Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[methyl(2-pyridinylmethyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 35) (527 mg, 1.12 mmol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was azeotroped from toluene. The residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate (3 ml) and the pH was adjusted to pH 4 with aqueous citric acid solution (10% w/v). The aqueous phase was extracted with ethyl acetate (×2) and the combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a yellow oil (456 mg)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH2:3]1.[CH3:15][CH2:16][CH2:17][CH2:18][CH:19]([CH:21]([CH3:23])[CH3:22])C.[CH3:24]CCC(CC(C)C)C.CC(CC(C(C)C)C)C.[OH-].[OH-].[Ca+2]>O>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[C:8]([CH2:24][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:21]([CH3:22])[CH3:23])[CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH2:3]1
Reactant: CC1(C)CC(C)(C)c2cc(O)ccc21
Reactant: CCCCC(C)C(C)C
Reactant: CCCC(C)CC(C)C
Agent: CC(C)CC(C)C(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(C)CCCCCCc1cc2c(cc1O)C(C)(C)CC2(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
760 g 1,1,3,3-tetramethyl-5-hydroxy-indane, 2000 g tripropylene and 10 ml borofluoride-etherate are stirred for 1.5 hours at 20° to 25° C whilst being cooled with water. Then 30 g white-lime hydrate are added and stirred for 1 hour at 50° C. The reaction mixture is removed from the lime and the excess tripropylene is distilled off in a water stream vacuum to an absorbtion temperature of 150° C. The residue consists of 1268 g 1,1,3,3-tetramethyl-6-isononyl-5-hydroxy-indane in the form of a yellowish viscous oil.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:20])[C@:6]1([CH3:19])[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>C1COCC1.O>[C:12]([N:7]1[CH2:8][C@H:9]([O:11][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:10][C@@:6]1([CH3:19])[C:5]([OH:4])=[O:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
To a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry THF was added (2S,4R)-N-Boc-4-hydroxy-2-methyl-proline methyl ester (0.55 g) in 5 mL of dry THF. The reaction mixture was stirred for 45 min., and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The reaction mixture was refluxed for 3 h. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to afford (2S,4R)-N-Boc-4-(4-bromo-benzyloxy)-2-methyl-proline (0.25 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of 29 (9.85 g, 20.6 mmol) in CH2Cl2 (100 mL) was added Dess-Martin periodinane (9.61 g, 22.6 mmol). After 30 min, water (75 mL) and saturated Na2S2O4 solution (75 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 8.32 g of 30. 1H-NMR: 400 MHz, (CDCl3) δ: 7.91 (s, 1H), 4.40 (q, 2H, J=7 Hz), 2.49 (s, 3H), 1.39 (t, 3H, J=7 Hz). LCMS-ESI+: calc'd for C13H10BrF3NO6S2: 475.9 (M+H+); Found: 476.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:11]2[CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)=[N:5][N:6]=1
Reactant: O=C1CCOCC1
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(NC2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (3 g) and tetrahydro-4H-pyran-4-one (3.7 g) in acetic acid was added sodium cyanoborohydride (9.7 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.79 g, 14%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[CH3:13][O:14][CH2:15][CH2:16][Br:17]>>[BrH:17].[NH:11]=[C:8]1[N:7]([CH2:16][CH2:15][O:14][CH3:13])[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:10][S:9]1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COCCBr
Product: Br
Product: CCOC(=O)Cc1csc(=N)n1CCOC
Yield: 43.4 %

Procedure:
A mixture of (2-aminothiazol-4-yl)acetic acid ethyl ester (18.6 g, 100 mmol) and 2-bromoethyl methyl ether (15.3 g, 110 mmol) were processed using the method described in Example 2A to afford 14.1 g (83%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.14-1.28 (m, 3H) 3.24 (s, 3H) 3.54 (t, J=5 Hz, 2H) 3.91 (s, 2H) 4.04-4.25 (m, 4H) 6.92 (s, 1H) 9.50 (s, 1H); MS (DCI/NH3) m/z 231 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:37]#[C:38]Br.C(#N)C>CO>[CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:9]=2[CH2:10][N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)[C:38]#[N:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CBr
