Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([C:37]([OH:55])=[C:38]([C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[O:49])[C:39](=[O:47])[N:40]3[CH2:43][C:44]([OH:46])=O)=[N:35][CH:34]=2)=[CH:28][CH:27]=1.[OH-].[NH4+]>CN(C=O)C.O>[NH2:2][C:44](=[O:46])[CH2:43][N:40]1[C:41]2[C:36](=[N:35][CH:34]=[C:33]([CH2:32][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:42]=2)[C:37]([OH:55])=[C:38]([C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[O:49])[C:39]1=[O:47]
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(N)=O)c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of HATU (1.14 g, 3 mmol) in DMF (4 mL) was added in portions to a stirred suspension of [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid (1 g, 2.3 mmol) in 29% ammonium hydroxide (0.4 mL, 2.9 mmol), TEA (0.4 mL, 2.9 mmol) and DMF (4 mL) at 60° C. The mixture was stirred 40 min at rt and additional HATU (350 mg, 0.92 mmol), 29% ammonium hydroxide (0.15 mL, 1 mmol) and DMF (3 mL) were added. Stirring was continued 20 min and the suspension was diluted with water and filtered. The filter cake was washed with water and EtOH; then dried in a vacuum oven to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.25 (1H, t, J=5 Hz), 8.52 (1H, d, J=1 Hz), 7.83 (1H, s), 7.64 (1H, br s), 7.33 (2H, dd, J=8.6, 5.7 Hz), 7.27 (1H, br s), 7.11 (2H, t, J=8.6 Hz), 4.83 (2H, s), 4.11 (2H, s), 3.50 (4H, m), 3.28 (3H, s); HRMS calcd for C21H21FN4O5+H+: 429.1574. Found: 429.1575.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7]1.CCN(CC)CC.O>C(Cl)Cl>[CH3:1][S:2]([O:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][S:6][CH:7]=1)(=[O:4])=[O:3]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccsc1

Procedure:
Methylsulfonyl chloride (2.22 ml, 28.75 mmol) was added dropwise to a solution of 3-thiopheneethanol (2.46 g, 19.2 mmol) and Et3N (5.3 ml) in DCM (50 ml) as 0° C. The mixture was stirred for 15 min before DCM and water was added. Organic phase was separated and residue purified by flash chromatography using 20-25% EtOAc in iso-hexane as eluents. Yield: 3.93 g (99%); colourless oil. HPLC: RT=2.20 min, 96% (254 nm, 10-90% MeCN in 0.1% TFA, 3 min ACE). 1H NMR (400 MHz, CDCl3): δ 2.90 (s, 3H), 3.13 (t, J 6.8 Hz, 2H), 4.44 (t, J 6.8 Hz, 2H), 7.00-7.02 (m, 1H), 7.11-7.12 (m, 1H), 7.32-7.36 m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]1([CH:22]=[O:23])[CH2:21][CH2:20][CH2:19]1)=[O:16])=[CH:8][CH:7]=2)#[CH:2].C1(C)C=CC=CC=1.C1C[O:36][CH2:35]C1.[C:38]([O-])(O)=O.[Na+]>CO>[CH3:38][O:23][CH:22]([O:36][CH3:35])[C:18]1([NH:17][C:15](=[O:16])[CH:14]([O:13][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:12]3)[S:24][CH3:25])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C([O-])O
Reactant: C1CCOC1
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=O)CCC3)cc2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C(OC)OC)CCC3)cc2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-formyl-cyclobutyl)-2-methylsulfanyl-acetamide (180 mg) from Example 12f, Step 2 described above in a 10/1 mixture of toluene/THF (11 ml) p-toluene sulphonic acid (4 mg) was added followed by MeOH (1.10 ml), at room temperature. The mixture was stirred at 50° C. overnight and 60° C. during 6 hrs, then after cooling to room temperature poured into aq NaHCO3 soln and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate) to give N-(1-dimethoxymethyl-cyclobutyl)-2-(3-ethynyl-quinolin-6-yloxy)-2methylsulfanyl-acetamide as white solid. 1H NMR (CDCl3) δ ppm: 8.84 (1H, d); 8.19 (1H, d); 8.05 (1H, d); 7.46 (1H, dd); 7.23 (1H, d); 6.86 (1H, br s); 5.62 (1H, s); 4.57 (1H, s); 3.51 (3H, s); 3.47 (3H, s); 3.28 (1H, s); 2.47-2.21 (4H, m); 2.21 (3H, 5); 2.01-1.73 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([N:17](CC)C(C)C)(C)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(O)(=O)C>CN(C=O)C>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:17])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cccc(Br)c2s1
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1cc2cccc(Br)c2s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
