Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].C(N1C(C)=NC=N1)(C)C.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32](I)=[CH:33]3)[C:29]=2[CH:39]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[Br:24][C:25]1[CH:26]=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:9])[N:7]=4)=[CH:33]3)[C:29]=2[CH:39]=1
Reactant: Cc1ncn(C(C)C)n1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ncnn1C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A solution of 1-isopropyl-3-methyl-1H-[1,2,4]triazole (in a 6:4 mixture with 1-isopropyl-5-methyl-1H-[1,2,4]triazole, 0.75 g, 3.6 mmol) in THF (10 mL) was cooled to −25° C. and treated with n-butyllithium (2.5M in hexanes, 1.45 mL, 3.63 mmol) over 5 min under a nitrogen atmosphere and then stirred at this temperature for 1 h. The mixture was then cooled to −30° C. and a solution of zinc chloride (0.5M in THF, 4.22 mL, 2.11 mmol) was added over 5 min. The reaction mixture was stirred between −20° C. and −25° C. for 30 min, then slowly warmed to RT and stirred at this temperature for 30 min. A solution of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (1.0 g, 2.557 mmol) in THF (2 mL) was then added followed by Pd(PPh3)4 (148 mg, 0.128 mmol) and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h. After cooling to RT, volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was further washed with EtOAc and the combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM followed by Si-PCC, eluent 100% methyl acetate) affording the title compound as a white solid (214 mg, 22%). LCMS: RT 3.50 min [M+H]+ 387.8/389.9.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH2:30]([O:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO.O>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:42][NH:1][C:2]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:3]=2[CH:4]([OH:20])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=2)=[CH:44][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)COc1ccc(N)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)COc1ccc(NCc2ccc(OCc3ccccc3)cc2)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
NMR(CDCl3) δ: 1.02(6H,d,J=6.6 Hz), 1.449(9H,s), 2.05(1H,m), 3.64(2H,d,J=6.6 Hz), 4.31(2H,d,J=5.6 Hz), 4.85(1H,m), 6.797(1H,s), 6.6-7.5(7H,m) (5) In methanol (12 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-isobutyloxybenzyl alcohol (0.36 g), 4-benzyloxy-benzaldehyde (0.2 g) and acetic acid (0.05 g). To the solution was added cyano sodium borohydride (0.065 g). The mixture was stirred for 20 minutes at 60° C. To the reaction mixture was added water (6 ml), which was subjected to extraction with ethyl acetate (60 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-(4-benzyloxybenzylamino)-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-isobutyloxybenzyl alcohol as a yellow oily product (0.45 g).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=4[F:26])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:21][C:20]=4[F:26])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(C#C[Si](C)(C)C)cc4F)n(C)c(=O)c(C)c32)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Under a nitrogen atmosphere, to N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 59 (14.5 g) obtained in Example 4-1 were added chloroform (145 ml), trimethylsilylacetylene 60 (4.99 ml) and triethylamine (13.1 ml). Copper(I) iodide (22 mg) and bis(triphenylphosphine)palladium(II)chloride (83 mg) were added, and the mixture was stirred at room temperature for 20 hrs. The mixture was concentrated under reduced pressure, activated carbon (435 mg) and methanol (435 ml) were added to the residue, and the mixture was stirred with heating at reflux for 2 hrs. Activated carbon was filtered off while it was hot, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=10:1→4:1) and toluene-acetone [5:1 (volume ratio), 87 ml] was added to the obtained crystals. The mixture was stirred at 80° C. for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 61 (12.9 g, yield 93%) as pale-yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=1)(=O)=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([S:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:8][C:9]=1[CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24]
Reactant: COc1ccc(F)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC(C)(C)C)c1