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Solvent: CC#N
Solvent: CO
Product: COC(c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)phenyl)methanamine (150 mg, 0.28 mmol) and NaOAc.3H2O (77.6 mg, 0.57 mmol) in methanol was added cyanogen bromide in acetonitrile (5.0 M, 0.1 mL, 0.5 mmol). The slurry was stirred at room temperature overnight. The mixture was loaded onto a samplet and purified by chromatography over 25+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (144.1 mg, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.19 (m, 6H) 1.41-1.53 (m, 1H) 1.62 (d, J=7.88 Hz, 2H) 1.71-1.79 (m, 1H) 1.96 (d, J=12.45 Hz, 1H) 3.16 (s, 3H) 4.00 (d, J=7.47 Hz, 1H) 4.32 (d, J=14.11 Hz, 1H) 4.32 (s, 2H) 4.40 (d, J=14.11 Hz, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.54 (s, 1H) 7.63 (d, J=8.30 Hz, 1H) 7.78 (s, 2H) 7.91 (s, 1H). MS (ES−) Calc: 552.2, Found: 551.5 (M−1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].O[C@H]1CC[C@@H](NC2C(C#N)=CN=C(S(C)=O)N=2)CC1(C)C.[NH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([S:53]([NH2:56])(=[O:55])=[O:54])=[C:49]([Cl:57])[CH:48]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:57][C:49]1[CH:48]=[C:47]([CH2:46][CH2:45][NH:44][C:11]2[N:10]=[C:9]([NH:8][CH:5]3[CH2:6][CH2:7][CH:2]([OH:1])[C:3]([CH3:21])([CH3:22])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:52]=[CH:51][C:50]=1[S:53]([NH2:56])(=[O:55])=[O:54]
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: NCCc1ccc(S(N)(=O)=O)c(Cl)c1
Agent: CS(=O)c1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CC(Nc2nc(NCCc3ccc(S(N)(=O)=O)c(Cl)c3)ncc2C#N)CCC1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, 0.28 mmol) and 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile, 4-(2-amino-ethyl)-2-chloro-benzenesulfonamide (90 mg, 0.38 mmol) and DIEA (72 mg, 0.56 mmol) in THF (4 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (28.6 mg, 0.060 mmol, 26% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 7.93 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.26-4.12 (m, 1H), 3.66-3.46 (m, 2H), 3.31-3.25 (m, 1H), 2.87 (t, J=6.8 Hz, 2H), 1.86-1.35 (m, 6H), 0.90 (s, 3H), 0.88 (s, 3H). MS (ESI) m/z 479.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:6]([C:7]([O:9]C)=[O:8])=[C:5]([OH:15])[CH:4]=1)=O.[C:16]1([C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:31][C:32]([NH2:34])=[O:33].Cl>CCO>[OH:15][C:5]1[CH:4]=[C:3]([CH:1]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:12]=[C:11]([O:13][CH3:14])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(O)cc(C=O)cc1OC
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: COc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(O)c1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 9.8 %

Procedure:
A mixture of methyl 4-formyl-2-hydroxy-6-methoxybenzoate (Intermediate 87) (150 mg, 0.76 mmol), 1,2-diphenylethanone (160 mg, 0.76 mmol), urea (150 mg, 2.5 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxed under N2 overnight. The mixture was concentrated in vacuo. The residue was taken up in MeOH (10 mL) and aq. NaOH (2 M, 10 mL) and was stirred at 50° C. under N2 for 5 hours. The resulting mixture was cooled, and then acidified with aqueous HCl (2 M, 12 mL) to pH=3 followed by a standard aqueous/EtOAc workup and purification by prep-HPLC (0.1% TFA as additive) to give Compound 165 (31 mg, 2-step yield 10%). 1H NMR (CD3OD 400 MHz): δ 7.30-7.20 (m, 5H), 7.12-7.06 (m, 3H), 6.94-6.88 (m, 2H), 6.67 (d, J=1.6 Hz, 1H), 6.50 (d, J=1.6 Hz, 1H), 5.29 (s, 1H), 3.85 (s, 3H). MS (ESI): m/z 417.4 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=CC=C(C=C)C=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:20]([OH:32])(=O)[CH2:21][C:22]([CH2:27][C:28](O)=O)([C:24](O)=O)O.C[N+]1([O-])CC[O:37]CC1>CC(O)(C)C.C(O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:28][CH:27]=[C:22]([CH:21]([OH:37])[CH2:20][OH:32])[CH:24]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2cnn(Cc3ccccc3)c2c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: OCC(O)c1ccc2cnn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A sample of N1-benzyl-6-vinyl-1H-indazole (crude material, ˜24 mmol) was stirred in a mixture of tBuOH (25 mL), water (25 mL) and citric acid (10.1 g, 48.0 mmol). K2OsO4.2H2O (44 mg, 0.12 mmol, 0.5 mol %) and N-methylmorpholine-N-oxide (3.1 g, 26.4 mmol) were added, and the resulting oily, biphasic mixture stirred overnight at rt. 1H NMR of a sample showed approx. 