Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]=1.[C:15](=[O:17])=[O:16].O>C1COCC1>[F:6][C:7]1[N:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][C:12]=1[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(F)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(F)c(C(=O)O)c1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of DIPA (54.0 mL, 385 mmol) in THF (1101 mL, 385 mmol) at −60° C. was added BuLi, 2.5 M in hexanes (154 mL, 385 mmol) over 5 minutes such that the internal temperature was maintained below −60° C. After stirring for 45 minutes at −65° C. a solution of 2-fluoro-5-methoxypyridine (49 g, 385 mmol) in 200 mL of THF was added over the course of 2 minutes maintaining an internal temperature <−65° C. The reaction was stirred at −70° C. for 1.5 hours then reaction was poured into a 3 L flask containing 1200 g of crushed dry ice. The reaction was allowed to warm to 0° C. and then poured into 1000 mL of water. The organics were removed under reduced pressure and the aqueous layer was acidified with 1100 mL of 2 N HCl. The resulting thick white slurry was stirred for 1 hour then filtered to provide 2-fluoro-5-methoxynicotinic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.[N:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)([OH:26])[CH3:25])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cncs2)cc1
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1ncc(-c2ccc(F)cc2)s1
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of 5-(4-fluorophenyl)thiazole (0.1 g, 0.558 mmol) in dry THF (8 mL) at −78° C., was slowly added n−1.6 M BuLi in hexanes (0.7 mL, 1.117 mmol), the reaction mixture was stirred for 30 minutes and 1-(pyridin-4-yl)ethanone (0.13 mL, 1.117 mmol) in THF (8 mL) was added. The reaction mixture was stirred for 2 hours at −78° C., the reaction mixture quenched with saturated NH4Cl solution (50 mL), extracted with EtOAc (2×50 mL), the organic layer washed with water (50 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (5% methanol in dichloromethane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl) ethanol as off-white solid (35 mg, 22% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (br s, 1H), 8.03 (s, 1H), 7.66-7.63 (m, 2H), 7.53 (br s, 2H), 7.24 (t, 2H), 6.99 (s, 1H), 1.89 (s, 3H); LC-MS m/z calculated for [M+H]+301.07. found 301.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 35.9 %

Procedure:
A solution of 5-bromo-3-methyl-benzothiophene-2-sulfonyl chloride (Intermediate 10) (1.00 g, 3.26 mmol), ethyl 3-aminobenzoate (550 mg, 3.33.mmol) and pyridine (3 mL) in CH2Cl2 (150 mL) was stirred at room temperature overnight. The reaction was diluted with CH2Cl2, washed with water and aqueous HCl, dried and concentrated. The residue was purified on silica, using CH2Cl2 as eluent, resulting in 532 mg (36%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (t, J=7.09 Hz, 3 H) 2.44 (s, 3 H) 4.34 (q, J=7.09 Hz, 2 H) 6.85 (s, 1H) 7.36 (dd, J=8.03, 7.62 Hz, 1 H) 7.43 (ddd, J=8.03, 2.26, 1.25 Hz, 1 H) 7.57 (dd, J=8.66, 1.88 Hz, 1 H) 7.65 (dd, J=8.66, 0.50 Hz, 1 H) 7.72 (dd, J=2.26, 1.63 Hz, 1 H) 7.84 (ddd, J=7.62, 1.63, 1.25 Hz, 1 H) 7.87 (dd, J=1.88, 0.50 Hz, 1 H). MS (ESI+) m/z 454 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])=[O:8])([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])=[O:8]
Reactant: [H][H]
Reactant: Cc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(NC(=O)c2cccc(N)c2)c1C

Procedure:
To a solution of 1 (1 g) in 70 mL methanol and 30 mL of tetrahydrofuran was added 10% Pd/C (0.2 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture was filtered and concentrated in vacuo to obtain the product. NMR (300 MHz, CDCl3) δ 7.71 (1H, s), 7.55 (1H, d, J=9 Hz), 7.23 (1H, t, J=9 Hz), 7.19 (1H, s), 7.14 (1H, t, J=9 Hz), 7.04 (1H, d, J=9 Hz), 6.82 (1H, d, J=9 Hz), 3.84 (2H, b), 2.32 (3H, s), 2.20 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH2:4][CH:5]([OH:18])[C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[H-].[Na+].[CH3:21]I>C1COCC1>[CH3:21][O:18][CH:5]1[C:6]2([CH2:7][CH2:8][CH2:9]2)[O:10][C:11]2[C:3](=[C:2]([CH3:1])[C:14]([OH:15])=[C:13]([CH3:16])[C:12]=2[CH3:17])[CH2:4]1
Reactant: CI
