Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:28])[C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:14]=3[F:27])[CH:9]=2)[NH:4][N:3]=1.[CH3:29][N:30]([CH3:49])[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C(OCC)(=O)C.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>[CH3:29][N:30]([CH3:49])[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:28])[C:13]4[C:18]([F:19])=[CH:17][CH:16]=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:14]=4[F:27])[CH:9]=3)[NH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(Br)c3c2)c1F
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: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-c4cccc(OCCN(C)C)c4)c3c2)c1F
Temperature: 160 °C
Yield: 27.5 %

Procedure:
Pd(PPh3)4 (0.0075 g, 0.0065 mmol) was added to a suspension of N-(3-bromo-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.031 g, 0.065 mmol), N,N-dimethyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethanamine (0.029 g, 0.098 mmol) and K2CO3 (0.072 g, 0.52 mmol) in MeCN/H2O (4:1, 1 mL). The reaction mixture was heated to 160° C. in a microwave reactor for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through GF/F paper. The filter cake was rinsed with ethyl acetate (50 mL). The filtrate was transferred to a separation funnel, and the organic layers were washed with water (3×20 mL). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with DCM/MeOH (10:1), DCM/MeOH (10:1) containing 1% triethylamine to give N-(3-(3-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.010 g, 27%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.0 (s, 1H), 8.7 (s, 1H), 7.7 (m, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.2 (m, 1H), 7.1 (d, J=7.0 Hz, 1H), 4.3 (t, J=5.2 Hz, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 2.5 (s, 6H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-pos) M+1=559.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]([CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:29])[CH3:12])=[O:10].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:29][C@@H:15]1[C@@H:14]([CH2:13][N:11]([CH3:12])[C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([CH2:27][CH3:28])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN(C)C(=O)Cc3ccccc3Br)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CN(C)C(=O)Cc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.05 g of 5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine was dissolved in 2 ml of dry pyridine and the solution was treated with 0.12 ml of acetic anhydride. The mixture was stirred at room temperature for 5 hours and then evaporated. The residue was re-evaporated with toluene to give a solid which was triturated with diethyl ether and then removed by filtration. There was obtained 0.03 g of 3'-O-acetyl-5'-[2-(2-bromophenyl)-N-methylacet-amido]-2',5'-dideoxy-5-ethyluridine of melting point about 170° C.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C@@H:4]([NH3+:6])[CH3:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:2][C@H:3]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:6])[CH3:5])=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: C[C@H]([NH3+])[C@H](O)Cc1ccccc1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Cl-]
Product: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 from (2S,3R)-3-hydroxy-4-phenylbutan-2-aminium chloride (290 mg, 1.44 mmol) and 1-(4-fluorophenyl)-5-iodoindazole (583 mg, 1.73 mmol). Yield 340 mg (63%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([CH:8]=O)[C:5](=[O:10])[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:15])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][CH:8]=[C:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][C:5]1=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CCC(=O)C(C=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(=O)C(=CCl)C1
Reaction time: 0.06 h
Yield: 87.5 %

