Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([N:5]1[CH2:6][CH2:7][C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)([OH:1])[CH2:3][CH2:4]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a mixture of 24.5 g of 4-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidine (commercial) and 27.6 g of K2CO3 in 20 ml of DMF is added dropwise, at rt, 17.1 g of benzyl bromide, and the mixture is then heated at 40° C. for 2 hours and stirred overnight at rt. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 31 g of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[C:7](=[N:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:6][CH2:5][O:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[C@H:7]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)C1(C)COCCC1=N[C@H](C)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)C1(C)COCC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 36.5 %

Procedure:
Methyl 3-methyl-4-((R)-1-phenylethylimino)-tetrahydro-2H-pyran-3-carboxylate (crude, 13.53 mmol) in acetonitrile-acetic acid (1:1, 80 mL) was treated with NaBH(OAc)3 and stirred for 2.5 h at 0° C. Following concentration in vacuo, the residue was dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 until the aqueous phase was basic, dried over MgSO4, and purified by chromatography with 20% ethyl acetate/hexane to yield 1.37 g (37% in 2 steps) of (4R)-methyl 3-methyl-4-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-3-carboxylate. MS: (M+H)+=278.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:22][C:14]1=2)C(=O)OC(C)(C)C)[CH3:2].Cl>CO>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:22][C:14]1=2)[CH3:2]
Reactant: CCN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNCCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl ethyl(2-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (410 mg, 0.918 mmol) in methanol (6 mL) was added a 3N HCl solution (3.06 mL, 9.18 mmol). The resulting mixture was stirred at 90° C. for 30 minutes The mixture was then passed through a 0.45 μM syringe filter, and the filtrate was concentrated in vacuo to dry foam. The residue was then partitioned between 1:1 water:saturated sodium carbonate and dichloromethane. The organic layer was separated, and the aqueous phase was extracted again with dichloromethane. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:4:5 (2M NH3 in methanol):ethyl acetate:dichloromethane giving the desired product 24 (135 mg, 42.4%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.6 Hz, 1H), 7.58 (d, 5.1 Hz, 1H), 7.08 (t, J=4.4 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.33 (brs, 2H), 6.21 (s, 1H), 6.07 (dd, J=8.1, 1.5 Hz, 1H), 3.63-3.57 (m, 2H), 3.33-3.28 (m, 2H), 3.01-2.96 (m, 2H), 2.71-2.65 (m, 2H), 2.53 (q, J=7.0 Hz, 2H), 1.66 (brs, 1H), 1.17 (t, J=7.0 Hz, 3H); ESI-MS (m/z, %): 347 (MH+, 83), 276 (100); HRMS calculated for C17H23N4S2 (MH+), calculated: 347.1358, observed: 347.1346; HPLC purity: 97% by area.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[CH:4]([CH2:18][C:19]#[N:20])[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1
Reactant: N#CCCl
Reactant: COC(=O)Cc1n[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC#N)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl-1-H-indazole-3-ylacetate (1.9 g) in dimethylformamide (4 ml) was added sodium hydride (0.58 g; 50% by weight dispersed in oil) and the mixture stirred for 15 minutes at room temperature. Chloroacetonitrile (1.9 g) dissolved in dimethylformamide (2 ml) was then added and the reaction mixture stirred for 6 hours. The mixture was then poured onto ice-water (20 ml), the pH was adjusted to about 3 by the addition of sufficient dilute HCl, and the resulting precipitate was collected and air-dried (yield 1.87 g) m.p. 128°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[OH:27]S(O)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10](=[O:27])[CH3:11])[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Yield: 73.7 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynylbenzoic acid methyl ester (5) (79.4 mg, 0.20 mmol), HgSO4 (59.8 mg, 2.0 mmol), and conc. H2SO4 (0.02 mL, 0.40 mmol) in 80% aqueous acetone (2.5 mL), were refluxed for 48 hours. The reaction was concentrated under reduced pressure, and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated to give 50.1 mg (73%) of the desired product (6).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
A mixture of 3-(trifluoromethyl) benzaldehyde (25 g, 144 mmol), malonic acid (28.8 g, 277 mmol), anhydrous pyridine (100 ml) and piperidine (2 ml) was heated under reflux for 4 hours. The mixture was poured onto fresh ice (300 g) and concentrated hydrochloric acid (78 ml). The solid product was collected, dried and recrystallised (1:1 IMS/water) to give 30 g (96% of theory) of 3-(trifluoromethyl) cinnamic acid as off-white needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH2:14]([O:21][NH:22][C:23]([C@H:25]1[C@@H:30]([CH3:31])[N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27][NH:26]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.N1C=CC=CC=1>[CH2:14]([O:21][NH:22][C:23]([C@H:25]1[C@@H:30]([CH3:31])[N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH2:27][N:26]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1[C@H](C(=O)NOCc2ccccc2)NCCN1S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@H](C)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
A solution of 4-methoxybenzenesulfonyl chloride (284 mg) in dioxane (2 ml) was added to a solution of (2R,3R)-N-benzyloxy-4-methanesulfonyl-3-methyl-2-piperazinecarboxamide hydrochloride (200 mg) in pyridine (2 ml) with cooling on an ice bath. The mixture was stirred at ambient temperature for 3.5 hours. 4-Methoxybenzenesulfonyl chloride (60 mg) in dioxane (1 ml) was added thereto, and the mixture was stirred at ambient temperature for 2 hours. 4-Methoxybenzenesulfonyl chloride (60 mg) in dioxane (1 ml) was added to the mixture. The reaction mixture was stirred at ambient temperature for 2 hours, and the reaction was quenched by adding 3-(N,N-dimethylamino)propylamine (0.1 ml). The mixture was partitioned between 0.6N HCl and AcOEt. The organic layer was washed with 0.6N HCl, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt in n-hexane 60% to 80%) to give 273 mg of (2R,3R)-N-benzyloxy-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methyl-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: [OH-:1].[K+].[CH:3]1([N:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)=O)=[C:11]([C:26]#[N:27])[C:10]([CH3:28])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.OO>O.CO>[CH:3]1([N:8]2[C:12]3=[N:13][C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[C:20]5[C:25]=4[N:24]=[CH:23][CH:22]=[CH:21]5)=[N:27][C:26](=[O:1])[C:11]3=[C:10]([CH3:28])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nn(C2CCCC2)c(NC(=O)c2cccc3cccnc23)c1C#N
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1[nH]n(C2CCCC2)c2nc(-c3cccc4cccnc34)nc(=O)c1-2
Temperature: 25 °C
Yield: 19.3 %