156 mg (0.61 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid are mixed with 156.8 mg (1.21 mmol) of N,N-diisopropylethylamine in 4.0 ml of DMF. At 0° C., 183.7 mg (0.67 mmol) of diphenyl phosphorazidate are added. The reaction mixture is left to stand at 8° C. overnight and then stirred into ice-water. It is neutralized with acetic acid, and the resulting precipitate is filtered off with suction and carefully dried at 40° C. The solid is then suspended in xylene and heated under reflux for 1 h. The solvent is removed under reduced pressure, and the residue is put in water and heated for 3 h. The aqueous phase is extracted several times with ethyl acetate. The organic phase is dried over sodium sulfate and then the solvent is removed under reduced pressure. 128 mg of the title compound are isolated in a purity which is suitable for further reactions. The amine is reacted further without further purification.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=CC=1>>[CH3:23][C:20]1([CH3:22])[C:19]([CH3:24])([CH3:25])[O:18][B:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:16][CH:15]=2)[O:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (200 mg, 0.59 mmol). Crude product was purified by flash chromatography using EtOAc/hexanes as eluent (2:98 to 15:85) to give the title compound as a colourless oil (239 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.25-4.22 (m, 2H), 2.78 (t, J=12.5 Hz, 2H), 2.67-2.61 (m, 1H), 1.82-1.78 (m, 2H), 1.67-1.57 (m, 2H), 1.48 (s, 9H), 1.32 (s, 12H); MS ESI 410.1 [M+Na]+, calcd for [C11H34BNO4+Na]+ 410.25.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)Oc1ccc(O)cc1
Yield: 93.5 %

Procedure:
To a solution of the product of step (i) (4.5 g) in absolute ethanol (200 ml) was added 10% palladium-on-charcoal catalyst (1.2 g) and the resulting suspension hydrogenated at ambient temperature and pressure until uptake of hydrogen ceased. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give ethyl 3-(4-hydroxyphenoxy)butyrate as a low-melting crystalline solid (3.0 g) NMR (d6DMSO): δ1.25 (3H,t); 1.8-2.0 (2H,m); 2.5 (2H,t); 3.9 (2H,t); 4.1 (2H,q); 6.7 (4H,m); 8.8 (1H,br.s); m/e 224 (M)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:35])[CH2:23][C:24]([C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[F:34])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:27]1[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:26]=1[C:24]1[CH2:23][C:22](=[O:35])[NH:21][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cc(C#N)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(F)c(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K72) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (92 mg).
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[C:5]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([N:20]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH3:21])=[CH:13][C:12]=2[O:27][CH3:28])=[N:8][CH:9]=1>O.C(O)C.[Fe]>[Cl:3][C:4]1[C:5]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N:20]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH3:21])=[CH:13][C:12]=2[O:27][CH3:28])=[N:8][CH:9]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 105 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of NH4Cl (45 mg, 0.85 mmol) in water (10 mL) was added in one portion to a stirred mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 34, 600 mg, 1.21 mmol) and iron (405 mg, 7.24 mmol) in ethanol (30 mL). The resulting mixture was stirred at 105° C. for 3 h. The mixture was then concentrated in vacuo and the resulting residue was mixed with DMF (10 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M methanolic ammonia in CH2Cl2 and pure fractions were concentrated in vacuo to give the title compound (530 mg, 94%) as a brown gum; 1H NMR: 2.16 (6H, d), 2.38 (2H, t), 2.66 (3H, d), 2.92 (2H, t), 3.66 (3H, s), 4.60 (2H, s), 6.78 (1H, s), 6.92 (1H, s), 7.12 (1H, t), 7.27-7.4 (1H, m), 8.38 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.83 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 467.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1(O)[CH:9]=[CH:8][CH:7]=[N:6][CH2:5]1.[CH2:12](I)C.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH3:26][CH2:27][O:28]CC>>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:28][CH2:27][CH3:26])[CH:7]=[N:6][CH:5]=1)[CH3:12]
Reactant: CCI
Reactant: COC(=O)C1(O)C=CC=NC1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncc(OCC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-hydroxy-nicotinic acid methyl ester 16-1 (15 g, 90.8 mmol), ethyl iodide (14.5 ml, 181.6 mmol), cesium carbonate (29.5 g, 90.8 mmol) and DMF (150 mL) was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with Et2O and then washed with 10% K2CO3, brine, dried (MgSO4), and concentrated to give the ester 16-2 as a red oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1C.COC(C1C(=O)NN=C(C2C=CC=CC=2)C=1)=O>>[CH2:15]([N:13]1[C:12](=[O:19])[C:11]([C:20]([O:22][CH3:23])=[O:21])=[CH:10][C:9]([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[N:14]1)[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(-c2ccc(C)c(F)c2)nn(CC(C)C)c1=O
Agent: COC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccccc2)nn(CC(C)C)c1=O
Yield: 94.1 %

Procedure:
Following the procedure of Example 1 (6), 4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow oil (yield: 94.1%).
