Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].C[Sn](Cl)(C)C.[Cl-].[NH4+].FC1C=C([Sn](C)(C)C)C=C(F)C=1.[B:30](Cl)([Cl:32])[Cl:31]>C(OCC)C>[Cl:31][B:30]([Cl:32])[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: ClB(Cl)Cl
Agent: C[Sn](C)(C)Cl
Agent: C[Sn](C)(C)c1cc(F)cc(F)c1
Agent: [Cl-]
Solvent: CCOCC
Product: Fc1cc(F)cc(B(Cl)Cl)c1
Yield: 34.4 %

Procedure:
1-bromo-3,5-difluorobenzene (38.6 g, 0.2 mol) was added slowly to a mixture of magnesium turnings (4.8 g, 0.2 mol) in 200 ml anhydrous ethyl ether. After the reaction mixture was refluxed for 2 hrs, trimethyltin chloride (40 g, 0.2 mol) was dropped in to the solution and kept refluxing for one more hour. Then the reaction mixture was hydrolyzed by saturated ammonium chloride. The organic layer of 3,5-difluorophenyltrimethyltin was separated and purified by distillation in a 62% yield. Then the 3,5-difluorophenyltrimethyltin (11 g, 0.04 mol) was reacted with boron trichloride (11 g, 0.093 mol) in a sealed tube at 0° C. for 1 hr and at room temperature for 12 hrs. Dichloro-3,5-difluorophenylborane (6.3 g, 0.032 mol) was obtained from the reaction in 81% yield. Dichloro-3,5-difluorophenylborane (5.84 g, 0.03 mol) was added into a solution containing perfluoropinacol (10 g, 0.03 mol) in 50 ml anhydrous chloroform at −40° C. Then the reaction mixture was stirred continuously at room temperature for 4 hrs. Then the insoluble material was filtered off from the solution. The chloroform solvent was removed by evaporation. The pure product compound 4 (10 g, 0.022 mol) was obtained by distillation of the residue in 73% yield. Boiling point: 80° C./14 mm-Hg. NMR (CDCl3 ppm) δ: 6.9-7.4 (m, 1H), 7.35-7.7 (m, 2H). IR (neat cm−1), ν 3092.0, 1593.8, 1480.6, 1432.0, 1388.2, 1248.9, 1109.8, 1080.5, 986.9, 952.8, 889.6, 870.4, 748.2, 721.8.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:16]=[C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: Nc1ncccn1
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N)sc1-c1cn2cccnc2n1
Yield: 27.5 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (5.9 g), 2-aminopyrimidine (5.7 g) and triethylamine (8.4 ml) in ethanol (100 ml) was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate, and the resulting mixture was acidified to pH 0.5 with conc. hydrochloric acid. The separated aqueous layer was treated with charcoal and filtered. To the filtrate was added ethyl acetate and the resulting mixture was adjusted to pH 7.0 and 20% aqueous potassium carbonate. The precipitate was collected by filtration, washed successively with water, ethyl acetate and ethanol, and dried over phosphorus pentoxide to give 2-(2-amino-4-ethoxycarbonyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (1.6 g). mp 282° C. (dec.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12]Br>CCCCCC>[Br:12][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrBr
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(CBr)ccc1F
Temperature: 50 °C

Procedure:
To a stirred melt of 1-fluoro-4-methyl-2-nitro-benzene (10 g) at 150° C. under a sunlamp was slowly added 3.65 ml of bromine over a 5 hr period. Cooled the brown mixture to 50° C. and poured into 125 ml of hexane. Cooled in an ice bath, filtered, and obtained 10.1 g of 4-bromomethyl-1-fluoro-2-nitro-benzene as white crystals. ##STR146##
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[Si:27]([CH:7]([OH:8])[C@H:6]1[O:9][C@@H:1]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([OH:3])[C@@H:4]1[OH:5])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)C(O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 1 gram of uridine in 20 ml dry N, N-dimethylformamide is added 2.4 molar equivalents of imidazole followed by 1.2 molar equivalents of t-butyldimethylchlorosilane. The mixture is stirred with protection from moisture at room temperature for 20 hours, at which time the solvent is removed at 50° C. in vacuo. The residue is dissolved in 15 ml of ethyl acetate, the solution is washed with 10 ml of water, and the extract is dried with magnesium sulfate and evaporated to give a syrup. Crystallization from 10 ml