Procedure:
To a solution of 5,5-dimethyl-2-oxo-cyclohexanecarbaldehyde (51 g, 331 mmol) in chloroform (250 mL), oxalyl chloride (40 mL, 465 mmol) is rapidly added. After stirring for 3-4 min ice followed by 2 N aq. NaOH (100 mL) is added. The organic phase is separated and the aq. phase is extracted once more with chloroform. The combined organic extracts are washed with water and dried over Na2SO4. The solvent is removed in vacuo to give 2-chloromethylene-4,4-dimethyl-cyclohexanone (50 g) as a brown oil; LC-MS: tR=0.96 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2]([B:22]([OH:27])[OH:23])=[CH:3][C:4]=2[CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(Cc2ccc3occc3c2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(Cc3ccccn3)ccc2o1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of 2-(benzofuran-5-ylmethyl)pyridine (66 mg, 315 mmol) in THF (2 mL) was cooled to −78° C. (under argon), treated with 2.5 M n-BuLi (in hexanes, 2.5 equiv, 0.315 mL) and stirred for 2 min, warmed to 0° C. for 30 min, cooled to −78° C., and treated with triisopropyl borate (178 μL, 946 μmol). After 5 min, cooling was removed, the mixture slowly warmed to room temperature and stirred for 2 h. The mixture was diluted with EtOAc, washed with 1× with brine, dried over MgSO4 and evaporated yielding yellow solids used without further purification. MS (ESI) m/z: Calculated: 253.1; Observed: 254.1 (M++1).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][CH:12]=1)([OH:10])=[O:9].[CH3:20]N(C=O)C>CCOCC>[CH3:20][O:9][C:8]([C:11]1[CH:12]=[CH:13][C:14]([B:17]([OH:19])[OH:18])=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (trimethylsilyl)diazomethane (3 mL, 2 M in hexanes) (Aldrich) was added to a suspension of 4-carboxyphenylboronic acid (1.0 g, 6 mmol) (Lancaster) in ether (50 mL). After stirring for 2 h at room temperature, DMF (8 mL) was added to obtain a clear solution. An additional portion of (trimethylsilyl) diazomethane (3 mL, 2 M in hexanes) was added. After stirring for an additional 2 h, the reaction was quenched by adding acetic acid and concentrating under reduced pressure. Residue was recrystallized from water to give product. (Yield 0.81 9, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10](C=C)[N:9]1[C:16](=[O:20])[CH2:17][CH:18]=[CH2:19].C(N(CC)CC)C>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]2[N:9]1[C:16](=[O:20])[CH2:17][CH:18]=[CH:19]2
Reactant: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccccc1F
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC=C[C@@H]2CCC[C@H](c3ccccc3F)N12
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(2-fluorophenyl)-6-vinylpiperidin-1-yl]-3-buten-1-one (442 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (69 mg) in methylene chloride (180 mL) was heated under reflux in a nitrogen atmosphere for two hours. The reaction solution was left to cool to room temperature. Then, triethylamine (0.5 mL) was added thereto, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 368 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5](=[O:18])[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]=[CH:8][C:9]=1Cl.C([OH:21])C>O>[Cl:3][C:4]1[C:5](=[O:18])[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]=[CH:8][C:9]=1[OH:21]
Reactant: CCO
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)c(O)cnn1-c1ccc(Cl)cc1

Procedure:
In 140 ml of water was dissolved 18.3 g (0.28 mol) of potassium hydroxide, and thereto were added 25.6 g (0.093 mol) of 4,5-dichloro-2-(4-chlorophenyl)-3(2H)-pyridazinone and 140 ml of ethanol. The reaction mixture was refluxed for 6 hours. After allowing to cool, ethanol was distilled off from the mixture under reduced pressure and then 300 of water was added to the mixture. Insoluble matter was removed by filtration and filtrate was acidified with hydrochloric acid. The solid thus precipitated was taken out by filtration, washed with water, and recrystallized from ethanol to give 11.1 g of the intended compound having melting point (hereinafter referred to as "m.p.") of 270°-271° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:15][CH2:16]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:12]#[N:13])[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: ClCCBr
Reactant: N#CCc1ccc(F)c(F)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(F)c(F)c2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 50% aqueous solution of sodium hydroxide (18 g, 46 mmol) was slowly added to a mixture of (3,4-difluoro-phenyl)-acetonitrile (7.1 g, 46 mmol), benzyltriethylammonium chloride (0.26 g, 1.2 mmol) and 1-bromo-2-chloroethane (15 g, 105 mmol) at 70° C. The mixture was stirred overnight at 70° C. The cooled reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness to give crude 1-(3,4-difluoro-phenyl)-cyclopropanecarbonitrile which was used directly in the next step. 1H NMR (CDCl3): δ 7.18-7.03 (m, 3H), 1.79-1.69 (m, 2H), 1.43-1.38 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13]C(=O)OC(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1cnccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1ccccc1-c1cnccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.6 %

