Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@H:7]([OH:9])[CH2:6]1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@H:7]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C[C@H]1C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution trans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (168 mg, 1.17 mmol) in DMF (1.5 mL) is added, NaH (60% in oil, 70 mg, 1.75 mmol) at 0° C. After stirring at 0° C. for 15 minutes, benzyl bromide (167 uL, 1.40 mmol) is added at 0° C. The mixture is stirred at room temperature for 2 hours and quenched with H2O. The mixture is extracted with dichloromethane, and the organic layer is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give trans-(3-benzyloxy-cyclobutyl)-acetic acid methyl ester (110 mg, 40%); ESI-MS m/z 235 [M+1]+, retention time 1.97 min (condition A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[O:17][CH3:18])\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[O:17][CH3:18])\[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1OC
Yield: 56.1 %

Procedure:
To a stirred mixture of (E)-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (4.20 g, 0.016 mol) in carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.22 g, 0.024 mol) and benzoyl peroxide (380 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (3.10 g, 57%) as a yellow oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:35]N1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[Br:35][C:8]1[C:9]2[N:10]([N:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[N:17]=2)[CH:11]=[CH:12][C:7]=1[NH:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc(-c2nn3ccc(NC4CCCC4)c(Br)c3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo-[1,5-α]pyridin-5-amine (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL) and treated with N-bromosuccinimide (40 mg, 0.22 mmol). The reaction mixture was stirred for 10 minutes. Additional dichloromethane and 1N aqueous sodium hydroxide was added. The phases were separated, the organic phase washed with water, dried (magnesium sulfate), filtered and concentrated to dryness to give 100 mg of the title compound as a yellow foam. 1H NMR (CDCl3): δ 8.32 (d, 1H), 8.22 (d, 1H), 7.53 (q, 2H), 7.04 (t, 2H), 6.53 (m, 2H), 5.17 (d, 1H), 4.72 (d, 1H), 4.33 (m, 1H), 3.95 (m, 1H), 2.1–1.4 (m, 16H); 19F NMR (CDCl3): δ −113.97; MS m/z 536 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.C(=O)([O-])O.[Na+:12].[N:13]1([CH2:18][C:19]([NH:21][C@@H:22]2[C:51](=[O:52])[N:24]3[C:25]([C:48]([OH:50])=[O:49])=[C:26]([CH2:29]OC(=O)C4C=CC=CC=4S(=O)(=O)NC(OCC)=O)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:17]=[N:16][N:15]=[N:14]1>P([O-])([O-])([O-])=O>[N:13]1([CH2:18][C:19]([NH:21][C@@H:22]2[C:51](=[O:52])[N:24]3[C:25]([C:48]([O-:50])=[O:49])=[C:26]([CH2:29][S:1][C:2]4[S:6][C:5]([CH3:7])=[N:4][N:3]=4)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:17]=[N:16][N:15]=[N:14]1.[Na+:12]
Reactant: Cc1nnc(S)s1
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cc1nnc(SCC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1

Procedure:
In a phosphate buffer solution of pH 6.4(3 ml) are dissolved 5-mercapto-2-methyl-1,3,4-thiadiazole (79 mg), sodium hydrogen carbonate (92 mg) and 7β-(1H-tetrazol-1-yl)acetamido-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (298 mg) and the resultant solution is heated at 60° C. for one hour. Then, the mixture is concentrated and the residue is subjected to column chromatography on Sephadex LH-20, elution being carried out with water. The fractions containing the desired product are pooled and lyophilized. The procedure provides sodium 7β-(1H-tetrazol-1-yl)acetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate. This product is in good agreement with the authentic sample in NMR spectrum.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][C:21]1[CH:22]=[C:23]([NH2:32])[N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:32][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Product: Cc1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-methyl-2-phenyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 409.50 [M+H]+; tR=1.21 min (System 3).
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl.[Cl-].[Na+].O>[Br:31][CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CO)s1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)s1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a stirred solution of 2-hydroxymethyl-5-nitro-thiophene (18.8 g, 118 mmol) in dichloromethane (500 ml) at 0° C. was added triphenylphosphine (3 1.5 g, 120 mmol) followed by carbon tetrabromide (39 g, 118 mmol). The mixture was stirred for 2 hours, poured into half saturated brine and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent removed at reduced pressure. The crude product was purified by silica gel chromatography using 15% ethyl acetate/hexane as the eluant to give 2-bromomethyl-5-nitrothiophene (19 g, 61%) as a brown oil.
Reaction SMILES: [CH2:1]([PH:8](=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[O:16]>>[CH2:1]([P:8]([CH2:15][OH:16])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CCCCO[PH](=O)Cc1ccccc1
Product: CCCCOP(=O)(CO)Cc1ccccc1