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)cc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl trifluoromethanesulfonate (1.88 g) in toluene (22 mL) were added 4-methoxy-α-toluenethiol (748 μL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78 mg), N-ethyldiisopropylamine (1.56 mL) and tris(dibenzylideneacetone)dipalladium(0) (123 mg) at room temperature, and the mixture was stirred at 120° C. for 20 hr. The mixture was poured into ice water at room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.68 g) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.C=O.[C:37]([O-])(=O)C.[Na+].[BH4-].[Na+]>CO.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][N:21]([CH3:37])[CH2:22]3)[C@@H:18]2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: CC(=O)[O-]
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 30 mg (0.063 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL methanol was added ˜20 mg (excess) aq. formaldehyde and 40 mg sodium acetate. The resulting mixture was stirred at RT for 10 min then 20 mg of NaBH4 was added. The resulting mixture was stirred at RT for 1 hr then water was added. The methanol was evaporated under vacuum and residue extracted with ether (2×25 mL). The combined extracts were dried over drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by prep TLC eluting with EtOAc/MeOH (9/1) to give the title compound. 1H-NMR (CDCl3): δ: ppm. 7.68 (1 H, s), 7.23 (2 H, s), 7.02 (2 H, m), 6.87 (2 H, m), 4.45 (1 H, m), 3.27 (1 H,), 2.78-2.65 (2 H, m), 2.57 (2 H, m), 2.45-2.30 (3 H, m), 2.23-2.12 (2 H, m), 1.98 (1 H, m), 1.83-1.68 (2 H, m), 1.30 (3 H, 6.2) MS: (MH)+489.9.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:2].Br[CH2:14][CH2:15]Br.Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+]>[C:1]([C:3]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH2:15][CH2:14]1)#[N:2]
Reactant: BrCCBr
Reactant: N#CCc1ccc(C(=O)O)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Product: N#CC1(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
To 2 g (12.4 mmol) of 4-(cyanomethyl)benzoic acid (Ubichem, Eastleigh, UK) and 10.9 ml (124 mmol) 1,2-dibromoethane (Fluka, Buchs, Switzerland) cooled at 0° C. with an ice-bath are added a solution of 14.4 g (62 mmol) benzyltriethylammonium chloride in 50 ml 8 M aqueous NaOH. The reaction mixture is stirred over night at rt and then is acidified at pH 1-2 with 6 M aqueous HCl and is extracted with EtOAc. The organic layer is washed with H2O (2×) and evaporated to dryness. The solid is triturated in MeOH to provide the crude title compound. ES-MS: 186 (M−H)−; analytical HPLC: tret=4.43 minutes (Grad 2).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH:16]([C:25]([O:27][CH3:28])=[O:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.O.[BH3-][C:37]#N.[Na+]>CO.CCN(CC)CC.CCOC(C)=O.CC(O)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:37])[CH:16]([C:25]([O:27][CH3:28])=[O:26])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [BH3-]C#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Nc1ccccc1-3
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)N(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethyl 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-6,10-dicarboxylate was dissolved in anhydrous MeOH (0.05M) and HOAc was added. the mixture was treated with a 37% solution of formaldehyde in water (1.2 eq.), then NaCNBH3 (1.2 eq.) was added. The solution was stirred for 2 h at RT. The product was isolated by flash chromatography (PE:EtOAc, 9:1, 0.5% NEt3). After evaporation of the solvents a colourless solid was obtained (quant.). (ES+) m/z 447 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(CO)CC1
Temperature: -50 °C
Reaction time: 2.5 h
Yield: 105.7 %

Procedure:
Lithium aluminum hydride (500 mg) was suspended in 40 ml of tetrahydrofuran, a solution of 3.55 g of ethyl 1-isopropylpiperidine-4-carboxylate in 10 ml of tetrahydrofuran was added thereto at −50° C. and the mixture was stirred for 2.5 hours from under ice-cooling to at room temperature. To this were added 0.5 ml of water, 0.5 ml of a 2N aqueous solution of sodium hydroxide, 1.5 ml of water and anhydrous magnesium sulfate under ice-cooling, the resulting precipitate was removed by filtration and the solvent was evaporated in vacuo to give 2.96 g of (1-isopropyl-4-piperidyl)methanol.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][NH:3]1>[Pd]>[OH:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: OC1NC=Cc2c1[nH]c1cc(C(F)(F)F)ccc21