Procedure:
To tert-butyl 2-(2-pyrazinyl)phenylcarbamate (0.62 g, 2.29 mmol), dichloromethane (10 mL), and anisole (1 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 h and allowed to stand at room temperature overnight. The reaction mixture was concentrated in vacuo to give 0.41 g of 2-(2-pyrazinyl)aniline, which was coupled with CMI (0.20 g, 1.3 mmol), under conditions described in the general procedure for CMI couplings, to give 0.022 g of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(2-pyrazinyl)aniline.
Reaction SMILES: Br[C:2]1[C:3]([C:27]#[N:28])=[CH:4][C:5]([F:26])=[C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:30][C:31]1[S:35][N:34]=[C:33]([CH3:36])[CH:32]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]([C:3]1[C:2]([NH:30][C:31]2[S:35][N:34]=[C:33]([CH3:36])[CH:32]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])=[C:5]([F:26])[CH:4]=1)#[N:28]
Reactant: N#Cc1cc(F)c(N[C@H](Cc2ccc(-c3ccncc3)cc2)C(N)=O)cc1Br
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h
Yield: 18.1 %

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (62 mg, 0.14 mmol), 5-amino-3-methylisothiazole hydrochloride (35 mg, 0.23 mmol), K2CO3 (65 mg, 0.47 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) and water (0.1 mL) was degassed with argon, then was stirred at 120 C for 18 h. The mixture was purified by HPLC to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (12 mg).
Reaction SMILES: [F:1][CH:2]([F:15])[C@@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[ClH:16]>O1CCOCC1>[ClH:16].[F:1][CH:2]([F:15])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(F)F)C1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
(R)-tert-Butyl 3-(difluoromethyl)pyrrolidine-1-carboxylate (0.45 g, 2.03 mmol) in 1,4-dioxane (1 mL) was cooled to 15° C. in an ice bath. HCl (4M in 1,4-dioxane, 1.5 mL, 6.11 mmol) was then added and the resulting solution was stirred at room temperature overnight. The solvent was removed on a rotary evaporator and the residue was triturated with diethyl ether. Diethyl ether was removed under vacuum and solid was dried to afford 0.31 g of (R)-3-(difluoromethyl)pyrrolidine hydrochloride as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (bs, 2H), 6.19 (td, 1H), 3.34 (m, 1H), 3.22-3.06 (m, 3H), 2.82 (m, 1H), 2.05 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCCc2ccccc21)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (100 mg, 0.46 mmol), 1,2,3,4-tetrahydroquinoline (122 mg, 0.92 mmol) and DMF (1 ml) was stirred at 80° C. for 8 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-(3,4-dihydro-2H-quinolin-1-yl)-2-methylpropan-2-ol (134 mg, yield 83%) as an orange oil.
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[Na].C(O)(C1C=CC=CC=1)(C)C.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]1([CH2:35][CH2:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH3:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:23]1([CH2:22][CH2:21][CH:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36][C:37]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([CH3:39])[CH3:38])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)(CCc1ccccc1)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: [Na]
Solvent: CC(C)c1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(CC(CCc1ccccc1)c1ccccc1)c1ccccc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A one-liter glass flask equipped with a stirrer, a dropping funnel with a gas introduction conduit, a reflux with a calcium chloride tube, and a thermometer was charged with 240 grams (2.0 moles) of commercially available cumene saturated with water, 4.0 grams (0.17 mole) of metallic sodium, and 2.7 grams (0.02 mole) of cumyl alcohol while introducing argon gas through the gas introduction conduit, and the resulting mixture was heated to 135° C. A mixture of 69 grams (0.66 mole) of commercially available styrene saturated with water and 60 grams (0.50 mole) of commercially available cumene saturated with water was dropped thereto over 2 hours with stirring while maintaining the temperature of the reaction system at 135°-140° C. After dropwise addition was completed, the reaction mixture was further stirred while heating for 1 hour and then cooled to room temperature. An excess of metallic sodium was decomposed by dropping methanol in small portions while stirring. Introduction of argon gas was stopped, and the contents were transferred to a separating funnel and then washed with water. The aqueous layer was removed, and the remaining oily layer was analyzed by gas chromatography. This gas chromatographic analysis showed that 58.7 grams (0.26 mole) of 1,3-diphenyl-3-methylbutane and 36.9 grams (0.11 mole) of 1,3,5-triphenyl-5-methylhexane were formed. The total yield (per styrene) was 73 mole %.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:14]([CH2:13][CH2:12][CH2:11][Cl:10])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)NS(=O)(=O)CCCCl
Temperature: 120 °C
Yield: 72.5 %