Procedure:
To potassium hydroxide (0.2 g, 3.0 mmol) in water (75 ml) cooled in an ice bath was added 1-cyclopentyl-3-methyl-4-cyano-5-(8-quinolinecarboxamido)-1H-pyrazole (2.05 g, 5.9 mmol) in methanol (30 ml) followed by 30% hydrogen peroxide (3.0 ml, 30 mmol). The reaction mixture was slowly warmed to room temperature and then refluxed for 24 hours. Additional potassium hydroxide (3.0 mmol) and 30% hydrogen peroxide (30 mmol) were added and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled in an ice-bath, the precipitated product was collected by filtration through a glass frit and was washed with water, then ether. Recrystallization from ethyl acetate afforded 0.2 g (10%) of 1-cyclopentyl-3-methyl-6-(8-quinolinyl)-pyrazolo[3,4-d]pyrimidin-4-one as yellow crystals, m.p.242°-244° C. when dried for 24 hours at 120° C. in high vacuum.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)CCC.Cl[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1>CCO>[F:16][C:13]1[CH:14]=[CH:15][C:10]([NH:2][NH2:3])=[N:11][CH:12]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: NN
Solvent: CCCCO
Solvent: CCO
Solvent: O
Product: NNc1ccc(F)cn1

Procedure:
To a mixture of hydrazine monohydrate (14.75 mL, 304 mmol) and 1-butanol (10 mL) was added 2-chloro-5-fluoropyridine (5.00 g, 38.0 mmol). The solution was microwaved in a sealed, thick-walled glass tube at 180° C. for 1 h. The resulting white suspension was transferred with EtOH to a round bottom flask then concentrated. The resulting white solid was taken up in ethyl acetate (250 mL) and the insoluble material removed by filtration. The filtrate was concentrated to give the title compound a pale orange solid. This solid was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])/[CH:5]=[C:6]1\[N:7]=[C:8]([CH3:12])[O:9][C:10]\1=O.[CH3:17][NH2:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])/[CH:5]=[C:6]1\[N:7]=[C:8]([CH3:12])[N:18]([CH3:17])[C:10]\1=[O:9]
Reactant: CN
Reactant: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(Z)-4-(3-fluoro-4-hydroxybenzylidene)-2-methyloxazole-5(4H)-one (13.2 g, 0.05 mol) was suspended in ethanol (100 mL), and water solution of methylamine (40%, 11.6 g, 0.15 mol) was added. The reaction mixture was stirred at r.t. for 2 hours, then potassium carbonate (13.8 g, 0.1 mol) was added, and the mixture refluxed for 4 hours. Then it was cooled down to r.t., diluted with water (400 mL) and acidified with HCl (10% in water) until the precipitate stopped to form. The precipitate was filtered, washed with cold (−20° C.) ethanol, then diethyl ether and dried under vacuum: 8.78 g. (Yield 75%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1C(CC2C=CC(C3C(C(OC(C)(C)C)=O)=CC=CC=3)=CC=2)=C2CCCCN2N=1)[CH2:9]CC.BrCC(=O)C>CC(C)=O>[CH3:12][C:8]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: Nc1ccccn1
Reactant: CCCCc1nn2c(c1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)CCCC2
Agent: CC(=O)CBr
Solvent: CC(C)=O
Product: Cc1cn2ccccc2n1
Yield: 245.9 %