Agent: [Pd]
Product: Oc1nccc2c1[nH]c1cc(C(F)(F)F)ccc12
Temperature: 50 °C
Yield: 16.8 %

Procedure:
A portion of dihydro 1-hydroxy-7-trifluoromethyl-β-carboline (6 mg) in xylenes (1 ml) was treated with Pd/C (10%, 7 mg) and the mixture heated at 50° C. for one week. The reaction was concentrated after filtering it through celite, and the residue was chromatographed (1:1 hexane-ethyl acetate) on silica gel to give 1 mg of 1-hydroxy-7-trifluoromethyl-β-carboline. A portion of dihydro 1-hydroxy-7-trifluoromethyl-β-carboline (25 mg) in THF (1 ml) was treated with a solution of lithium aluminum hydride in THF (1M, 0.5 ml). The reaction was stirred at 60° C. for 6 h before quenching with water (5 ml) and extracting with ethyl acetate (3 times 10 ml). The combined organic layers were dried (MgSO4) and concentrated to provide tetrahydro 7-trifluoro-methyl-β-carboline. This material was taken up in xylenes (5 ml) and treated with Pd/C (10%, 15 mg). The mixture was stirred at 150° C. for 48 h before filtering through celite and concentrating. The residue was chromatographed (ethyl acetate) on silica gel to give 5 mg of 7-tri-fluoromethyl-β-carboline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15](O)[CH2:16]O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][CH2:16][CH2:15][O:10]2)=[CH:4][C:3]=1[C:11]([F:14])([F:12])[F:13]
Reactant: OCCO
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Fc1ccc(B2OCCO2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 115.4 %

Procedure:
The mixture of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (2.08 g, 10 mmol) and ethane-1,2-diol (3.72 g, 60 mmol) in toluene (150 ml) was refluxed with a Dean-stark trap for 2 h, then cooled to rt. The solvent was concentrated to dryness to afford the crude product (2.7 g, 100%). 1H NMR (300 MHz, CDCl3): δ 8.08-8.05 (d, 1H), 8.01-7.96 (t, 1H), 7.24-7.17 (t, 1H), 4.40 (s, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[F:16][C:17]([F:47])([F:46])[C:18]([F:45])([F:44])[C:19]([F:43])([F:42])[C:20]([F:41])([F:40])[C:21]([F:39])([F:38])[C:22]([F:37])([F:36])[C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[CH2:25][CH2:26][CH2:27][CH:28](I)[CH2:29][CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([F:32])([F:33])[C:23]([F:34])([F:35])[C:22]([F:36])([F:37])[C:21]([F:38])([F:39])[C:20]([F:40])([F:41])[C:19]([F:42])([F:43])[C:18]([F:44])([F:45])[C:17]([F:47])([F:46])[F:16])([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([F:33])([F:32])[C:23]([F:35])([F:34])[C:22]([F:37])([F:36])[C:21]([F:39])([F:38])[C:20]([F:41])([F:40])[C:19]([F:43])([F:42])[C:18]([F:45])([F:44])[C:17]([F:47])([F:46])[F:16])[C:4]=2[CH:3]=1
Reactant: CCC(I)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCC1(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a magnetically stirred solution of 2,7-dibromofluorene 1 (2.00 g, 6.17 mmol) and semi-perfluoroalkyl iodide 4 (9.72 g, 15.4 mmol) in toluene (12 cm3) were added 50% (w/w) NaOH aqueous solution (24 g) and Bu4NBr (0.20 g, 0.62 mmol). The mixture was then heated to 80° C. After the reaction was stirred overnight under N2 atmosphere, it was allowed to cool to ambient temperature and quenched by the addition of water (150 cm3). The product was extracted with hexanes (150 cm3). The organic layer was then washed with water (150 cm3), dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, hexanes) and then recrystallized from hexanes (40 cm3) twice to give the dibromofluorene 6 as colorless crystals (5.91 g, 72%); mp 82-83° C. (hexanes); (Found: C, 37.4; H, 2.1. C41H30Br2F34 requires C, 37.1; H, 2.3%); IR (KBr) νmax: 2932, 2855, 1600, 1448, 1371, 1329, 1245, 1208, 1150, 1054, 1017, 980, 954, 810, 705 cm−1; 1H NMR (500 MHz, CDCl3, δ) 7.55 (d, J=8 Hz, 2H, Ar—H), 7.49 (dd, J=1.5, 8 Hz, 2H, Ar—H), 7.46 (d, J=1.5 Hz, 2H, Ar—H), 2.00-1.90 (m, 8H, 2×ArCCH2 and 2×CH2CF2), 1.47-1.41 (m, 4H, 2×CH2CH2CF2), 1.20-1.09 (m, 8H, 2×ArCCH2CH2CH2 and 2×CH2CH2CH2CF2), 0.65-0.59 ppm (m, 4H, 2×ArCCH2CH2); 13C NMR (126 MHz, CDCl3, δ) 152.1, 139.1, 130.3, 126.0, 121.6, 121.2, 55.5, 40.0, 30.7 (t, J=22 Hz), 29.4, 28.7, 23.5, 20.0 ppm; m/z (ESI) 1328.0 [M+. C4H30Br2F34: requires M, 1328.01].
