Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[Li]C1C2C(=C3C(=CN=2)CCCC3)CCC1.C[Si]([N:45]=[C:46]=[S:47])(C)C.Cl>C1C=CC=CC=1>[CH2:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:4]([C:46](=[S:47])[NH2:45])[CH2:3][CH2:2]1
Reactant: c1nc2c(c3c1CCCC3)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: Cl
Agent: [Li]C1CCCc2c1ncc1c2CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: NC(=S)C1CCCc2c1ncc1c2CCCC1
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
A solution of 1,2,3,4,7,8,9,10-Octahydrophenanthridine (17.1 g, 0.91 mole) in benzene (100 ml.) was cooled to 0° C. and treated portionwise under an inert atmosphere with a 9% w/v solution of n-butyl-lithium in hexane (40 ml. 0.56 mole). After the addition was complete the mixture was stirred for a further 0.5 h and the resulting 4-lithio-1,2,3,4,7,8,9,10-octahydrophenanthridine then treated in situ with trimethylsilylisothiocyanate (13 ml., 0.91 mole) and stirred a further hour. The reaction mixture was treated with 2N HCl (100 ml.), the layers separated and the aqueous layer washed with ethyl acetate (100 ml.). The pH of the aqueous solution was adjusted to 9 with Na2CO3 and the solution was extracted with chloroform (3 × 100 ml.). Drying (MgSO4) and evaporation of the combined organic layers gave a yellow oil which crystallised in trituration with hexane. Recrystallisation of the solid from benzene gave the title compound as white needles (4 g, 18%) M.P. 162° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[OH:15])=[O:8].[CH3:17][C:18](O)([CH3:20])[CH3:19]>FC(F)(F)C(O)=O>[C:18]([C:11]1[C:12]([OH:16])=[CH:13][C:14]([OH:15])=[C:9]([C:7](=[O:8])[CH3:6])[CH:10]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)O
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(C(C)(C)C)c(O)cc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Sulphuric acid (4 ml, 75 mmol) was added to a suspension of 2,4-dihyroxyacetophenone (22.8 g, 150 mmol) in a mixture of 2-methyl-2-propanol (35 g, 470 mmol) and trifluoroacetic acid (80 ml), under a nitrogen atmosphere. The resulting suspension was heated, oil bath temperature 75° C., for ˜3 hrs. to give a pale red solution. The resulting solution was allowed to cool and poured into ice/water (350 ml), to give a pale pink precipitate. The solids were removed by filtration and washed with water (600 ml) and hexane (200 ml) to give a pale pink powder. Dried in vacuo (40° C.), to give 1-(5-tert-butyl-2,4-dihydroxy-phenyl)-ethanone as a pale orange powder (28.8 g, 92%).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH2:37]([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51](=O)[CH3:52])=[C:47]([OH:54])[C:46]=1[CH3:55])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH2:37]([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:52]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[C:47]([OH:54])[C:46]=1[CH3:55])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCc2ccccc2)ccc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1O
Yield: 10 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-benzyloxy-2-hydroxy-3-methyl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (73 mg, 10% yield). MS: 584.29 (M+H+); HPLC Procedure A, retention time=18.27 min.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][SH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](=O)(OC1C=CC=CC=1)[O:13]C1C=CC=CC=1>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][S:11][C:12]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: SCCNCc1ccccc1
Solvent: CCO
Product: O=C1SCCN1Cc1ccccc1
Yield: 56.4 %

Procedure:
A solution containing 33.6 g (0.2 mol) of N-phenylmethylcysteamine and 42.8 g (0.2 mol) of diphenyl carbonate in 200 ml of ethanol is refluxed under nitrogen for 24 hours, then ethanol is evaporated under reduced pressure. The residue is taken up in ethyl acetate, washed with 2N sodium hydroxide solution until it becomes free of phenol, then washed with water, dried and evaporated. The residue is distilled under reduced pressure to give 21.8 g (56.4%) of the title compound, b.p.: 140° C./1.5 Hgmm, which solidifies under petroleum ether, m.p.: 50°-51° C.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:39][O:40][C:41]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:42]=1[CH:43]=[CH:44]C(O)=O>>[CH3:39][O:40][C:41]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:42]=1[CH:43]=[CH:44][C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:17]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Product: COc1ccc(OC)c(C=CC(=O)N[C@@H](COC(C)(C)C)C(=O)NCCc2ccc(O)c(O)c2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-seryl]dopamine (572 mg, 1.1 mmol, example 42, step A) as described for example 42 (step B) using 2,5-dimethoxycinnamic acid (345 mg, 1.7 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using 10% EtOAc/CH2Cl2/1% AcOH and 50% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as a yellow powder (300 mg, 56%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1.Cl[O-].[Na+]>ClCCl>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(C)OC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)OC(=O)N=Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To the product (0.42 g) of Step 4 of Example 1 was added dichloromethane (10 mL) and 5% aqueous sodium hypochlorite (20 mL). The two-phase mixture was stirred vigorously overnight at room temperature, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red oil (0.4 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:26])([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:27].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:24][N:21]1[CH2:22][CH2:23][C:11]2[N:10]([CH2:9][C:8]([C:7]3[C:2](=[O:27])[NH:3][CH:4]=[CH:5][CH:6]=3)([OH:26])[CH3:25])[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]=2[CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2Cl)CCN(C)C1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc[nH]c2=O)CCN(C)C1