of hot chloroform, to which is added hexane to the point of opalescence, followed by slow cooling to room temperature, gives 5′-(t-butyldimethylsilyl) uridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:37][CH:35]2[CH2:36][O:33][CH2:34]2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: NC1COC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NC1COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.8 g, 4.42 mmol), CDI (1.07 g, 8.28 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (1.8 ml, 13.25 mmol) and oxetan-3-amine (0.484 g, 6.62 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a stirred solution of 4-bromo-4′-hydroxybiphenyl (5.05 g, 20.2 mmol) in DMF (100 ml) were added K2CO3 (4.20 g, 30.4 mmol) and 1 -bromoheptane (4.14 ml, 26.4 mmol), and then the mixture was heated at 80° C. After being stirred at 80° C. for 20 h, the mixture was cooled to room temperature. The mixture was diluted with Et2O (250 ml) and then the solution was washed with sat. brine (150 ml×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from CH2Cl2-petroleum ether to give 4-bromo-4′-heptyloxybiphenyl (6.21 g, 88%) as a white solid; FAB-MS: m/z 347[MH+].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]2)=[N:11][C:12]=3[NH:16][CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:4]([OH:46])[C@@H:3]1[OH:47].C([O:51][C@@H:52]([CH3:56])[C:53](Cl)=[O:54])(=O)C.C([O-])([O-])=O.[Na+].[Na+].CO>C1COCC1.CC#N>[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][NH:16][C:12]2[N:11]=[C:10]([N:31]3[CH2:35][CH2:34][C@@H:33]([NH:36][C:37]([NH:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:38])[CH2:32]3)[N:9]=[C:8]3[C:13]=2[N:14]=[CH:15][N:7]3[C@@H:5]2[CH2:6][C@H:2]([NH:1][C:53](=[O:54])[C@@H:52]([OH:51])[CH3:56])[C@@H:3]([OH:47])[C@H:4]2[OH:46])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising 1-{(R)-1-[9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-3-pyridin-3-yl-urea (Example 26 step 2) (0.1 g, 0.16 mmol) and TEA (24 μA, 0.18 mmol) in THF (7 ml) at room temperature is treated with (S)-(−)-2-acetoxy-propionyl chloride (24 mg, 0.16 mmol) in MeCN (1 ml) at (0° C.) over 1 minute. The mixture is allowed to stir at room temperature for 18 h and then treated with sat. Na2CO3 (1 ml) and MeOH (1 ml) and then stirred for a further 2 days. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.3% NH3) affords the title compound as a white solid. (MH+ 707.7)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
The product of Example 237A (0.301 g, 1.22 mmol), 4-mercaptophenol (0.184 g, 1.46 mmol, 1.2 eq) and cesium carbonate (0.952 g, 2.92 mmol, 2.4 eq) in dimethylformamide (10 mL) was heated in a 100° C. oil bath for 3 hours and then cooled to room temperature. Water (20 mL) was added and the mixture was stirred at room temperature for 2 hours, and the resulting solid was isolated by vacuum filtration and dried to provide the title compound (0.405 g, 94%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:41])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][O:30][Si](C(C)C)(C(C)C)C(C)C)[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:42][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:41])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CO)cn12
Reaction time: 1 h

Procedure:
To a solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (64) (230 mg, 0.39 mmol) in THF (5 mL), was added TBAF (1M in THF, 0.43 mL) and the resulting mixture was stirred for 1 hour. THF was removed and the residue was added to a mixture of water (10 mL), MeOH (5 mL) and EtOAc (5 mL). Organic solvents were removed slowly to give a precipitate which was filtered and dried to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (F37). 1H NMR (400 MHz, CDCl3) δ 9.39 (m, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.04 (s, 1H), 7.70 (dd, J=1.7, 7.9 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J=1.7, 9.2 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 3.63-3.41 (m, 1H), 3.09-2.85 (m, 4H), 2.28 (s, 3H), 1.82 (t, J=5.9 Hz, 1H). MS m/z 440.1 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([PH:6](=[O:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[C:9]1([CH2:15][CH2:16][C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[Cl-].[Na+]>[OH-].[Na+]>[CH3:4][CH:3]([CH3:5])[CH:2]([PH:6](=[O:7])[OH:8])[NH:1][C:17](=[O:18])[CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C(N)[PH](=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