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[OH-].[K+].I[CH3:14]>CO.O>[CH3:14][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2]1=[O:1]
Reactant: O=C(O)c1ccc[nH]c1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cccc(C(=O)O)c1=O

Procedure:
To 2-oxo-1H-pyridine-3-carboxylic acid (2.00 g, 14.4 mmol) in methanol (20 mL) was added a solution of KOH (1.60 g, 28.5 mmol) in water (3 mL) and the mixture was vigorously stirred until a thick suspension formed. Iodomethane (10 μL, 0.16 mmol) was added and the mixture was heated at reflux for 1.5 h. The mixture was concentrated to ⅓ volume and was acidified to pH 1 with 6N HCl. The solids were filtered off and were washed with water (3×2 mL) and acetonitrile (2×2 mL), and then dried in vacuo to give 1-methyl-2-oxo-pyridine-3-carboxylic acid as a white solid. ESI-MS m/z calc 153.0. found 154.1 (M−1)−. Retention time: 0.65 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH2:28][CH2:29]Cl)[CH2:26][CH3:27].Cl>>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:24])[CH2:28][CH3:29])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CCN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Product: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Yield: 151.7 %

Procedure:
3 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.7 g of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride are treated in the same manner as described in Example 5. The product is converted to its hydrochloride and recrystallized from a mixture of ethanol and ether. 3.1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.OO.C([O-])([O-])=[O:12].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(Cl)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
2-chloro-4-methylpyridine (10 g, 80 mmol) was dissolved in acetic acid (100 ml). Hydrogen peroxide (31%, 86.8 g, 80.7 ml, 790 mmol)) was added in 4 portions and the solution stirred under nitrogen at 65° C. for 18 hours. The mixture was poured into ice water (300 ml), and solid Na2CO3 added until the solution was alkaline. The mixture was extracted with DCM (3×300 ml), the organic fractions combined, washed with sodium thiosulfate (1M, 100 ml), brine, dried over Na2SO4, and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([CH2:9][O:10][CH2:11][C@@H:12]1[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])([OH:8])=[O:7].C(N(CC)CC)C.Cl>ClCCl.O>[C:6]([CH2:9][O:10][CH2:11][C@@H:12]1[CH2:16][C@@H:15]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][N:13]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19])([OH:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.62 ml) in dichloromcthane (2 ml) was dropwise added to a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-hydroxy-1-(4nitrobenzyloxycarbonyl)pyrrolidine (1.42 g) and triethylamine (1.4 ml) in dichloromethane (14 ml) at 0°-5° C., and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into water (50 ml), adjusted to pH 2.5 with 6N hydrochloric acid and extracted with dichloromethane (50 ml×2). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccc(O)cc1
Agent: Cl[Sn]Cl
Product: Nc1cc(Cl)ccc1Oc1ccc(O)cc1
Yield: 80.3 %

Procedure:
The product from Example 165b (1.0 g, 3.7 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.7 g, 78%).