Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:46][CH2:47][CH2:48][CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:50](O)=[O:51])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[ClH:59].[ClH:1].[NH2:46][CH2:47][CH2:48][CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[Cl:59])[C:50]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:8][CH2:7]1)=[O:51]
Reactant: c1nc(N2CCNCC2)c2cn[nH]c2n1
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCCC(C(=O)N1CCN(c2ncnc3[nH]ncc23)CC1)c1ccccc1Cl
Reaction time: 4 h
Yield: 133.1 %

Procedure:
The 4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine bis-hydrochloride salt (60 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), EDCI (46 mg, 0.24 mmol), and 4-tert-butoxycarbonylamino-2-(2-chlorophenyl)-butyric acid [prepared by procedures described in Example 61 (68 mg. 0.22 mmol)] were suspended/dissolved in 1.5 mL of DMF then treated with triethylamine (121 μL, 0.87 mmol). The mixture was allowed to stir for four hours to completion then partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 1 mL of 1,4-dioxane and treated with 1 mL of 4M HCl in 1,4-dioxane. The solution stirred overnight to completion at room temperature and diluted with diethyl ether to afford a precipitate. This material was broken up to afford a suspended granular solid which was stirred for 30 minutes. The suspension was filtered, washed with diethyl ether, and dried over a stream of nitrogen to afford the 4-amino-2-(2-chlorophenyl)-1-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazin-1-yl]-butan-1-one bis-hydrochloride salt as a tan solid (69.2 mg, 67%). 1H NMR (D6O, 400 MHz) δ 8.52 (brs, 1H), 8.31 (s, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.12 (m, 3H), 4.42 (t, J=6.8 Hz, 1H), 4.11 (m, 1H), 3.98 (m, 3H), 3.70 (m, 2H), 3.61 (m, 1H), 3.41 (m, 1H), 2.96 (m, 1H), 2.80 (m, 1H), 2.21 (m, 1H), 1.94 (m, 1H). LCMS (APCI+) m/z 400 [M+H]+; Rt=1.52 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:16]#[C:17][CH3:18]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:18][C:17]#[CH:16])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: CC#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
3-Fluorophenol (5.10 g, 45.5 mmol) was dissolved in DMF (10 mL) and potassium carbonate (7.55 g, 54.6 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. Bromoprop-1-yne (5.05 mL, 45.5 mmol) was added and the reaction was stirred overnight at ambient temperature. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated under reduced pressure to give a yellow oil (7.27 g) that was used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.30-7.23 (m, 1 H), 6.81-6.69 (m, 3 H), 4.70 (d, J=2.3 Hz, 2 H), 2.56 (t, 1 H); LCMS (m/z) ES+=151 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][OH:26]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][OH:26])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 59.6 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0638 g, 0.217 mmol) and 2-bromoethanol (0.035 mL, 0.494 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0541 g, 60.1%). EI-MS m/z 338 (M+) Rt (1.42 min).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCCC(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (300 mg, 1.2 mmol) and triethylamine (260 μL, 1.8 mmol) in methylene chloride (50 mL) was added dropwise butyryl chloride (140 μL, 1.3 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 1 h and then washed with a dilute aqueous sodium hydrogen carbonate solution. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methano/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 330 mg (86%) of the title compound as white crystals: mp 131-132° C.; [α]21D +24° (c 0.05, chloroform); EIMS (70 eV) m/z (relative intensity) 315 (39, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1-c1c(Cl)cnn1C