Reaction SMILES: [CH2:1]([I:3])[CH3:2].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=1>CC(C)=O>[I-:3].[CH2:1]([N+:15]1([CH2:14][CH2:13][CH:12]([C:7]2[CH:6]=[C:5]([CH3:4])[CH:10]=[CH:9][C:8]=2[OH:11])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:2]
Reactant: CCI
Reactant: Cc1ccc(O)c(C(CCN2CCCC2)c2ccccc2)c1
Solvent: CC(C)=O
Product: CC[N+]1(CCC(c2ccccc2)c2cc(C)ccc2O)CCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl iodide (10 equivalents) was added to a solution of the free base 4-methyl-2-(1-phenyl-3-pyrrolidin-1-ylpropyl)phenol of Example 30 (0.3 g, 1.02 mmol) in acetone (4 mL). The reaction mixture is stirred overnight at room temperature. The solution is concentrated to initiate the precipitation of the resulting quaternary ammonium salt. The white precipitate is filtered, washed with diethyl ether and dried under vacuum to give a quaternized salt.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]2=[N:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2ccccn2c1/C=C/CCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c1CCCCOC)CCCC2
Reaction time: 12 h
Yield: 79.7 %

Procedure:
Ethyl 3-[(1E)-4-methoxybut-1-en-1-yl]imidazo[1,2-a]pyridine-2-carboxylate (1.40 g) was dissolved in ethyl acetate (30 ml), 10% palladium carbon (50% in water) (510 mg) was added and the mixture was stirred in a hydrogen stream at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (5:1) was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].O1CCCC1.CON(C)[C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C.CCCCCC>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][C:13](=[O:31])[CH2:1][CH3:2])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Ethyl magnesium bromide (1.15 mmol, 3.0M in ethyl ether) is added drop-wise to a tetrahydro-furan (3 mL) solution of N-methoxy-N-methyl-2-(4′-trifluoromethyl-biphenyl-4-yl)-acetamide (0.248 g, 0.77 mmol) at −45° C. and stirred for one hour. Gradually raise temperature to −20° C. and stirred for one hour. The reaction is quenched by saturated ammonium chloride solution (1 mL) at 0° C., extracted with ethyl acetate and washed with water and brine. Organics are dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel with 0-30% ethyl acetate/hexane gradient gives 0.095 g (0.33 mmol, 42%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[O:30]1CCCC1.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:30])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cccc(CO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4.24 g (25 mmol) of silver nitrate were added to a solution of 10.14 g (25.0 mmol) N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (iv) above] in a mixture of 500 ml of acetone, 100 ml of tetrahydrofuran and 200 ml of water, and the resulting mixture was stirred for 7 hours at 60° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 6.41 g (yield 66%) of the title compound as crystals.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[C:20]([C:21]2([F:25])[CH2:24][CH2:23][CH2:22]2)=[CH:19][CH:18]=[C:17]([CH3:26])[N+:16]=1[O-].[OH-].[Na+]>ClCCl>[Cl:14][C:15]1[N:16]=[C:17]([CH2:26][OH:4])[CH:18]=[CH:19][C:20]=1[C:21]1([F:25])[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(C2(F)CCC2)c(Cl)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1ccc(C2(F)CCC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.1 %

Procedure:
Trifluoroacetic anhydride (1.27 g, 840 μL, 6.04 mmol) was added under ice cooling to a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine 1-oxide (Example 130 c, 869 mg, 4.03 mmol) in dichloromethane (10.9 mL). The mixture was stirred at ambient temperature for 72 h. Upon ice bath cooling 5 N NaOH solution (1 mL) and afterwards ice water (20 mL) were added. The mixture was extracted with dichloromethane (2×40 mL). The combined organic layers were washed with icewater/brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, heptane/EtOAc 0-40% in 120 min.) to give the title compound (279 mg, 32%) as light yellow oil, MS (ESI): m/e=216.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[N:6][C:5]2=[C:14]([C:16]([OH:18])=O)[CH:15]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)=[N:6][C:5]=13)=[O:18])[CH2:23]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccsc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccsc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
A mixture of 6-chloro-2-(thiophen-3-yl)benzo[d]oxazole-4-carboxylic acid (70 mg, 0.25 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (57 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide (30 mg, 29%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=7.5 Hz, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75 (dd, J=5.0, 1.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.52 (dd, J=5.5, 3.0 Hz, 1H), 4.60-4.53 (m, 1H), 3.12 (d, J=10.5 Hz, 2H), 2.65-2.58 (m, 2H), 2.53 (s, 3H), 2.12-1.95 (m, 3H), 1.60-1.52 (m, 1H), 1.49-1.43 (m, 2H), 1.14 (d, J=12.5 Hz, 2H); MS (ESI+) m/z 416 (M+H); HPLC 98.2% (AUC), tR=12.82 min.
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].[CH2:7]([N:9]1[C:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:17]=[CH:18][C:13]=2[C:12](=[O:25])[C:11]([C:26]([OH:28])=[O:27])=[CH:10]1)[CH3:8].C(O)C>O>[CH2:7]([N:9]1[C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[N:17]=[CH:18][C:13]=2[C:12](=[O:25])[C:11]([C:26]([O-:28])=[O:27])=[CH:10]1)[CH3:8].[K+:5]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)[O-])c(=O)c2cnc(N3CCNCC3)nc21
Yield: 61.6 %

Procedure:
To a solution of potassium carbonate (2.76 g) in 60 ml of water was added 6.06 g of 5,8-dihydro-8-ethyl-2-(1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid. The resulting mixture was heated on a steam bath until it became a clear solution. Ethanol was added to the solution, and the mixture was then kept below room temperature by external cooling to yield the precipitate, which was collected and washed with ethanol. There is obtained 4.2 g of the product m.p. above 300°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:21][C:22]1[S:26][C:25]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH2:27][C:25]3[S:26][C:22]([Cl:21])=[CH:23][CH:24]=3)[C:29]2=[O:38])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a pale yellow solution of 4-(benzyloxy)phenol (9.01 g, 45.0 mmol) in anhydrous tetrahydrofuran (100.0 mL) was added isopropylmagnesium chloride (26.3 mL, 52.5 mmol, 2.0 M solution in tetrahydrofuran) at 0° C. The reaction solution was stirred for 0.5 h followed by the addition of 1-((5-chlorothiophen-2-yl)methyl)indoline-2,3-dione (8.31 g, 30.0 mmol) in portions. The reaction mixture was stirred for 16 h at ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (50.0 mL) and concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride solution (2×25.0 mL), brine (2×25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 28%) as a colourless solid: mp 174-175° C.; 1H NMR (300 MHz, CDCl3) δ8.45 (br, 1H), 7.40-7.27 (m, 7H), 7.14 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=2.9 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.79 (d, J=3.7 Hz, 1H), 6.70 (d, J=3.7 Hz, 1H), 6.43 (d, J=2.9 Hz, 1H), 4.86 (ABq, 2H), 4.84 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 178.3, 152.6, 149.790, 141.7, 136.8, 135.8, 130.4, 130.1, 129.1, 128.6, 127.9, 127.6, 126.3, 126.2, 126.0, 125.9, 124.3, 120.2, 116.3, 114.4, 109.6, 79.1, 70.6, 39.2; MS (ES+) m/z 478.2 (M−1), 476.2 (M−1).