 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chloro-6-methoxy-phenyl)-3-methoxy-cyclopent-2-en-1-one (0.500 g, 1.51 mmol) in anhydrous tetrahydrofuran (10 mL) under an nitrogen atmosphere at −78°C. was added KHMDS (potassium hexamethyldisilazide) (1.81 mL of a 1.0M solution in tetrahydrofuran, 1.81 mmol) dropwise and the reaction was allowed to stir at this temperature for 55 minutes. Propargyl bromide (80 wt % in toluene, 0.202 mL, 1.81 mmol) was diluted in anhydrous tetrahydrofuran (2.5 mL) under an nitrogen atmosphere and then added dropwise to the reaction mixture. The reaction was stirred at −78°C. for 30 minutes and then allowed to warm to room temperature over 18 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (10 mL) followed by EtOAc (10 mL). Water (1 mL) was added and then the phases were separated and aqueous was extracted with further EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give an orange gum. The crude product was dissolved in dichloromethane, adsorbed onto silica and purified by flash chromatography over silica using a dichloromethane/MeOH gradient to give the desired product (254 mg, 46%) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (s, 1H), 6.95 (s, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 3.14-3.10 (m, 1H), 2.79-2.51 (m, 4H), 2.00 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCNC1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCN(c2ccccc2C=O)C1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
3-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methoxy]piperidine (59.1 mg, 0.183 mmol) and 2-fluorobenzaldehyde (0.0984 mL, 0.915 mmol) were dissolved in dimethylsulfoxide (2 mL). To this solution, cesium carbonate (119 mg, 0.366 mmol) was added and the mixture was stirred at 130° C. for 3 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate and the extracted washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 47.8 mg (61%) of the desired compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.O>CN(C=O)C>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:4]([CH3:3])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)(=[O:7])=[O:6])=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)nn2)cc1
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.42 g (10.5 mmol)) in 10.0 ml of DMF, N-methyl-p-toluenesulfonamide (1.85 g (9.99 mmol)) was added under ice-cooling and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3,6-dichloropyridazine (1.49 g (10.0 mmol)) was added. The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 1.41 g (47%) of the title compound as white crystals.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:13][C:12]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:11]=3[NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[NH:29]1[CH:33]=[C:32]([CH2:34][N:10]2[C:11]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:12]=3[CH2:13][N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[C@H:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[N:31]=[CH:30]1
Reactant: O=Cc1c[nH]cn1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H- 1,4-benzodiazepine-7-carbonitrile (10 g) and imidazole-4-carboxaldehyde (2.6 g) were mixed in toluene (20 mL) at 20 to 25° C. To this stirred slurry, first trifluoroacetic acid (9.4 mL) and then trifluoroacetic acid anhydride (5.2 mL) were added sequentially while maintaining the temperature below 30° C. The biphasic mixture was vigorously stirred at 20 to 25° C. for 2 hours. Triethylsilane was then added and the reaction mixture was stirred at 20 to 25° C. until the reaction was determined to be complete according to HPLC assay. The reaction mixture was polish-filtered, e.g., through filter paper or a celite bed. The solvent was removed by evaporation, and a viscous yellow oil containing approximately 100% yield of the crude title product was collected.