Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([C:12](=[O:21])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2].C(OC(C)(C)C)(=O)CC(C)=O.CC(C)([O-])C.[Na+].C1(SCC(Cl)=O)C=CC=CC=1>C(OCC)C>[C:15]1([S:14][CH2:13][C:12](=[O:21])[CH2:4][C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)C(C(=O)CSc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)CSc1ccccc1
Solvent: CCOCC
Product: CC(=O)CC(=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
1,1-Dimethylethyl 2-acetyl-3-oxo-4-(phenylthio)butanoate Add tert-butyl acetoacetate (1.30 mL, 8.0 mmol) dropwise to a solution of sodium tert-butoxide (770 mg, 8.0 mmol) in diethyl ether (15 mL) at 0° C. under nitrogen. Stir the white precipitate at RT for 20 h and cool to 0° C. Add (phenylthio)acetyl chloride (1.2 mL, 8.0 mmol) dropwise and observe as the suspension turns yellow, then becomes a clear solution, and finally forms a white precipitate when all the reagent is added. Stir the reaction for 24 h at RT. Quench with 2 N HCl (15 mL), wash the aqueous layer with EtOAc (15 mL). Dry (MgSO4), concentrate and purify (silica gel chromatography, eluting with 100:0 to 90:10 2-methylpentane:EtOAc) to give the title compound as light yellow solid (1.11 g, 48%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OC(C)(C)C)=O.CC#N.O>C(Cl)Cl.O.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=[O:14])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC=O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1

Procedure:
The title compound is prepared in a similar manner as described for Example 9/reaction step E, from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10.4 g, 58.9 mmol) and Dess-Martin periodinane (25.0 g, 58.9 mmol) in CH2Cl2 (150 mL), slowly wet CH2Cl2 (1.17 mL of water in 150 mL of CH2Cl2) as colorless oil. MS: 244.2 [M+H-Boc]+. tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.46 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl (3-nitrophenyl)carbamate (10.75 g, 45.12 mmol) in MeOH (150 mL) was added catalyst 10% Pd/C (0.48 g). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a pale yellow solid (7.59 g, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:21])[F:22])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoate (7.23 g, 21.1 mmol, 1.0 eq.) in ethanol (40 ml) is added 1M NaOH (30.6 ml, 30.6 mmol, 1.4 eq.). After stirring for 2 h at room temperature a clear pale yellow solution is obtained. The mixture is evaporated to a volume of 30 ml. Then, the solution is adjusted to pH 7 by addition of 1M HCl and the solvent is stripped off. The residue is taken up three times in toluene (70 ml) and evaporated. The crude material is dissolved in ethanol/THF 1:9 (150 ml), filtered, evaporated, triturated with ethyl acetate, and vacuum dried at 60° C. over night to afford a beige powder: HPLC: tR=3.61 min (purity: >99%, gradient A), ESI-MS: 303.3 [MH]+
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:12]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: O=C1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(N3CCC(=O)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
A suspension of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one (1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7 mmol), and tetrakis(triphenylphosphine) palladium (0.20 g, 0.17 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a golden yellow foam.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 95.8 %

Procedure:
In a 200 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 9.2 g (31.6 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 7.5 mL (143 mmol) of acetonitrile, 45 mL of toluene (dielectric constant at 25° C.: 2.38), and 1.99 g (36.8 mmol) of sodium methoxide. The content was reacted at 50° C. for 8 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 40 mL of toluene and 34.0 mL (34.0 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with 30 mL of saturated aqueous sodium chloride solution, the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 9.52 g (yield: 96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced. The organic portion was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane (15/85, vol. ratio) to obtain 9.29 g (yield 88%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile as a yellow crystalline product (purity: 94%, measured by high performance liquid chromatography).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.C1C=CC2C(=O)C=CC(=O)C=2C=1.[C:23]([OH:34])(=[O:33])[C:24]1[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:26]([OH:28])=O.C(O)(=O)/C=C\C(O)=O.C(O)(=O)CCC(O)=O>[O-2].[O-2].[O-2].[O-2].[O-2].[V+5].[V+5]>[C:26]1(=[O:28])[O:34][C:23](=[O:33])[C:24]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [V+5]
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C(O)CCC(=O)O
Solvent: c1ccc2ccccc2c1
Product: O=C1OC(=O)c2ccccc21
Yield: 99 %

Procedure:
The optimum yield of phthalic anyhdride is produced in the temperature range of 360° ± 10° C, with temperatures over or under this range resulting in over or under oxidation, respectively, of the napthalene yielding undesirable products such as 1-4 napthoquinone, phthalic acid, maleic acid, succinic acid, etc. With a vanadium pentoxide catalyst structure made according to the present invention, a yield of 99% phthalic anhydride was obtained with only a slight trace of 1-4 napthoquinone. Throughout this reaction, the temperature of the catalyst structure was easily maintainable within the optimum operating temperature range of 360° C ± 10° C.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16](O)=[O:17]>C1COCC1>[Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17]
Reactant: O=C(O)c1cccc2c(Br)c3ccccc3cc12
Solvent: C1CCOC1
Product: OCc1cccc2c(Br)c3ccccc3cc12