40% conversion, and so the mixture was warmed to 50° C. (giving a single phase) for 7 h. Ethanol (50 mL) was added, and the mixture again left to stir overnight. Precipitated OsO2 was removed by filtration through celite (washing with ethanol and ethyl acetate), and the filtrate was concentrated on a rotary evaporator. The residue was taken up in 1.0 M aq. HCl and EtOAc; the layers were separated and the aqueous phase extracted with further EtOAc. The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was passed through a short silica plug, eluting with EtOAc, and concentrated to afford the title compound (6.26 g, 92% over two steps) as a reddish gum. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.27-7.18 (m, 3H), 7.16-7.09 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 5.50 (s, 2H), 4.86 (d, J=7.6 Hz, 1H), 3.78-3.68 (m, 1H), 3.60 (m, 1H), 3.46 (s, 1H), 2.84 (s, 1H). MS (ES+): 269 ([M+H]+), calcd for [C16H16N2O2+H]+ 269.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20]CO)[CH3:19])[CH3:14].CO>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:12][CH:13]([CH3:14])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)CCCC(C)CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)CCCC(C)CCOC(=O)c1ccc(N)cc1
Yield: 28.8 %

Procedure:
Na metal (200 mg, cat.) was added to a suspension of methyl 4-aminobenzoate (45 g, 300 mmol), tetrahydrogeraniol (48 g, 300 mmol) in PhMe (250 mL). The suspension was heated under reflux for 3 hours with the azeotropic removal of MeOH. The mixture was cooled and filtered through a plug of silica (400 mL) with cyclohexane: EtOAc (9:1) as eluant to give the ester (24 g, 30%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:43][C:5]2[C:6](=[O:42])[N:7](COCC[Si](C)(C)C)[C:8]3[C:9]([CH3:33])=[CH:10][C:11]([O:31]C)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C@@H:20]([CH3:30])[CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:16][CH:15]=4)[C:13]=3[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[ClH:1].[NH2:22][CH2:21][C@@H:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:13]3[C:4]4[CH:3]=[C:2]([Cl:1])[S:43][C:5]=4[C:6](=[O:42])[NH:7][C:8]=3[C:9]([CH3:33])=[CH:10][C:11]=2[OH:31])=[CH:15][CH:16]=1)[CH3:30]
Reactant: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(Cl)sc1c(=O)n2COCC[Si](C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c(-c2ccc([C@@H](C)CN)cc2)c2c1[nH]c(=O)c1sc(Cl)cc12
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-(4-(2-chloro-8-methoxy-6-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (32 mg, 0.050 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) and the reaction was stirred at that temperature for 1 h and quenched by pouring onto water or ice-water. The resulting mixture was concentrated and the residue was dissolved methanol (2 mL) and treated with NH4OH (2 mL). The resulting mixture was stirred at rt for 2 h and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired fractions were combined, concentrated and the residue was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a hydrochloride salt: 1H NMR (500 MHz, MeOD) δ 7.57 (dd, J=7.9, 1.8 Hz, 1H), 7.48 (dd, J=7.8, 1.8 Hz, 1H), 7.35 (dd, J=7.9, 1.7 Hz, 1H), 7.29 (dd, J=7.8, 1.6 Hz, 1H), 7.10 (d, J=0.7 Hz, 1H), 5.75 (s, 1H), 3.28-3.19 (m, 3H), 2.55 (s, 3H), 1.50 (d, J=6.4 Hz, 3H). ESI MS m/z 399 [C21H19ClN2O2S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
