Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:54])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:38]=[C:39]([CH2:45][O:46]C3CCCCO3)[S:40][C:41]=2[CH2:42][CH2:43][CH3:44])[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:54])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:38]=[C:39]([CH2:45][OH:46])[S:40][C:41]=4[CH2:42][CH2:43][CH3:44])[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCCc1sc(COC2CCCCO2)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1sc(CO)nc1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (79 mg) (Example J6) and 3-oxo-3-{3-[-5-propyl-2-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl}-propionic acid tert-butyl ester (138 mg) (Example K41) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as yellow solid (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCO.C1COCC1>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
A mixture of 4-fluorobenzamide (2.5 g, 17.9 mmol) and 1,3-dichloroacetone (2.7 g, 21.6 mmol) in EtOH-THF (20 mL-10 mL) was heated to 85° C. for 24 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO3 solution. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 6-10% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(4-fluorophenyl)oxazole (1.2 g, yield 32%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.70 (m, 1H), 7.19-7.13 (t, J=8.8 Hz, 2H), 4.58 (m, 2H). MS (ESI) m/z: Calculated for C10H7ClNO: 211.02. found: 212.0 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14](O)[CH3:15])=[C:9]([O:17][CH2:18][CH3:19])[C:8]=1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:24][CH:25]=1)#[N:6]>C(Cl)Cl.CN(C)C=O>[Cl:3][CH:14]([C:10]1[C:9]([O:17][CH2:18][CH3:19])=[C:8]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:24][CH:25]=2)[C:7]([C:5]#[N:6])=[C:12]([CH3:13])[CH:11]=1)[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 3 h
Yield: 91 %

Procedure:
Thionyl chloride (900 μL, 10 mmol) was added dropwise to a solution of 5-[2-cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.3 g, 6.5 mmol) in methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 3 hrs, was diluted with methylene chloride (100 mL) and washed with water saturated NaHCO3. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude 5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.2 g, 91%). LCMS calculated for C20H23ClN3O2(M+H)+: m/z=372.1; found: 372.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:14]=[O:15]>C1COCC1>[CH2:16]([NH:13][C:14]([N:9]1[C:10](=[O:11])[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:12])[NH:8]1)=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: CCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O

Procedure:
In analogy to example 1c, 500 mg (2.72 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 346.3 mg (2.72 mmol) of 1-isocyanatohexane in THF at 60° C. Yield: 428 mg (51%), M+H+: 311.27.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([S:12]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CCCCCCC>[CH3:18][C:16]([CH3:17])([CH3:19])[CH2:15][S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:35]([C:34]3[CH:36]=[CH:37][C:31]([O:30][C:29]([F:38])([F:39])[F:28])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)(C)C)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Yield: 54.1 %

Procedure:
This material was prepared in analogy to example 1 step D) 1-(2,2-dimethyl-propane-1-sulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.17 g), dimethylaluminium chloride in heptane (1.0 molar, 1.46 ml) and 4-(trifluoromethoxy)-aniline (0.129 g) to give the desired 8-(2,2-dimethyl-propane-1-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.118 g) as an off-white solid. MS (ESI): 449.17 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CCCC(CCC)n1ccc(=O)c2c(Br)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CCC)n1ccc(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Yield: 84.4 %

Procedure:
A mixture of 5-Bromo-1-(1-propylbutyl)quinolin-4(1H)-one (0.096 g, 0.30 mmol), 2,4-dimethylbenzeneboronic acid (0.067 g, 0.45 mmol), potassium carbonate (0.124 g, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were put under nitrogen gas. Dioxane (4 mL) was added followed by water (27 μL 1.5 mmol). The reaction was heated at 90° C. overnight. The solution was cooled and concentrated. Flash chromatography (60% ethyl acetate/hexanes) gave 0.088 g (85% yield) of the desired product.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH2:49])=[CH:43][CH:42]=1>C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH-:49])=[CH:43][CH:42]=1
Reactant: COc1ccc(CCN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: COc1ccc(CC[NH-])cc1