Procedure:
A glass reactor equipped with a stirrer, reflux condenser and gas inlet was charged with hexamethyldisilazane (0.4235 mol, 91.2 ml) and 3-chloropropanesulfonyl chloride (0.4193 mol, 75.0 g). The contents of the reactor were heated. A refluxing liquid was first observed at a temperature of 85°-95° C., and the mixture became clear. The mixture became cloudy at a temperature of about 105 degrees. The temperature of the mixture was maintained at 120° C. for 90 minutes and at 145°-150° C. for 15 minutes. The mixture was then allowed to cool to room temperature, at which time it was filtered, the solids were washed with benzene, and the washing liquid combined with the liquid portion of the mixture. The combined liquids were then heated at 60°-65° C. under reduced pressure to remove volatile materials and then distilled. The fraction boiling from 127°-129° C. under a pressure of from 0.04-0.07 mm. Hg was collected, and was equivalent to a 72.5 % yield based on initial reactants. The 1H NMR spectrum was consistent with the expected product.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)(Cl)=O.ClC(NC(=O)C1C=CC=NC=1)C(Cl)(Cl)Cl.[CH3:35][O:36][CH2:37][CH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cccnc1
Reactant: COCCN
Agent: O=C(NC(Cl)C(Cl)(Cl)Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COCCNC(NC(=O)c1cccnc1)C(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 41.3 %

Procedure:
150 ml of benzene was added to 5.0 g of N-(1-hydroxy-2,2,2-trichloroethyl)nicotinamide. 2.6 g of thionyl chloride was added dropwise to the mixture under stirring and the obtained mixture was heated under stirring at 60° to 80° C. for about 5 h to complete the production of N-(1,2,2,2-tetrachloroethyl)nicotinamide. The reaction solution was cooled to a temperature of 30° C. or below. 1.4 g of 2-methoxyethylamine was added thereto and then 3.7 g of triethylamine was added dropwise to the liquid mixture kept at 5° C. After stirring at room temperature for 3 h, the mixture was left to stand at room temperature overnight. The reaction solution was poured in an aqueous sodium bicarbonate solution. A benzene layer thus separated was washed with a saturated aqueous common salt solution and water and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 2.5 g of N-(2-methoxyethylamino-2,2,2-trichloroethyl)nicotinamide. m.p. 75° to 77° C.
Reaction SMILES: [CH3:1][N:2]1[C:3]2[C:8]([S:9]/[C:10]/1=[N:11]\[NH2:12])=[CH:7][CH:6]=[CH:5][CH:4]=2.C=O.Cl.CN1[C:21]2C=CC=[CH:25][C:20]=2SC1=NN>O>[CH3:21][C:20]([CH3:25])=[N:12]/[N:11]=[C:10]1/[N:2]([CH3:1])[C:3]2[C:8]([S:9]/1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cn1c(=NN)sc2ccccc21
Reactant: Cn1/c(=N/N)sc2ccccc21
Agent: C=O
Agent: Cl
Solvent: O
Product: CC(C)=N/N=c1\sc2ccccc2n1C
Temperature: 25 °C

Procedure:
All reagents were the purest commercially available grade and deionized water was used throughout the preparation. The synthesis was a modification of the Hunig and Fritsch method for the preparation of MBTH-formaldehyde condensation product (Liebigs, Ann. Chem., 1957, 609, 172). 3-Methyl-2-benzothiazolinone hydrazone hydrochloride (Aldrich), 4.0 g, was dissolved in 200 mL of water with stirring and the free base precipitated by the addition of 10 mL of concentrated ammonium hydroxide solution. The crystalline product was filtered with suction and washed until the wash water no longer tested alkaline with pH indicator paper. The solid product was then vacuum dried at room temperature, and dissovled with vigorous shaking in 100 mL of absolute ethanol in a 250 mL round-bottom flask. To this solution, 20 mL of acetone and 10 mL of glacial acetic acid were added, and the solution refluxed over a boiling water bath for 0.5 h. After cooling to room temperature; the slow addition of 300 mL of water produced a white product which, upon filtering and drying at room temperature, was obtained in nearly theoretical yield as 3-methyl-2-benzothiazolinone acetone azine. The product was sufficiently pure for use but it may be further purified by recrystallization for cyclohexanol.