Procedure:
The title compound was prepared from benzylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:21][C:20]([OH:22])([CH2:19][CH2:18][NH:17][C:2]1[CH:7]=[N:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1)[CH3:23]
Reactant: CC(C)(O)CCN
Reactant: Brc1cnc(C#Cc2ccccc2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(O)CCNc1cnc(C#Cc2ccccc2)cn1
Yield: 509.8 %

Procedure:
A solution of 2-bromo-5-(phenylethynyl)pyrazine (Example 168, step 1) (158 mg, 0.061 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (255 mg, 1.83 mmol, 30 equiv.) and triethylamine (185 mg, 255 μl, 1.83 mmol, 30 equiv.) in 3 ml pyridine was stirred overnight at 85° C. The reaction mixture was concentrated in vaccuo. After workup with dichloromethane/water/brine, and drying over magnesium sulfate, the organic phases were concentrated in vacuo. The crude product was chromatographed over a prepacked 20 g silica column eluting with a 25% to 100% ethyl acetate in heptane gradient which yielded the title compound (87.5 mg, 51% yield) as an off-white solid, MS: m/e=282.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:32][OH:33])[CH2:27]1)(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[OH:33][CH2:32][C@H:28]1[CH2:27][NH:26][CH2:31][CH2:30][N:29]1[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNC[C@@H]3CO)s2)noc1C(F)(F)F
Reaction time: 2 h
Yield: 83 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-hydroxymethyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried afford intermediate N-Boc protected product as a colorless solid (102 mg, 86%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately ¼ volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 83% overall). 1H NMR (D2O) 2.17 (s, 3 H), 3.26-3.46 (m, 3 H), 3.60-3.80 (m, 3 H), 4.00-4.04 (m, 1 H), 4.48 (dd, J=12.7, 5.3, 1 H), 4.60 (obs dd, J=13.2, 3.5, 1 H), 7.46 (d, J=4.3, 1 H), 7.82 (d, J=4.0, 1 H). 19F NMR −63.5. LC/MS 3.89 min, [M+1]+ 376.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH3:23])[CH:18]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:15]([F:14])[CH:16]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: Cc1ccc(C=O)cc1F
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 44.2 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18, found 305.9 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[CH:24][C:23]=2[F:29])[CH:21]=1>>[F:28][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([F:29])[C:22]=1[C:20]1[CH:21]=[C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)[CH:17]=[CH:18][C:19]=1[F:30]
Reactant: Fc1ccc(Br)cc1-c1c(F)cncc1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4c(F)cncc4F)c3)cnc2c1F
Yield: 40 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 4-(5-bromo-2-fluorophenyl)-3,5-difluoropyridine as described in Example 6 to give 2-{3-[3-(3,5-difluoropyridin-4-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (80 mg, 40%): δH (360 MHz, d6-DMSO) 1.57 (6H, s), 7.22 (1H, t, J 7), 7.66 (1H, t, J 9), 7.83 (1H, s), 7.94 (2H, dd, J 6 and 2), 8.37 (1H, d, J 7), 8.75 (2H, s); m/z (ES+) 402 [MH+].
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]2[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:8]=[CH:7][C:6]=2[N:5]([CH3:31])[C:4]1=[O:32])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:23][CH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C:9]1[N:8]=[CH:7][C:6]2[N:5]([CH3:31])[C:4](=[O:32])[C@@H:3]([CH2:1][CH3:2])[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]=2[N:10]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(=O)OC(C)(C)C)nc2N1C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 91, with (R)-tert-butyl (4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)pyridin-3-yl)methylcarbamate (Example 107) instead of (R)-tert-butyl 4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)pyridin-3-ylcarbamate (Example 92). LCMS (0.05% TFA): 341.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.66 (s, 1H), 8.60 (d, 1H, J=5.0 Hz), 8.18 (s, 1H), 8.07 (d, 1H, J=5.0 Hz), 4.71 (m, 1H), 4.46 (m, 1H), 4.11 (s, 2H), 3.43 (s, 3H), 1.99 (m, 1H), 1.81 (m, 1H), 1.49 (d, 3H, J=6.5 Hz), 1.46 (d, 3H, J=6.5 Hz), 0.89 (t, 3H, J=7.5 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9](/[CH:11]=[CH:12]/[CH2:13][O:14][CH3:15])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: COC/C=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COC/C=C/c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 85 mg of (E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na2CO3 aqueous solution and 1 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 5-50% EtOAc/hexane to yield 2-chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (87 mg, 68%). 2-Chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine (40 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 29.1 mg of 334. MS (Q1) 408.1 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:4]=1[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O.I[C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:4]=1[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1
Reactant: Oc1cccc(I)c1
Reactant: COc1cc(OC)c(CSc2ccccc2B(O)O)c(OC)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(CSc2ccccc2-c2cccc(O)c2)c(OC)c1
Yield: 79 %