Yield: 64.9 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (55 mg, 0.23 mmol) was treated with 3-Cyanophenyl isocyanate (37 mg, 0.26 mmol) in a similar manner to Example 1.53, providing 57 mg (65%) of Compound 109: LCMS m/z (%)=382 (M+H35Cl, 100), 384 (M+H37Cl, 38). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.85 (s, 1H), 7.98 (t, 1H), 7.68 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.59 (dd, J1=12 Hz, J2=2 Hz, 1H), 7.50 (t, 1H), 7.42 (t, 1H), 7.42 (d, J=4 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH3:4].[CH2:9](I)[CH3:10].[OH-].[Na+]>>[CH3:1][O:2][CH:3]([N:5]([CH2:9][CH3:10])[C:6](=[O:8])[CH3:7])[CH3:4]
Reactant: COC(C)NC(C)=O
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Product: CCN(C(C)=O)C(C)OC
Yield: 51 %

Procedure:
58.5 g (0.5 mole) of N-α-methoxyethyl-acetamide and 84.2 g (0.55 mole) of ethyl iodide are simultaneously added dropwise to 300 ml of 50% strength sodium hydroxide solution at 10° C. Two hours after the addition has ended, the phases are separated in a separating funnel, the aqueous portion is extracted with hexane and, after stripping off the solvent, the residue is distilled in vacuo. 37 g (51% of theory) of N-α-methoxyethyl-N-etyl-acetamide of boiling point16 83°-85° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>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>[C:17]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ccnc(Br)c1
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: COCCOC
Product: O=C(O)c1ccnc(-c2ccccc2)c1
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
2-bromoisonicotinic acid (0.210 g, 1.040 mmol) was dissolved in degassed DME (Volume: 8 ml) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol) was added, the resulting reaction mixture was stirred for 15 min. Then aqueous potassium carbonate (4.16 ml, 8.32 mmol) and phenylboronic acid (0.171 g, 1.403 mmol) were added subsequently. The resulting RM was refluxed at 95° C. for 18 h and then cooled to rt. After filtration over celite the reaction mixture was acidified to pH 3-4 and the white precipitate was filtered off and washed with water
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11](NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)[CH:12]=2)[CH2:7]1)[CH3:4].[CH2:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:45][CH2:44][C:41]3[CH:40]=[CH:39][C:38]([C:35]4[CH:36]=[CH:37][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=4)=[CH:43][CH:42]=3)[CH:12]=2)[CH2:7]1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(CO)cc2)cc1
Reactant: CN(C)CC1CCc2cc(NS(=O)(=O)c3ccc4ccccc4c3)ccc2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (300 mg; obtained in Reference Example 16), (4′-ethylbiphenyl-4-yl)methanol (372 mg) and triphenylphosphine (460 mg) were dissolved in THF (5 ml), to which was dropwise added diethyl azodicarboxylate (305 mg) with cooling with ice. The reaction mixture was stirred at room temperature for 4 hours, and then the solvent was evaporated out. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from ethanol-diisopropyl ether to obtain the entitled compound (310 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(O)cccc1OCCCCl
Temperature: 70 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
To a solution of 2′,6′-dihydroxy-acetophenone (500 mg, 3.28 mmol) in dimethylformamide (20 ml) were added potassium carbonate (680 mg, 4.93 mmol) and 1-bromo-3-chloropropane (0.34 ml, 3.45 mmol) and the mixture was stirred at 70° C. for 4 h. Water was added and the organics were extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-15%) to yield 6′-(3-chloropropoxy)-2′-hydroxy-acetophenone (348 mg, 46%) as a pale yellow solid. To a solution of 6′-(3-chloropropoxy)-2′-hydroxy-acetophenone (345 mg, 1.50 mmol) in acetonitrile (15 ml) was added potassium carbonate (416 mg, 3.0 mmol) and morpholine (0.396 ml, 4.52 mmol). The mixture was stirred for 18 hours at room temperature then 60° C. for 3 days. Water was added and the organics were extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient ethyl acetate/methanol: 0-10%) to yield 2′-hydroxy-6′-(3-morpholino-4-yl-propoxy)-acetophenone (171 mg, 40%) as an orange oil that solidified.