Procedure:
Boc-Asp(OBzl)-OH (38.8 g; 0.12 Mole) was dissolved in CH2Cl2 (250 ml) and cooled in a dry ice/acetone bath. DCC (24.75 g: 0.12 Mole) dissolved in CH2Cl2 (50 ml) was added slowly. After stirring for 10 minutes 4-methoxyphenylethyl amine(15.1 g; 0.1 Mole) was added dropwise and stirring was continued for another hour at room temperature. The mixture was filtered and the filtrate was washed with saturated NaHCO3 solution (3 x 50 ml) and 1N HCl (50 ml). The organic phase was dried over sodium sulfate and evaporated to an oil. Yield: 41.5 g; FAB-MS: (M+Li)=463.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.S(Cl)([Cl:46])=O>ClC(Cl)C>[Cl:46][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (1400 mg, 2.381 mmol) and thionyl chloride (1.738 mL, 23.81 mmol) in dichloroethane (15 mL) was heated up at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to provide the desired product as brown solid (1.3 g, 90%). LCMS: m/e 606.48 (M+H)+, 2.46 min (method 11).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN1C(=O)CCC1>[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[C:7]([CH:8]3[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)=[O:26]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1CCC(c2cccnc2F)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 200 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(3-(2-fluoropyridin-3-yl)pyrrolidin-1-yl)ethanone (86 mg, 0.41 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (197 mg, 0.826 mmol), cesium carbonate (309 mg, 0.95 mmol), copper(i) iodide (79 mg, 0.413 mmol), and NMP (1.4 mL). The reaction mixture was degassed and flushed with N2 and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 200° C. for 1 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqeuous layer was back extracted with EtOAc (2×) and the combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH in EtOAc, followed by trituration with ether, dried to provide 1-(3-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)pyrrolidin-1-yl)ethanone as off-white solid. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:16]=1[C:17]#[N:18]>CN(C)C(=O)C.CCOCC>[Br:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([S:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)[C:16]=1[C:17]#[N:18]
Reactant: SC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1c(F)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) and the reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1 g) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](F)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CN1CCOCC1
Reactant: O=C(F)C(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CCOCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Methyl 3-morpholin-4-ylacrylate (96.3%, 8.5 g, 50 mmol) and triethylamine (5.2 g, 50 mmol) were initially charged in toluene (250 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 50 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. Under reduced pressure, the reaction mixture was freed from the solvent. The residue obtained was 15.5 g of an orange solid which, according to quant. 1H-NMR, consisted to 66.4% of methyl 4,4-difluoro-3-oxo-2-(morpholin-4-ylmethylidene)butyrate (yield: 82%). 1H-NMR (CDCl3): δ=3.4 (m, 2H), 3.7 (m, 2H), 3.75 (s, 3H), 3.85 (m, 2H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(Cl)OCC
Reactant: Cl[Mg]CCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g,0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrlochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H)(9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: [N:1]([CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[N+:2]=[N-:3].[OH-].[Na+]>CO.O1CCCC1>[N:1]([CH:4]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)C1(c2ccc(COc3cccc(C(N=[N+]=[N-])c4ccccc4)c3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C3(C(=O)O)CC3)cc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 1-(4-((3-(azido(phenyl)methyl)phenoxy)methyl)-phenyl)cyclopropanecarboxylate (0.569 g, 1.375 mmol) in methanol (12.9 mL) and tetrahydrofuran (5.1 mL), was added 2M aqueous sodium hydroxide (12.9 mL). The reaction was stirred at 50° C. for 3 hours 30 minutes and then at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to pH4 using 2M aqueous hydrochloric acid with stirring. The mixture was extracted with dichloromethane (×3), and the combined organic extracts washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (0.552 g, quantitative yield). The material was used directly in the next step with no further purification
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:19]#[C:18][C:16]([CH3:17])([OH:20])[CH3:15])=[CH:9][CH:8]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 71.1 %