1-Amino-2-methylpropylphosphinic acid (99.8 mg) prepared by the method described in J. Chem. Soc. Perkin tans 1, 2845(1984) was dissolved in 5 N aqueous sodium hydroxide (0.3 ml). 3-Phenylpropanoyl chloride (0.1 ml) was added to the solution at 0° C., and the resulting mixture was stirred at 0° C. for 1 hour and at room temperature for 3 hours. The mixture was acidified with hydrochloric acid and added with sodium chloride, and then the organic substances were extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 2-methyl-1-(3-phenylpropanoylamino)propylphosphinic acid (162 mg, 82%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]12.[Br:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.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.[Na].[O-]CCCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:1]2[CH2:5][CH2:4][C@@H:3]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]23)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN[C@H]2C1
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: CCCC[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Temperature: 140 °C

Procedure:
tert-Butyl(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1, 1.5 g, 7.0 mmol), 1,4-dibromobenzene (2.8 g, 20.4 mmol), Pd2(dba)3 (275 mg, 0.3 mmol), BINAP (375 mg, 0.6 mmol) and sodium tent-butoxide (1.93 g, 20.0 mmol) were placed in glass microwave tubes and then purged three times with N2 gas, followed by the addition of toluene (45 mL). The mixture was heated to 140° C. for 15 minutes in a microwave reactor. The mixture was then cooled to room temperature, was filtered, and the crude mixture was purified via chromatography (SiO2, 0-25% ethyl acetate:hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ=7.30 ppm (m, 2H), 7.39 (m, 2H), 4.11 (m, 1H), 3.57 (m, 3H), 3.31 (m, 3H), 2.99 (m, 1H), 2.15 (m, 1H), 1.92 (m, 1H), 1.43 (s, 9H). MS (ESI, M+1): 310.9.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][C:5]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1.Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C([O-])(=O)C.[K+]>CCO.O>[F:1][C:2]1[C:7]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)=[CH:6][C:5]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(CN2CCOCC2)cnc1F
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
To a 20 mL microwave reaction tube was added 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (Example 129, Step 3) (2.00 g, 8.33 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 0.501 g, 3.47 mmol), Am-Phos (Aldrich, 0.124 g, 0.175 mmol) and potassium acetate (Aldrich, 1.14 g, 11.6 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 10 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. After the reaction mixture was cooled to room temperature, insoluble material was removed via filtration. The filtrate was partitioned between saturated aqueous sodium chloride (60 mL) and 10% isopropanol in chloroform (60 mL). The aqueous phase was extracted with 10% isopropanol in chloroform (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 25%) to afford 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.27 g, 26% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (dd, J=9.00, 2.35 Hz, 1H) 8.27 (s, 1H) 5.83 (br. s., 2H) 3.70-3.75 (m, 4H) 3.56 (s, 2H) 2.54 (s, 3H) 2.44-2.50 (m, 4H). m/z (ESI, positive ion): 305.