Procedure:
A mixture of 5 g of 2-amino pyridine and 250 ml of acetone were added at ambient temperature to a mixture of 7.25 g of 1 bromo 2-propanone and 20 ml of acetone and the mixture was refluxed for 30 minutes. Using the procedure of Stage C of Example 22, 5.3 g of the expected product were obtained in the form of an orange oil.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].[N+:32]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O)([O-:34])=[O:33].C1CC23[N+](=[N-])C(CCC2)=C3C1>C(#N)C>[N+:32]([C:35]1[CH:36]=[C:37]([CH:38]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)[CH:40]=[CH:41][CH:42]=1)([O-:34])=[O:33]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [N-]=[N+]1C2=C3CCCC31CCC2
Solvent: CC#N
Product: COC(=O)c1ccc(C=Cc2cccc([N+](=O)[O-])c2)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
71.2 g of 4-methoxycarbonylbenzyltriphenylphosphonium bromide and 23 g (0.15 M) of 3-nitrobenzaldehyde are added to 360 ml of acetonitrile in a 1000 ml reactor. 19 ml (0.15 M) of 1,5-diazobicyclo[4.3.0]non-5-ene (DBN) are then added and the reaction medium is then refluxed with stirring for 1 hour. The solvent is then evaporated off and the residue obtained is then purified by chromatography on silica, using dichloromethane as eluent. After evaporation, 41.6 g of a white solid are obtained (yield: 95%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH:27]([C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[CH2:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=1)[O:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1.[NH2:51][C:52]1[N:61]=[C:60]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)[C:59]2[C:54](=[CH:55][C:56]([C:69](O)=[O:70])=[CH:57][CH:58]=2)[N:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:51][C:52]1[N:61]=[C:60]([N:62]2[CH2:63][CH2:64][N:65]([CH3:68])[CH2:66][CH2:67]2)[C:59]2[C:54](=[CH:55][C:56]([C:69]([NH:26][CH:27]([C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[CH2:28][C:29]3[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=3)[O:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)=[O:70])=[CH:57][CH:58]=2)[N:53]=1
Reactant: COC(=O)c1ccc(Oc2cccc(CC(N)C(=O)N(C)C)c2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Oc2cccc(CC(NC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)C(=O)N(C)C)c2)cc1
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-{3-[2-amino-3-(dimethylamino)-3-oxopropyl]phenoxy}benzoate HCl salt (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified with out workup by HPLC (pH=10) to give the desired(0.012 g, 37%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 8.82 (d, 1H), 7.71 (d, 2H), 7.68 (d, 1H), 7.61 (d, 1H), 7.29 (m, 2H), 7.17 (d, 1H), 7.06 (s, 1H), 6.88 (d, 1H), 6.82 (d, 2H), 6.38 (s, 1H), 5.02 (m, 1H), 3.72 (s, 3H), 3.46 (bs, 4H), 3.27 (s, 4H), 2.98 (bs, 5H), 2.77 (s, 3H), 2.17 (s, 3H). Analytical LCMS (M+H)+: m/z=612.0.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[O:6][C:7]3[C:25](F)=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[F:29]C1C=CC=C(F)C=1C=O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[C:22]([F:29])[C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3c(F)cccc3[C@H]12)C(F)(F)F
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3cccc(F)c3[C@H]12)C(F)(F)F
Yield: 6 %

Procedure:
Preparation according to the procedures described in Example 72 for trans-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide starting from 2,6-difluorobenzaldehyde (0.54 mL, 5 mmol) delivered the crude title compound. This compound was purified by column chromatography on silica gel with heptanes/ethyl acetate, column chromatography on silica gel with toluene/ethyl acetate=9/1 and finally crystallization from acetonitrile to yield the title compound (136 mg, 6% overall yield). Data: 1H-NMR (400 MHz, DMSO d6) 1.57-1.76 (m, 2H), 1.89-2.04 (m, 2H), 3.09-3.18 (m, 1H), 3.93 (br.d, J=14, 1H), 4.42 (d, J=10, 1H), 4.52-4.62 (m, 1H), 6.74 (dd, J=9, 3, 1H), 6.95-7.16 (m, 4H), 7.27-7.33 (m, 1H), 9.30 (d, J=9, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CCOCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
2-Bromo-thiazole (0.27 mL, 2.99 mmol) was dissolved in Et2O (8 mL) and cooled down to −78° C. BuLi (1.3 mL, 2.5 M) was added dropwise. The resulting yellow solution was stirred at −78° C. for 45 min. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (720 mg, 3.61 mmol) in Et2O (5 mL) was then added dropwise. The reaction temperature rose to rt naturally overnight. H2O (10 mL) was added to quench the reaction and extracted with ethyl acetate. The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to give 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (800 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[OH:31])=[CH:26][CH:25]=1.[C:40](O)(C(F)(F)F)=O>CO>[CH3:40][O:31][CH:30]([P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[CH:25][CH:26]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: CO
Product: CCOP(=O)(OCC)C(OC)c1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 27.2 %