Temperature: 90 °C
Yield: 36 %

Procedure:
2-(2-Chloropyridin-3-yl)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol (100 mg, 0.277 mmol) and crushed potassium hydroxide (106 mg, 1.89 mmol) in 3 mL tert. butanol were heated at 90° C. for 4 h. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was cooled at RT, diluted with 100 mL brine solution and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to get the 35 mg of 3-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridin-2(1H)-one as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.79 (d, 1H), 7.35 (m, 2H), 7.17 (s, 1H), 6.93 (d, 1H), 6.34 (t, 1H), 4.61 (d, 2H), 4.3 (d, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.36 (m, 2H), 3.1 (s, 3H), 2.37 (s, 3H), 1.51 (s, 3H). Separation by chiral HPLC provides enantiomers II-143a-b.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18].O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH3:20][Si:19]([C:17]#[C:18][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:22])[CH3:21]
Reactant: N#Cc1cccnc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ncccc1C#N
Temperature: 70 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of 2-chloronicotinonitrile (21.6 g, 156 mmol) in toluene (200 mL) was added Pd(dppf)Cl2 (2.3 g, 3.12 mmol), copper (I) iodide (594 mg, 3.12 mmol), triethylamine (32 mL, 312 mmol) and ethynyltrimethylsilane (23 g, 234 mmol). The reaction mixture was stirred at 70° C. under N2 for 5 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give a residue. 40 mL of water was added to the residue, and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with a gradient of PE/EtOAc v/v 40:1, 20:1, 10:1, 5:1) to yield 2-((trimethylsilyl)ethynyl)nicotinonitrile as a yellow solid (19.14 g, yield 61%). ESI MS: m/z 201 [M+H]+.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].S(O)(O)(=O)=O.[CH3:24][N:25](C(OC(C)(C)C)=O)N.C(=O)([O-])O.[K+].Cl>CN(C)C=O>[ClH:1].[ClH:1].[CH3:18][NH:17][C:5]([NH:4][NH:25][CH3:24])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CNNC(=NCCSCc1[nH]cnc1C)NC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of the isothiourea dihydrochloride of Example 1 (i) (6.7 g), N-methyl-N-tert-butoxycarbonylhydrazine sulphate (5.7 g), potassium hydrogen carbonate (10.0 g) and anhydrous dimethylformamide (80 ml) was stirred at 90° C. for 3 hours. After cooling, filtration and concentration to yield the free base, this was heated under reflux with ethanolic hydrogen chloride. Concentration and trituration of the residual product yielded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(CC)C.[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C(OCC)(=O)C.C1COCC1.C1CCCCC1.CCCCCC>[CH2:14]([CH:19]1[CH2:20][CH2:21][C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[F:8])([OH:25])[CH2:23][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC1CCC(=O)CC1
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCCCC1CCC(O)(c2cccc(F)c2F)CC1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
1,2-Difluorobenzene (6) (100.0 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 876.5 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. Then, 4-pentylcyclohexanone (7) (177.0 g) in a THF (200 ml) solution was added dropwise thereto in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. The reaction mixture obtained was poured into a vessel containing an aqueous 1N-HCl solution (500 ml) and ethyl acetate (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, giving 215.1 g of 4-pentyl(2,3-difluorophenyl)cyclohexanol (8). The compound (8) obtained was a yellow oil.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]([C:18]([NH:23][CH3:24])=[CH:19][N+:20]([O-:22])=[O:21])[CH3:17])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:4])[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([N:16]([CH2:15][C:12]1[CH:13]=[N:14][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:17])[NH:23][CH3:24]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CNC(=C[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=C(C(O)C(Cl)(Cl)Cl)[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Chloral hydrate (0.40 g) was added slowly in 40 minutes to a mixture of 1-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-1-methylamino-2-nitroethylene (0.26 g), triethylamine (0.1 g) and acetonitrile (3 ml). The mixture was stirred at room temperature for 21 hours and under refluxing for 9 hours. The resultant crystals were collected by filtration to give 1,1,1-trichloro-4-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-4-methylamino-3-nitro-3-buten-2-ol (Compound No. 11) (0.23 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of ethyl 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.00 g), 4N aqueous sodium hydroxide solution (2.3 ml), tetrahydrofuran (5 ml) and methanol (5 ml) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and acidified with 10% aqueous citric acid solution, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (0.88 g, yield 95%) as colorless crystals. melting point >290° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(F)(F)F)CC1
Yield: 72.6 %

Procedure:
tert-Butyl 4-(2,2,2-trifluoroacetyl)piperazine-1-carboxylate (0.908 g, 3.22 mmol) was added to a solution of borane-tetrahydrofuran complex (8 mmol) in tetrahydrofuran (24 mL) and the reaction mixture was heated at reflux for 2 h. After cooling, 2 N hydrochloric acid (4 mL) was carefully added and the reaction mixture was stirred until gas evolution ceased and then diluted with ethyl acetate (200 mL). Aqueous sodium hydroxide (0.2 M, 75 mL) was then added and the phases were separated. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography (eluting with 20% ethyl acetate in hexanes) to give tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.627 g, 73%) as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[N:26]([CH2:29][CH3:30])[N:27]=[CH:28][C:23]2=[C:22]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=2)[C:21]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH2:29]([N:26]1[C:24]2=[N:25][C:20]([CH2:19][OH:18])=[C:21]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:22]([C:31]3[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=3)=[C:23]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCOC(=O)CCc1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(CO)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a stirred solution of ethyl 3-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (313 mg) in THF (10 ml) was added 1N tetrabutyl ammonium fluoride in THF (0.52 ml) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (3:1) then a mixture of MeOH and CHCl3 (1:50) to give ethyl 3-[1-ethyl-6-(hydroxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (100 mg) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]([OH:21])=O)[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]([Cl:24])=[O:21])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2(C(=O)O)CCC3(CC2)OCCO3)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2(C(=O)Cl)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 245 parts of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid, 150 parts of thionyl chloride and 1350 parts of benzene is stirred first for 30 minutes at room temperature and further for 4 hours at reflux. The reaction mixture is evaporated, yielding 275 parts of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4,5]decane-8-carbonyl chloride as a residue.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH3:15])[C:12](=[O:14])[N:13]=1.C([N-]C(C)C)(C)C.[Li+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]Br)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:37][CH:34]2[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]2)([CH3:15])[C:12](=[O:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: CC1SC(N[C@H]2CC3CCC2C3)=NC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one in anhydrous THF (30 mL) at −78° C. under N2 was added lithium diisopropylamide (Aldrich, 2.0 M in heptane/THF/ethylbenzene, 9.2 mL, 18.4 mmol). After stirring the reaction mixture at −78° C. for 1 h, a solution of 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (Pharma Core, 5.12 g, 18.4 mmol, 4.0 eq) in anhydrous THF (10 mL) was added under N2. The resulting reaction mixture was stirred at −78° C. for 4 h. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for ca. 18 h. Saturated NH4Cl was then added, and the THF was removed in vacuo. The residue was extracted with EtOAc (3×180 mL), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 0-60% EtOAc in hexane) afforded the title compound as an off-white solid (1.42 g). MS (ESI, neg. ion) m/z: 420 (M−H).
Reaction SMILES: CS(OCCCCO[C:11]1[CH:12]=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:24][C:25]1[CH:26]=[C:27]([SH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:24][C:25]1[CH:26]=[C:27]([S:32][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:12]2[CH:11]=[CH:23][C:15]3[C:16]([CH3:21])([CH3:22])[O:17][C:18](=[O:20])[NH:19][C:14]=3[CH:13]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(S)cc1C
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCOS(C)(=O)=O)cc21
Product: Cc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([OH:20])(=[O:19])[C@@H:12]([C@H:14]([C:16]([OH:18])=[O:17])[OH:15])[OH:13]>>[C:16]([CH:14]([CH:12]([C:11]([OH:20])=[O:19])[OH:13])[OH:15])([OH:18])=[O:17].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(N)c1ccc(Cl)cc1
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 72 h

Procedure:
The (-)-enantiomer (starting material for Example 57) was prepared in conventional manner as follows. A warm solution of (±)1-(4-chlorophenyl)ethylamine (101 g) and L(+)tartaric acid (97.3 g) in IMS (7 l) was allowed to cool slowly and to stand at ambient temperature for 3 days. The solid formed was collected by filtration, washed with IMS and recrystallised twice from IMS to give (-)1-(4-chlorophenyl)ethylamine (+) tartrate, m.p. 195°-196° C. The salt was suspended in water and basified with aqueous ammonia (specific gravity 0.88). The mixture was extracted with diethyl ether to give (-) 1-(4-chlorophenyl)ethylamine (free base) which was distilled at 122°-124° C. (28 mmHg). Chiral HPLC indicated enantiomeric purity of 96.8%.
Reaction SMILES: ClC(Cl)(Cl)C(C1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[F:24])[NH:7][CH:6]=1)=O.CO.C1COCC1.[OH-].[Na+].C[CH2:37][O:38][C:39]([CH3:41])=[O:40]>>[F:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:7][CH:6]=[C:41]([C:39]([O:38][CH3:37])=[O:40])[C:13]=12
Reactant: CCOC(C)=O
Reactant: O=C(c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 2,2,2-trichloro-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (490 mg, 1.17 mmol, See: Step A of Example 270) in a mixed solvent (10 mL of MeOH and 10 mL of THF) was added 1 N NaOH (10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 h, and diluted with EtOAc (30 mL). The organic layer was washed with sat. aq. NaHCO3, solution, dried and concentrated in vacuo to give the desired product (235 mg, 61%) as a light brown solid. MS(ESI+) m/z 332.2 (M+H)+.