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[N:17]=[CH:18][C:19]([C:25]2[CH:26]=[N:27][N:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:32][CH2:31]3)[CH:29]=2)=[C:20]2[CH:24]=[CH:23][O:22][C:21]=12)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[B:52](OC)([O:55]C)[O:53]C>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[N:17]=[CH:18][C:19]([C:25]2[CH:26]=[N:27][N:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:32][CH2:31]3)[CH:29]=2)=[C:20]2[CH:24]=[C:23]([B:52]([OH:55])[OH:53])[O:22][C:21]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of di-tert-butyl{4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-yl}imidodicarbonate (1 g, 2 mmol) in anhydrous THF (10 mL) was added lithium diisopropylamide (2 M in THF, 1.47 mL, 2.94 mmol), and the mixture stirred for 30 min. Boric acid, trimethyl ester (0.371 mL, 3.26 mmol) was added, and the mixture stirred for 10 min before warming to 0° C. The mixture was quenched with water (0.2 mL) and warmed to RT. The THF was removed by rotary evaporation, and the residue was partitioned between ethyl acetate and water. Following separation of the layers, the organic layer was dried over sodium sulfate and evaporated. To the resulting foam was added heptane, and the solution was stirred until the particles were reduced to a powdery solid. The mixture was filtered and washed with heptane (10×). The solid was dried under vacuum to afford 0.6 g (60%) of the title compound as a beige solid. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 8.22 (s, 1 H), 8.01 (s, 1 H), 7.07 (s, 1 H), 4.39-4.18 (m, 1 H), 3.93-3.70 (m, 1 H), 2.26-2.13 (m, 2 H), 2.11-1.92 (m, 4 H), 1.60-1.53 (m, 2 H), 1.33 (s, 18 H), 0.93 (s, 9 H), 0.12 (s, 6 H).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[C:10]([OH:14])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:27]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(O)cc2S(=O)(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Yield: 95.2 %

Procedure:
A mixture of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (WO 96/16051; 0.3 g), ethyl bromoacetate (0.14 g), sodium carbonate (0.3 g), tetrabutylammonium bromide (0.02 g) in MeCN (10 ml) were refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was partitioned between DCM/H2O and the organic layer was separated. The solvent was evaporated and the residue was purified by chromatography (DCM/EtOAc, 90:10) to give the title compound 0.34 g (95%). NMR (500 Mz; CDCl3): 0.7–0.9 (m, 6H), 1.0–1.8 (m, 11H), 3.2 (m, 2H), 3.6–3.8 (br s, 2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0–7.1 (m, 3H), 7.15 (s, 1H), 7.3 (m, 2H), 7.4 (s, 1H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](I)=[C:8](F)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>C(NCC)C.[Cu]I>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(I)c(F)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCNCC
Product: CCCCCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.1 mol of 4-pentyl-2-fluoro-iodobenzene, 0.12 mol of trimethylsilylacetylene, 0.0014 mol of bis(triphenylphosphine)-palladium(II) chloride Pd(PPh3)2Cl2 and 0.7 mmol of copper (I) iodide in 250 ml diethylamine is stirred at room temperature for 20 hours. After evaporation of the solvent the crude product is purified by chromatography on alumina (4:1 petrol/difluoromethane) to give 2-(4-pentylphenyl)-1-trimethylsilylacetylene. Removal of the trimethylsilylgroup is accomplished by treatment this acetylene in methanol with 1M KOH for 1 hour at room temperature. Evaporation of the methanol and either extraction yields 4-pentyl-2-fluoro-phenylacetylene.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH:23]=2)[N:18]=1.[Cl-].[NH4+]>CN(C=O)C>[O:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]1[O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=1)[CH:26]=[CH:25]2
Reactant: Clc1ccc2cc(OC3CCCCO3)ccc2n1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(COc2ccc3cc(OC4CCCCO4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of (4-(trifluoromethoxy)phenyl)methanol (1.65 ml, 11.4 mmol) in DMF (40 ml) was added 60% sodium hydride (0.46 g, 11.4 mmol) at 0° C. and further stirred for 20 minutes. While stirring the resulting mixture under ice cooling, 2-chloro-6-(tetrahydropyran-2-yloxy)-quinoline (3.0 g, 11.4 mmol) was added thereto and warmed to room temperature, followed by further stirring for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=80:20). The resulting crude crystal was washed with hexane-diethylether to afford the title compound as a white powder (3.84 g, yield 81%).