Procedure:
257.1 g of 4-Bromobenzoic acid tert.-butyl ester, 168 g of 2-methyl-3-butyn-2-ol and 15.6 g of (Ph3P)2PdCl2 in 1.5 l of absolute acetonitrile and 480 ml of triethylamine are stirred together at reflux for 6 hours under nitrogen. The product is then concentrated by evaporation and worked up with toluene/H2O to yield 185 g of an oil which slowly crystallises.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[O-2].[Nb+5:7].[O-2].[O-2].[O-2].[O-2].[Nb+5]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Nb+5:7].[Nb+5:7]
Reactant: O=P(O)(O)O
Agent: [Nb+5]
Agent: [O-2]
Product: O=P([O-])([O-])[O-]
Temperature: 150 °C

Procedure:
A mixture is prepared containing niobic acid, Nb2O5.xH2O, (60.33 g 0.211 moles) and 85% phosphoric acid (602.20 g; 5.22 moles). The mixture is heated to 150° C. with stirring. The niobium oxide dissolves to form a pink solution, and upon further heating a precipitate forms. The precipitate is boiled in the phosphoric acid for about 2 hours. The mixture is cooled to room temperature, and the liquid is decanted from the precipitate. The precipitate is washed by adding 500 ml of water with stirring, after which the mixture is filtered. The washing and filtering cycle is repeated five times. The filtered solid is dried at 110° C. under air for 21/2 days to yield a catalyst of niobium phosphate. The elemental analysis and X-ray diffraction spectrum of the catalyst are consistent with the composition NbOPO4.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[OH:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.I[CH:27]([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[O:14][CH:27]([CH3:29])[CH3:28])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)I
Reactant: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Yield: 53.9 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-5-nitro-4-oxoquinoline-3-carboxylate (393 mg, 1.11 mmol), 2-Iodopropane (0.167 mL, 1.67 mmol) and K2CO3 (231 mg, 1.67 mmol) in DMF (5 mL) was stirred at 80° C. for 5 h. After the reaction mixture was poured into ice-water, the crude product was extracted with CH2Cl2, washed with 1M HCl, saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product washed with hot EtOH and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-5-nitro-4-oxoquinoline-3-carboxylate (237 mg, 54%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[ClH:22]>CO.CCOC(C)=O>[ClH:22].[NH2:20][C:19]([NH2:21])=[N:18]/[N:17]=[C:1](/[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)\[CH3:2]
Reactant: N=C(N)NN
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: C/C(=N\N=C(N)N)c1ccc(C(=O)O)cc1
Temperature: 20 °C

Procedure:
4-Acetylbenzoic acid (L1) (1.041 g, 6.34 mmol), amino guanidine bicarbonate (1.12 g, 8.2 mmol, 1.3 eq) and c.HCl (0.7 ml, 7.0 mmol) in MeOH (30 mL) was refluxed for 1 h. The reaction mixture was diluted with EtOAc cooled to 20° C. and the resulting precipitate was filtered and recrytallized from MeOH/EtOAc to give L2 (887 mg, 55%), mp (MeOH/EtOAc)>300° C.; 1H NMR ([(CD3)2SO] δ7.97-7.89 (m, 4 H, ArH), 6.75 (br, 4 H, 2×NH2), 2.25 (s, 3 H, CH3), mass APCI+ 221.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:6]1([C:7]([F:10])([F:9])[F:8])[NH:15][NH:14][C:4](=[O:3])[CH2:5]1
Reactant: NN
Reactant: CCOC(=O)C=C(C)C(F)(F)F
Solvent: CCO
Solvent: O
Product: CC1(C(F)(F)F)CC(=O)NN1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(300 mg, 1.65 mmol) 4,4,4-Trifluoro-3-methyl-but-2-enoic acid ethyl ester (CAS 24490-03-7) was dissolved in ethanol (3 ml) and hydrazine monohydrate 64% in ethanol (0.13 ml, 1.73 mmol, 1.05 equiv.) was added at room temperature and stirred in a sealed tube for 16 hours at 80° C. The reaction mixture was evaporated to dryness. The desired (RS)-5-methyl-5-trifluoromethyl-pyrazolidin-3-one (280 mg, quant.) was obtained as a white solid, MS: m/e=169.2 (M+H+).