Procedure:
To a mixture of 1.05 g 2-(2,4,6-trimethoxybenzylthio)phenylboronic acid (3.14 mmol), 1.07 g 3-iodophenol (4.9 mmol) and 0.195 g Pd catalyst was added 40 ml toluene followed by 15 ml 2M Na2CO3. The mixture was refluxed under nitrogen overnight. The mixture was extracted with ethyl acetate. The organic was washed with water, brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica flash chromatography (hexane:ethyl acetate 80:20) to afford 0.948 g product (2.48 mmol, 79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.CC[CH2:18][CH:19]([C:21](NC1C=CC(C)=C(Cl)C=1)=[O:22])C>C1(C)C=CC=CC=1>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:19]3[CH2:21][O:22]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: CCCC(C)C(=O)Nc1ccc(C)c(Cl)c1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
At rt under an inert atmosphere, (±)-glycyclol (0.129 g, 1.74 mmol, 120 uL) is added into a solution of 3,6-dibromo-9-H-carbazole (0.565 g, 1.74 mmol) in anhydrous toluene (10 mL). Then CMMP (which is prepared according to the protocol of Tetsuto, Tsunoda Tett. Lett. 1996, 37(14), 2459-2462) (0.20 g, 1.74 mmol) is added. The resulting mixture is allowed to stir at rt for 16 hours. The solvent is evaporated and the crude compound is purified via flash chromatography using Biotage device and Petroleum Ether/DCM (3/1) as eluant to give the title compound in a 60% yield as a white solid and 5% of (±)-3,6-dibromo-9-[(1E)-3-(3,6-dibromocarabazol-9-yl)propen-1-enyl]carbazole as a grey powder.
Reaction SMILES: CC1C=CC(S(O[C@H:12]([CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:13])(=O)=O)=CC=1.[CH2:21]([O:23][C:24](=[O:40])[CH2:25][N:26]=[C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[C:28]1([C:27](=[N:26][CH:25]([C@H:12]([CH3:13])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:24]([O:23][CH2:21][CH3:22])=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=CCCC(C)C[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCCC(C)C[C@@H](C)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 110 °C
Yield: 105.2 %

Procedure:
To a solution of (2S)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (54 g, 0.182 moles) and N-(diphenylmethylene)glycinate ethyl ester (48.7 g, 0.182 moles) in toluene (500 mL) was added LiHMDS (36.5 g, 0.218 moles, 1 M solution in THF) at 0° C. The reaction mass was allowed to come to room temperature and was then heated at 110° C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude compound (3R)-ethyl 2-((diphenylmethylene)amino)-3,5-dimethylnon-8-enoate (75 g). The crude compound was taken to the next step without further purification.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])C=C>>[Si:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C=CCCCCCCCCO[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)/C=C/CCCCCCCCO[Si](C)(C)C(C)(C)C
Yield: 95 %

Procedure:
The representative procedure was followed using tert-butyl(dec-9-enyloxy)dimethylsilane (135 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 2% EtOAc/hexanes) afforded the product as a colorless oil (176 mg, 95%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH:13]4[CH2:19][CH2:18][N:16]([CH2:17][C:7]=3[C:6]=2[CH:5]=1)[CH2:15][CH2:14]4.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23]>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24](/[CH:22]=[CH:23]/[N:9]2[C:10]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][C:6]=3[C:7]3[CH2:17][N:16]4[CH2:15][CH2:14][CH:13]([C:8]2=3)[CH2:19][CH2:18]4)[CH:25]=1
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C#Cc1cccnc1
Product: FC(F)(F)Oc1ccc2c(c1)c1c(n2/C=C/c2cccnc2)C2CCN(CC2)C1

Procedure:
The coupling of 9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (140 mg, 0.473 mmol; Example 175) and 3-ethynylpyridine (97 mg, 0.945 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.09-2.18 (m, 4H), 3.03-3.16 (m, 2H), 3.19-3.29 (m, 2H), 3.42-3.49 (m, 1H), 4.25 (s, 2H), 6.86 (d, J=14 Hz, 1H), 7.10 (ddd, J=9, 2, 1 Hz, 1H), 7.28 (d, J=1 Hz, 1H), 7.45 (dd, J=8, 5 Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.79 (d, J=15 Hz, 1H), 8.10 (dt, J=8, 2 Hz, 1H), 8.43 (dd, J=5, 2 Hz, 1H), 8.71 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]=O.O.[OH-].[Na+].[CH3:20][C:21]([CH3:23])=[O:22]>>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]=[CH:20][C:21](=[O:22])[CH3:23]
Reactant: CC(C)=O
Reactant: Cc1c(C)c2c(c(Cl)c1C=O)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)OC(C)(C)C2
Temperature: 40 °C

Procedure:
To a solution of 12 g of the 7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzo-furan-6-carboxaldehyde in 25 ml of acetone was added 8 ml of water and 2 ml of 10% aqueous solution of sodium hydroxide. After refluxing at 40° C. for 15 hours, the reaction mixture was quenched with 2N aqueous solution of hydrochloric acid and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 10 g of 4-(7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzofuran-6-yl)-3-buten-2-one