Reactant: Cc1c(C)c2c(c(C)c1O)CC(O)C1(CCC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1Cc2c(C)c(O)c(C)c(C)c2OC12CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyldimethylsilyl derivative of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-3,6-diol (30 mg), prepared as described in Example 22, in 1 mL of THF was added to NaH (8 mg) suspended in THF (1.5 mL). The resulting mixture was stirred at room temperature for 10 min and methyl iodide (34 mg) was added. The reaction was stirred at room temperature for 10 h and quenched onto 30 g of ice. It was extracted with hexane/EtOAc (2:1, 3×30 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford the 6-tert-butyldimethylsilyl derivative of 3-methoxy-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol which was used directly for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (3.0 g, 19 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (3.0 g, 21 mmol) and potassium carbonate (5.4 g, 39 mmol) in 2-butanone (75 mL) was heated to reflux for 20 hours. An additional portion of 2-(dimethylamino)ethyl chloride hydrochloride (2.0 g, 14 mmol) was added, and stirring at reflux proceeded for 24 hours. The mixture was cooled and evaporated under vacuum, and the residue was partitioned between ethyl acetate (100 mL) and water (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×150 mL) and extracted into dilute aqueous HCl (3×75 mL). The combined aqueous extracts were washed with ethyl acetate (2×100 mL) and basified (NaOH), and the resulting mixture was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 2.9 g as a yellow oil, in 67% yield; 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.76 (t, J=5.5 Hz, 2H), 4.13 (t, J=5.5 Hz, 2H), 6.72-6.81 (m, 2H), 8.09 (t, J=9.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][C@@H:3]1[C:12]([O:14]CC)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH2:17]([NH:24][C:12]([C@H:3]1[N:2]([CH3:1])[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1)=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)OCC)N1C
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)[C@H]1CC[C@@H](C(=O)NCc2ccccc2)N1C

Procedure:
A solution of diethyl cis-1-methylpyrrolidine-2,5-dicarboxylate (10.95 g, 0.0478 mole) and benzylamine (5.2 ml, 0.048 mole) in 30 ml xylene was refluxed 72 hours at 140°C. After evaporation of the xylene in vacuo, the oily residue was fractionated on a Vigreux column. After an initial fraction of the starting compound (0.49 g), the product was collected: 7.11 g (boiling point 160°C, 0.25 mm).
Reaction SMILES: [CH:1]1([C:4]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH3:5])[CH2:3][CH2:2]1.CC(C(C1C2C(=C(CS(C)=[O:52])C=CC=2)NC=1)C1C=CC(C(F)(F)F)=CC=1)CC#N>>[CH:1]1([C:4]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:52])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(CC#N)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Reactant: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 273 mg (0.81 mmol) of the compound from Example 95 in analogy to the synthesis of the compound from Example 91. 213 mg (73% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18](#[N:22])[CH2:19][C:20]#[N:21]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:18]#[N:22])[C:20]#[N:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(I)cc1
Reactant: N#CCC#N
Product: N#CC(C#N)C(CC(=O)c1ccc(I)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-iodophenyl)-3-phenylprop-2-en-1-one and malononitrile, 2-(3-(4-iodophenyl)-3-oxo-1-phenylpropyl)malononitrile was obtained as colourless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:21]=1.N(CC)CC>C1COCC1.[Cu](I)I>[CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:21]=2)[C:3]1=[O:18]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reactant: C#CC[C@@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
Copper iodide (22.64 mg, 0.1200 mmol), followed by PdCl2(Ph3P)2 (41.73 mg, 0.060 mmol) was added portionwise to a solution of tert-butyl N-[(3R)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 10) (300 mg, 1.19 mmol), 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 12) (584.44 mg, 1.61 mmol) and Et2NH (0.62 mL, 5.95 mmol) in THF (10 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was purified by Biotage SP4, using a 25 g SNAP cartridge, eluting with 0 to 100% EtOAc/i-hexane affording tert-butyl N-[(3R)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (D13) (482 mg, 0.987 mmol, 83.0% yield) as a pale yellow foam.