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][O:4][C:5]1[C:14]2[C:15](=O)[O:16][C:17](=[O:18])[C:13]=2[C:12]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36]([NH2:39])(=[O:38])=[O:37])=[CH:31][C:30]=1[CH3:40]>CC(O)=O>[O:16]=[C:15]1[C:14]2[C:5]([O:4][CH2:3][C:2]([F:26])([F:1])[F:27])=[C:6]3[C:11](=[C:12]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])[C:13]=2[C:17](=[O:18])[N:28]1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36]([NH2:39])(=[O:37])=[O:38])=[CH:31][C:30]=1[CH3:40])[N:10]=[CH:9][CH:8]=[CH:7]3
Reactant: Cc1cc(CS(N)(=O)=O)ccc1N
Reactant: O=C1OC(=O)c2c1c(OCC(F)(F)F)c1cccnc1c2OCC(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(CS(N)(=O)=O)ccc1N1C(=O)c2c(c(OCC(F)(F)F)c3ncccc3c2OCC(F)(F)F)C1=O
Yield: 82.3 %

Procedure:
A mixture containing 5,9-bis(2,2,2-trifluoroethoxy)furo[3,4-g]quinoline-6,8-dione (42 g, 106 mmol) 5 and 1-(4-amino-3-methylphenyl)methanesulfonamide 15 (24 g, 1.13 equiv) from Preparative Example 1 in AcOH (350 ml) was degassed under vacuum and heated to reflux under nitrogen for 6.5 h. The solvent was then evaporated and the residue was partially dissolved into 50% EtOAc/toluene (800 ml) and cooled down to 0 C. The solid was filtered and washed with toluene to yield a first crop of material as a brownish solid (50.36 g).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40](C(F)(F)F)[CH:41]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:2]([F:47])([F:46])[F:1])[CH:41]=1)[CH2:6][N:7]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:12][N:13]=1)[CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:22]=1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
Trifluoromethanesulfonic acid 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl ester (200 mg) is dissolved in 1,4-dioxane (3 ml), and thereto are added phenyl boronic acid (69 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (23 mg) and cesium carbonate (183 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (52 mg). MS (m/z): 641 [M+H]+
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[CH2:1]([Sn:5]([C:2]#[C:1][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:17][CH2:16][CH3:20])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: O
Product: CCCC[Sn](C#C[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Yield: 88 %

Procedure:
A mixture of 48.8 g (0.150 Mol) of tri-n-butyl-tin chloride and 20.7 g (0.225 Mol) of lithium acetylide ethylenediamine complex in 300 mL of anhydrous THF was heated at reflux under argon for 24 h, cooled and treated with 200 mL of water. The layers were separated and the THF phase was suction-filtered through Celite with a 150 mL THF wash to afford a clear solution. This solution was washed with water (3×200 mL), saturated aqueous sodium bicarbonate (2×100 mL), 5% HCl (2×100 mL), and dried over anhydrous sodium sulfate. Removal of the solvent gave 40.2 g (88%) of the bis(tri-n-butylstannyl)ethyne as a colorless liquid. A mixture of 42.0 g (120 mMol) of 4-bromofluorobenzene, 30.2 g (50 mMol) of bis(tri-n-butylstannyl)acetylene and 2.5 g (2.24 mMol) of tetrakis(triphenylphosphine)palladium[0] under an argon atmosphere was dissolved in 200 mL of dry THF. The reaction mixture was refluxed under an argon atmosphere for 60 h. The solution was cooled to room temperature and subsequent cooling in a refrigerator overnight yielded 11.2 g (67%). The reaction was run at double the scale mentioned above and gave similar yields without any complication in the work-up procedure.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Phenoxybenzoic acid (214 mg, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3-phenoxybenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:12](=O)[CH2:13][CH3:14]>C(O)C>[CH2:12]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH2:13][CH3:14]