Procedure:
Under N2, a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (40.0 mg, 0.12 mmol) and diethyl [(4-aminophenyl)(hydroxy)methyl]-phosphonate (37.6 mg, 0.15 mmol) in a mixture of TFA (28 uL, 0.36 mmol) and MeOH (0.5 mL) was stirred at 105° C. for 45 min in a Biotage microwave reactor. LC-MS showed that the reaction was complete. The solvents were removed under reduced pressure and to the residue was added sat. NaHCO3 (aq) (2 mL) and DCM (5 mL). Layers were separated and the aqueous layer was extracted with DCM (3×5 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N NH3 in MeOH in DCM) to afford the desired product as a white-colored solid (18.5 mg, yield: 27%). 1H NMR (CD3OD, 400 MHz): δ=1.21 (dt, J=0.8, 7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3 H), 2.90 (s, 3 H), 3.35 (s, 3 H), 3.93-4.14 (m, 4 H), 4.61 (d, J=15.2 Hz, 1 H), 7.18 (dt, J=1.2, 7.6 Hz, 1 H), 7.34 (dd, J=2.0, 8.4 Hz, 2 H), 7.49 (dd, J=1.6, 8.4 Hz, 1 H), 7.62-7.66 (m, 3 H), 8.34 (s, 1 H), 8.46 (m, 1 H). MS (ES+): m/z 568.11 [MH+]. HPLC: tR=3.31 min (OpenLynx, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][CH2:10][CH2:9][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCO
Reactant: Brc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCC#Cc1cccc(Br)c1
Reaction time: 18 h

Procedure:
A stirred, cooled solution of 1-bromo-3-iodobenzene (31 g) and 3-butyn-ol (7 ml) in acetonitrile (100 ml) and triethylamine (100 ml) was purged with nitrogen for 20 min under nitrogen. Dichlorobis(triphenylphosphine)palladium (500 mg) and cuprous iodide (800 mg) were added. The mixture was stirred for 18 h and then the solvent was removed in-vacuo. The residual oil was triturated with ethyl acetate (200 ml) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on Biotage (90 g) eluting with light petroleum 40-60°-diethyl ether (3:2) to give the title compound (21 g). LCMS RT=3.26 min.
Reaction SMILES: C(O[C:8]1[CH:24]=[CH:23][C:11]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=[O:18])=[O:13])=[C:10](C)[CH:9]=1)CCCCC.[C:26](O)(=O)C.S(=O)(=O)(O)O.[OH2:35]>>[OH:35][C:10]1[CH:9]=[C:8]([CH3:26])[CH:24]=[CH:23][C:11]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:13]
Reactant: CCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(C)c1
Reactant: CC(=O)O
Reactant: O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1

Procedure:
A mixture of 3-(2-hydroxy-4-methylbenzoyl)benzonitrile (5.78 g; see Example 29), acetic acid (48 g), and a solution of 75% sulfuric acid (48 g) is refluxed for 3 hours. The resulting mixture is diluted with water (100 ml) and extracted with ether (3×75 ml) followed by methylene chloride (2×75 ml). The combined extracts are dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (methylene chloride then hexanes:ether:acetic acid; 50:50:1). The resulting yellow solid is recrystallized from ligroin/isopropyl ether to yield 3-(2-hydroxy-4-methylbenzoyl)benzoic acid (3.62 g), m.p. 198°-215° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:4].O.[N-:11]=[N+:12]=[N-:13].[Na+]>O1CCCC1.CCOCC>[N:11]([CH2:2][C:3]([CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCC(=O)CCl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloro-3-acetoxyacetone (15.05 g.) is dissolved in tetrahydrofuran (50 ml.) and water (25 ml.) is added. Sodium azide (8.7 g.) is added and the mixture is allowed to stir overnight at room temperature. The reaction mixture is diluted with ether (200 ml.) and the aqueous phase is separated. The organic phase is washed once with brine, then dried and evaporated to give 1-azido-3-acetoxyacetone.