Reaction SMILES: [CH2:1]([S:13][CH:14]([CH3:27])[CH2:15][C:16]([CH:18]1[C:23]([CH3:25])([CH3:24])[CH2:22][CH:21]=[CH:20][CH:19]1[CH3:26])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC[OH:30]>CO.O>[CH2:1]([S:13]([CH:14]([CH3:27])[CH2:15][C:16]([CH:18]1[C:23]([CH3:24])([CH3:25])[CH2:22][CH:21]=[CH:20][CH:19]1[CH3:26])=[O:17])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCO
Reactant: CCCCCCCCCCCCSC(C)CC(=O)C1C(C)C=CCC1(C)C
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCS(=O)C(C)CC(=O)C1C(C)C=CCC1(C)C
Reaction time: 15 h
Yield: 38 %

Procedure:
A solution of 3-(dodecylthio)-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (2.00 g; 5.10 mmol) in MeOH (20 ml) was added at 0° C. to a solution of NaIO4 (1.14 g, 5.30 mmol) in H2O (11 ml). The temperature was brought to room temperature and EtOH (30 ml) was added. The suspension was stirred for 15 h and title compound extracted (ether/brine). The organic phase was washed with aqueous NaHSO3, H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated. (16.2 g). Flash chromatography (cyclohexane/ethyl acetate=7:3, then 1:1) on SiO2 (40 g) afforded 803 mg of the title compound (38%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1.[F-].[Cs+]>C(#N)C.O>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:27]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: Cc1c[nH]cn1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: Cc1cn(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 160 °C
Yield: 54.5 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (50 mg, 0.15 mmol), 4-methyl-1H-imidazole (36 mg, 0.44 mmol) and CsF (25 mg, 0.16 mmol) in acetonitrile (1.45 mL) was heated in a microwave to 160° C. for 20 minutes. The reaction was diluted with water (5 mL) and the resulting suspension was filtered. The precipitate was washed with water and then purified by column chromatography using gradient elution with methanol and dichloromethane to afford 6-((6-(4-methyl-1H-imidazol-1-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (28 mg, yield 56%)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[C:6]1([CH:2]([O:1][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(O)C(OC1CCCCO1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a stirred solution of hydroxy-phenyl-acetic acid (2 g, 13.4 mmol) in DCM (30 mL) was added PTSA (51.2 mg, 0.27 mmol) at 0° C. followed by the addition of 3,4-dihydro-2H-pyran (1.55 g, 18.4 mmol). The mixture was stirred at 0° C. for another 15 min and then gradually warmed up to room temperature and stirred for a further 1.5 hours. The reaction mixture was diluted with DCM (100 mL). The organic phase was washed with saturated aq. Na2CO3 (2×20 mL), water (20 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:5) to afford the title compound as a yellow sticky solid in 48% yield, 1.5 g. LCMS (system 10): Rt=1.82 min; m/z 237 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:44]=[C:43]([CH3:45])[O:42][N:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:44]=[C:43]([CH3:45])[O:42][N:41]=3)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1cc(C2(CN)CCN(C(=O)OC(C)(C)C)CC2)no1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5cc(C)on5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(5-methylisoxazol-3-yl)piperidine-1-carboxylate (amine intermediate “S”) were reacted to give the title compound. LC/MS (M+H)+: 640. Ret. time: 1.89 min. (Condition L).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].I[CH3:35].O>CN(C=O)C>[CH3:35][N:19]([C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[N:18]=1
Reactant: CI
Reactant: COc1ccccc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1nc(-c2ccccc2O)nc2ccccc12)[C@H]1CCNC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
(S)-tert-Butyl 3-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.259 g, 0.616 mmol) (prepared by methods analogous to those described in Synthesis 2) was dissolved in DMF (6.16 mL) and cooled to −30° C. NaH (60% dispersion in mineral oil, 0.041 mg, 0.678 mmol) was added and the mixture was stirred at −30° C. for 15 minutes. The mixture was cooled to −78° C. and iodomethane (0.046 mL, 0.727 mmol) was added dropwise. The solution was warmed to room temperature over 2 hours. Water (5 mL) was added and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (1.3 mL) and 1 M boron tribromide in dichloromethane (1.3 mL). The solution was stirred at room temperature for 18 hours. Methanol (5 mL) was added and the mixture was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with a gradient from 3% to 30% methanol in dichloromethane, gave the title compound as a yellow solid (0.028 g, 66%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1(=O)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1>C(O)C>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: OC1CCNCC1