Reactant: CCC=O
Reactant: Nc1cccc2ncccc12
Solvent: CCO
Product: CCCNc1cccc2ncccc12
Reaction time: 0.25 h

Procedure:
5 g of 5-aminoquinoline, 3 ml of propionaldehyde and 4.7 g of para-thiocresol are dissolved in 100 ml of ethanol in a 250 ml round-bottomed flask. The reaction mixture is heated at reflux for 2 hours and then evaporated to dryness. The residue is dissolved in 100 ml of ethanol and cooled in an ice bath and then 6.5 g of sodium borohydride are added portionwise. When addition is complete, the reaction mixture is heated at reflux for 2 hours and then, successively, 30 ml of water are added, the mixture is basified with 20 ml of concentrated sodium hydroxide and stirred for 15 minutes and the organic solvents are evaporated. Extraction is carried out with dichloromethane and the organic phase is washed with water and then dried over sodium sulphate. The organic phase is evaporated to dryness and the residue is purified on a column of silica gel, eluent: ethyl acetate, to obtain 4 g of an oil which crystallizes. 1H NMR (CDCl3): 1.05 (t, J=3H, --CH3), 1.82-1.71 (m, 2H, --CH2 --CH3), 3.15-3.26 (m, 2H, --NH--CH2 --), 4.37 (sl, 1H, --NH--), 6.61 (dd, J=1.0, J=8.6, 1H, H4), 7.26 (dd, J=4.2, J=8.6, 1H, H6), 7.44-7.59 (m, 2H, H3, H2), 8.12 (dd, J=0.95, J=8.6, 1H, H8), 8.84 (dd, J=1.5, J=4.2, H2).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19](C)[CH2:20]CCC(C)C)[CH2:10]1.S(CCCCCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(=O)C)C1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1[OH:39]>>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:39])[CH3:20])[CH2:10]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of pregn-5-en-20-one-3β-yl 6-iodohexyl ether, there was prepared 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (Step D). TLC data and Rf values are given in the above Table.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[S:13]>>[C:2]([NH:3][C:12]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[F:4])=[S:13])#[N:1]
Reactant: Fc1ccccc1N=C=S
Reactant: N#CN
Product: N#CNC(=S)Nc1ccccc1F

Procedure:
Cyanamide and 2-fluorophenyl isothiocyanate were processed as described in Example 44A to provide the desired product which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.B(O)(O)[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[N:11][CH:10]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:15][C:12]1[N:11]=[CH:10][C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: Cn1ccc(N)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc(Nc2ccc(Br)nc2)n1
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-ylamine (0.23 g, 2.3 mmol, 1.0 equiv) and 2-bromopyridyl-5-boronic acid (0.70 g, 3.5 mmol, 1.5 equiv) in 10 Ml dichloromethane was added pyridine (0.43 Ml, 5.4 mmol, 2.4 equiv), copper (II) acetate (0.63 g, 3.5 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3 H) 5.84 (s, 1 H) 7.45 (d, J=8.59 Hz, 1 H) 7.60 (d, J=2.02 Hz,1 H) 7.86 (dd, J=8.59, 3.03 Hz, 1 H) 8.41 (d, J=2.78 Hz, 1 H) 8.92 (s, 1. H); (M+H)+ 255.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH2:19])=[N:9]3)[CH:7]=1.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:23](=[O:22])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:9]3)[CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(4aS,5S,7aS)-7a-(5-Bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (620 mg, 1.63 mmol) was dissolved in THF (10 mL). (BOC)2O (0.45 mL, 1.95 mmol) and Et3N (0.27 mL, 1.95 mmol) were added and the reaction was stirred at 100° C. After 1 hour, the solvents were removed in vacuo. The residue was purified using column chromatography (Biotage SNAP 25 g, 20 mL/min eluting with 20-80% EtOAc in n-hexane) to leave the title compound as a foam. (704 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.54 (t, J=1.00 Hz, 1H), 6.86-7.01 (m, 1H), 4.49-4.71 (m, 3H), 4.45 (dd, J=1.22, 8.56 Hz, 1H), 3.68-3.92 (m, 1H), 2.95-3.20 (m, 2H), 2.73 (t, J=1.00 Hz, 1H), 1.46-1.64 (m, 9H)