Procedure:
10-Bromo-1-anthracenecarboxylic acid made from example 2B by the procedure of E. Barnett, J. W. Cook, and H. H. Grainger, Ber. 57 B, 1775 (1924), was reduced with BH3 in THF by the procedure outlined in 2C to give (10-bromo-1-anthryl)methanol mp 125°-127°, (EtOAc/hexane), (C, H, Br).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[F:12][C@@H:13]1[CH2:17][NH:16][C@H:15]([C:18]#[N:19])[CH2:14]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[Cl:27][CH2:28][C:29]([N:16]1[CH2:17][C@@H:13]([F:12])[CH2:14][C@H:15]1[C:18]#[N:19])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: N#C[C@@H]1C[C@H](F)CN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Yield: 94 %

Procedure:
A solution of step 3 intermediate (10 g, 32.89 mmol) and triethylamine (4.32 g, 42.77 mmol) in dichloromethane (200 ml) was added drop wise to a stirred and cooled (0° C.) solution of chloroacetyl chloride (4.81 g, 32.95 mmol) in dichloromethane (50 ml) over a period of 10 min. The mixture was stirred at the same temperature for 2 h and diluted with dichloromethane (100 ml) and water (100 ml) under stirring. The layers were separated. The organic layer was washed with water (2×50 ml), brine (50 ml) and dried (Na2SO4). The residue obtained after evaporation of the solvent was triturated with diethyl ether to give 5.89 g (94%) of the product as an off-white solid, IR (KBr) 2924, 2241, 1678, 1407, 1281, 1225, 1076, 1051, 958 cm−1; 1H NMR (CDCl3, 300 MHz) δ 2.26-2.48 (m, 1H), 2.66-2.80 (m, 1H), 4.06 (s, 2H), 3.81-4.29 (m, 2H), 4.95 (d, J=9.6 Hz, 0.8H, rotomer), 5.38 (brd, J=51.3 Hz, 0.2H, rotomer) 5.46 (d, J=9.0 Hz, 0.2H, rotomer), 5.46 (dt, J=44.4, 3.3 Hz, 0.8H, rotomer).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].[C:13]([Cu])#[N:14].CN(C=O)C>C(OCC)(=O)C>[Cl:11][C:4]1[C:3]([CH3:12])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[C:13]#[N:14]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1C#N
Yield: 60.2 %

Procedure:
A solution of 10 g (49 mmol) of 2,6-dichloro-3-nitrotoluene and 4.8 g (54.0 mmol) of CuCN in 100 ml of abs. DMF was stirred at 150° C. for 6 h, a further 2.4 g (27.0 mmol) of CuCN being added after 4 h. The solvent was stripped off and the residue obtained taken up in ethyl acetate. The precipitate deposited was filtered off and extracted several times with warm ethyl acetate. The combined ethyl acetate solutions were washed with H2O, dilute ammonia solution, and saturated NaCl solution, dried over Na2SO4, and concentrated to dryness. The resulting yellow, crystalline residue was purified by column chromatography on SiO2 using EA/n-heptane 1:10 as a solvent. 5.8 g of the title compound resulted in the form of yellow crystals.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].N12CCCN=C1CCCCC2>C(O)C>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CNC(N)=S
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Cn1c(S)nc(-c2ccncn2)cc1=O
Yield: 82.8 %

Procedure:
A solution of ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (36.10 g, 0.186 mol), N-methylthiourea (25.40 g, 0.282 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (29.11 g, 0.191 mol) in ethanol (150 ml) was refluxed for 21 hrs. A half amount of ethanol was evaporated under reduced pressure and hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with water and dried. The precipitate was stirred in hot ethyl acetate (1 L), and the precipitate was collected by filtration and dried to give 2-mercapto-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (33.91 g, 83%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]O)([CH3:34])[CH3:33].O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:37][CH2:36][N:35]([CH:39]([CH3:41])[CH3:40])[CH:32]([CH3:34])[CH3:33])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)N(CCO)C(C)C
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN(C(C)C)C(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(diisopropylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(diisopropylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c2ccccc12
Temperature: 80 °C
Yield: 96 %