Reactant: O=C1CCC(=O)CC1
Solvent: CCO
Product: Oc1ccc(N2CCC(O)CC2)cc1
Yield: 56.5 %

Procedure:
202 mg of 4-hydroxypiperidine and 448 mg of 1,4-cyclohexanedione were heated under reflux in 10 ml of ethanol and reacted for 9 hours with introducing air with a pump. During the reaction, ethanol was added as needed. After the completion of the reaction, the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=2:1) and 0.218 g of 1-(4-hydroxyphenyl)-4-hydroxypiperidine was obtained (yield 56.48%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.22 g of dl-trans-2-benzyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 6) in 10 ml of dimethylformamide was added dropwise, with ice-cooling, to 10 ml of dimethylformamide containing suspended in it 0.480 g of a 55% w/w suspension of sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for 60 minutes, after which 5.49 g of hexadecyl bromide were added, and the resulting mixture was stirred for a further 4 hours. Finally, the mixture was stirred at 60° C. for 60 minutes and then cooled. It was then poured into 100 ml of water, and extracted twice with ethyl acetate. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue was subjected to column chromatography resulting through 100 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:10 by volume gave 3.82 g of the title compound as a solid having a low melting point, melting at 28.5°-29.5° C. (cold methanol).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.C([Mg]Br)C.[O:23]=O>C1COCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([OH:23])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: O=O
Agent: CC[Mg]Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Oc1cccc2c1sc1ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cooled (−78° C.) solution of dibenzothiophene (20.8 g, 113 mmol) in anhydrous THF (400 ml) was added tert-butyl lithium (1.7 M in pentane; 100 ml, 170 mmol). The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm to room temperature and stirred like this for 16 hours. The mixture was then cooled to 0° C. and ethylmagnesium bromide (1M in THF; 170 ml, 170 mmol) added to the amber reaction mixture in a slow stream via cannula. The reaction was again allowed to room temperature whereupon it was stirred like this for 30 minutes. A reflux condenser was attached to the reaction vessel before oxygen was bubbled through the solution for 40 minutes. The mixture was then stirred for a further 1 hour before carefully pouring onto crushed ice and acidifying to pH 3 with concentrated HCl. The mixture was then extracted using ethyl acetate (3×80 ml). The organic extracts were then treated with 3M sodium hydroxide solution until pH 10 was attained. The basic, aqueous layer was separated, acidified to pH 3 with 2M HCl which caused an oily solid to precipitate. This was dissolved in diethylether (150 ml), dried using MgSO4, filtered and concentrated in vacuo and then recrystallised from ethanol:water (1:1) (250 ml) to give a buff coloured solid that corresponded to the title compound (21.6 g, 96%) and required no further purification. m/z (LC-MS, ESP), RT=3.64 min, (M+H)=201.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][CH:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][CH:20]([CH3:21])[CH3:19])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(C)O
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Cl

Procedure:
To a solution of 25 g (0.131 mol) of 2-chloro-4-fluoro-5-nitrotoluene in 250 ml of 2-propanol is added 208 g (0.659 mol, 5 eq.) of Cs2CO3. The mixture is stirred at 60° C. overnight and most of the 2-propanol is evaporated under reduced pressure. Water is added and the solution is extracted with EtOAc. The organic layers are combined, dried over MgSO4, concentrated and the crude product filtrated over a silica plug (eluent: 95/5 hexanes/EtOAc) to afford 2-chloro-4-isopropoxy-5-nitrotoluene as a pale yellow fluffy solid.