The above-mentioned ethyl 4-(4-chlorophenylthio)-3-nitrobenzoate (760 mg, 2.25 mmol) was dissolved in a mixture of ethanol (5 mL) and THF (10 mL). After addition of 2M aqueous sodium hydroxide (2.25 mL, 4.50 mmol), the mixture was stirred at room temperature for 4 hours and placed under reduced pressure to distill the solvent off. To the residue were added water (20 mL) and 2M aqueous hydrochloric acid until the mixture reached pH 2. The precipitated crystalline product was collected by filtration, washed successively with water (5 mL×3), a mixture (5 mL) of ethanol and water (1/4) and hexane (5 mL×2), and dried at 40° C. under reduced pressure, to obtain 703 mg (yield 100%) of the titled compound as a yellow crystalline product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][OH:35]>C(O)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Agent: [Cu]I
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1OCC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1 g 4-Iodo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 5 ml 2,2,2-trifluoro-ethanol 1.4 g Cs2CO3, 56 mg CuI and 106 mg 1,10-Phenanthroline were added. The reaction mixture heated for 4 h to 100° C. under microwave irradiation (100 W, CEM Discover™ apparatus). Then 10 HCl in ethanol (8M) was added and the solution was stirred at RT. After 16 h the solvents were removed under reduced pressure and the residue taken up in DCM and water. The organic phase was separated and the aqueous layer was extracted with DCM (2×50 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 359 mg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].N1C=CC=CC=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccccc1Br
Solvent: O
Solvent: c1ccncc1
Product: O=C(NCCc1ccccc1Br)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 2-bromophenethylamine (1800 mg, 9 mmol, Aldrich), pyridine (5 mL), 4-(trifluoromethyl)benzoyl chloride (2 mL, 9 mmol, Fluka). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with water (30 mL), saturated NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N-(2-bromophenethyl)-4-(trifluoromethyl)benzamide. MS (ESI pos. ion) m/z: 372 (M+1).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C@@H:25]1[C@@H:29]([CH2:30][NH2:31])[O:28][C@@H:27]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:26]1)(=O)C.C(Cl)Cl.CO>N1C=CC=CC=1>[C:1]([NH:31][CH2:30][C@H:29]1[O:28][C@@H:27]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:26][C@@H:25]1[OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CN
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 35 %

Procedure:
557 mg of trityl chloride were added to a solution of 560 mg (2 mmol) of 3'-O-acetyl-5'-amino-5'-deoxythymidine [which had been prepared by the procedure reported by J. P. Horwitz et al. in J. Org. Chem., 27, 3045 (1962)] in 20 ml of dry pyridine, and the resulting mixture was heated under reflux for 1 hour whilst excluding moisture. After the disappearance of the starting compound had been ascertained by thin layer chromatography (using methylene chloride containing 5% by volume methanol as the developing solvent), the solvent was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was mixed with 10 ml each of methanol and water, and then the mixture was concentrated by distillation under reduced pressure. This operation was repeated three times, after which the residue was dissolved in 30 ml of ethyl acetate, and the resulting solution was washed with 20 ml each of a saturated aqueous solution of sodium chloride, 0.2N aqueous hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate. The organic solution was then dried over anhydrous magnesium sulfate, and the solution was then evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml of methanol saturated with ammonia gas and the flask holding the solution was tightly closed. It was then allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was dissolved in 10 ml of methylene chloride. The solution was purified by column chromatography through silica gel, using methylene chloride containing 5% by volume of methanol as the eluent. Fractions containing the desired compound were combined and evaporated to dryness under reduced pressure. By lyophilizing the residue from benzene, 338 mg of the title compound were obtained as a white powder.