Procedure:
To a stirred solution of methyl 4-methyl-1-naphthoate (22.5 g, 0.112 mol) in CCl4 (500 mL) was added NBS (22 g, 0.123 mol) and benzoylperoxide (10% w/w). The reaction mixture was allowed to reflux at 80° C. for 7 h. The reaction mixture was cooled to rt and filtered off. The solid and concentrated under vacuum and the obtained crude product (30 g) was used for further reaction.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>[Cu]I.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.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), CuI (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[CH2:3][CH:4]=[O:5]
Reactant: CC(C)C(C)(C)CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(C)(C)CC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
Step C To a solution of 3,3,4-trimethyl-pentan-1-ol (5.4 g, 41 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (22 g 52 mmol) The reaction mixture was stirred at room temperature for 3 h. Aqueous Na2SO3 solution was added to quench the reaction. The organic layers were separated, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:30) to give 3,3,4-trimethyl-pentanal as a colorless oil (Yield: 1.1 g, 21%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[C:19]([Cl:25])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.O>ClCCCl.CO>[Cl:25][C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([Cl:23])[C:20]=1[F:24]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCNC2)cc1Cl
Yield: 129.4 %

Procedure:
To a stirred solution of 1-benzyl-3-(3,5-dichloro-4-fluoro-phenyl)-3-trifluoromethyl-pyrrolidine (Preparation 30, 6.1 g, 15.60 mmol) in 1,2-dichloroethane (50 mL) was added 1-chloroethyl chloroformate (3.01 mL, 28.08 mmol) at room temperature. Resulting reaction mixture was refluxed for 3 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford brown thick oil. Brown thick oil was dissolved in MeOH (50 mL) and refluxed for 2 hours. Progress of reaction was monitored by TLC. After complete consumption of starting material, reaction mixture was again concentrated to afford brown thick oil, to which water was added (100 mL) and washed with hexane (3×50 mL). Aqueous layer was basified by saturated sodium bicarbonate solution, extracted with ethyl acetate (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford product as brown thick oil (6.1 g, crude). Crude was purified by column chromatography on (100-200 mesh silica). Desired product was eluted in 25% ethyl acetate in hexane to afford brown semi solid (3.8 g, 80.68%). 1H-NMR (400 MHz, DMSO-d6) δ: 2.39-2.46 (m, 1H), 2.53-2.58 (m, 1H), 2.99-3.13 (m, 2H), 3.53 (d, 1H, J=12.84 Hz), 3.65 (d, 1H, J=12.84 Hz), 7.77 (d, 2H J=6.28 Hz). (m/z): 302.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].I([Cl:26])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.ClC(Cl)C.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH2:15]([O:14][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[C:4]([C:1](=[O:3])[CH2:2][Cl:26])[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12

Procedure:
7.0 g (23.9 mmol) 5-acetyl-7-benzyloxy-1H-quinolin-2-one and 19.0 g (54.6 mmol) benzyltrimethylammonium dichloriodate are stirred in 43 mL acetic acid, 7 mL water and 147 mL dichloroethane at 65° C. After 4.5 hours the raction is stopped by the addition of 400 mL sodium carbonate solution and 50 mL 5% sodium sulphite solution. The insoluble constituents are suction filtered, washed with water and dried.
Reaction SMILES: O[CH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:9]1(=[O:10])[C:3]2([CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH2:2][O:11]1
Reactant: O=C(O)C1(CO)CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OCC12CCOCC2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-hydroxymethyl-tetrahydropyran-4-carboxylic acid (3.84 Kg), 4-dimethylaminopyridine (0.6 Kg) in dichloromethane (32 liters) was added triethylamine (4.88 Kg). The mixture was cooled to -20° C., and a solution of benzenesulfonyl chloride (4.66 Kg) in dichloromethane (5 liters) was added over a period of 35 minutes, maintaining the temperature below -10° C. The mixture was stirred at -10° C. for 30 minutes, then 3N hydrochloric acid (10 liters) and water (10 liters) were added with stirring, then the layers allowed to separate. The organic layer was separated, the aqueous layer washed with dichloromethane (16 liters), the combined organics washed with aqueous 5% sodium bicarbonate solution (12 liters), then with water (12 liters), and solvent removed under reduced pressure, to give 2,7-dioxaspiro[3,5]nonane-1-one, a compound of Formula (10a)
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(=O)C)[N:17]=[CH:16]3)=CC=1)([O-])=O.C(O)C.CO.N12CCCN=C1CCCCC2>ClCCl>[CH3:7][O:10][P:11]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: CC(=O)n1ncc2cc(OP(=O)(Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc21
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COP(=O)(Oc1ccc2[nH]ncc2c1)c1ccccc1
Temperature: 20 °C
Yield: 62 %

Procedure:
A solution of 2.4 g of phenylphosphonic acid 1-acetyl-1H-indazol-5-yl ester 4-nitrophenyl ester in 30 ml of dichloromethane stabilized with ethanol is stirred at 20° C. A solution of 3.78 ml of methanol and of 836 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of dichloromethane is added thereto. The reaction is continued at this temperature overnight. The reaction mixture is evaporated under reduced pressure and the crude compound thus obtained is then purified by chromatography on silica (AIT BP-SUP 20-40 μm, eluent 90/10 dichloromethane/methanol). The fractions containing the expected compound are combined and evaporated under reduced pressure. 980 mg of phenylphosphonic acid 1H-indazol-5-yl ester methyl ester are isolated and characterized.