Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:5][C:4]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:1]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccnc2ccccc12
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc2c1CCCC2
Yield: 92 %

Procedure:
Using the general method of F. W. Vierhapper and E. L. Eliel (J. Org. Chem., 1975, 40, 2729), a solution of 4.97 g (34.7 mmol) of lepidine in 35 mL of trifluoroacetic acid was shaken with 580 mg of platinum oxide under 50 psi of hydrogen for 18 h. After filtering off the catalyst, the solution was concentrated to about 20 mL and diluted with 25 mL of water. The aquous solution was chilled in ice, and basified carefully with 35 mL of 50% aqueous sodium hydroxide. The aqeuous layer was then extracted with 4×50 mL of diethyl ether. The organic layers were dried over potassium hydroxide, decanted, and concentrated to yield 4.7 g (92% yield) of 4-methyl-5,6,7,8-tetrahydroquinoline as an amber oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]([CH3:18])=O>CC(C)=O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([C:11]2[CH:12]=[CH:13][C:8]([OH:14])=[CH:9][CH:10]=2)([CH3:18])[CH3:15])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Phenol and acetone were passed through a column type reactor in which an ion exchange resin having a sulfonic group packed, in a molar ratio of phenol/acetone of 13, and a reaction solution of bisphenol A was obtained with 95% of conversion of acetone by a reaction at an inlet temperature of 55° C. and an outlet temperature of 75° C. Then, the above reaction solution was subjected to distillation to remove low boiling point substances such as unreacted acetone and water as a by-product, followed by crystallization at 50° C. by means of external intercooling to obtain a slurry containing an adduct crystal (adduct) comprising bisphenol A and phenol. The crystal adduct slurry was subjected to filtration under reduced pressure by means of a filter having a filter cloth with an aperture of 106 μm set thereto, while keeping the slurry temperature at 50° C., and the obtained crystal adduct cake was washed with refined phenol. The finally obtained adduct was a mixture with a composition of bisphenol A/phenol=7/3 (weight ratio). Impurities in the adduct at this stage were 2,4-bisphenol A=84 ppm, chroman-1=5 ppm and trisphenol=30 ppm, and no 4-isopropenyl phenol was detected. In order to hold the adduct in a molten state in a stock tank (made of SUS316) under conditions of the temperature and time as identified in Table 1, phenol was added to obtain a composition adjusted to have the composition as identified in Table 1. Then, the composition was held in a molten state under normal pressure under nitrogen sealing under conditions as identified in Table 1, and then the content of 4-isopropenyl phenol (IPP) contained in the composition was measured. The results are shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:8]([CH3:6])[CH2:9][CH2:10][CH3:11])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CO
Product: CCCN(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 165.4 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol) in MeOH (5 ml) was added NaBH3 CN (32 mg, 0.5 mmol, 1 eq.). The pH of the reaction mixture was adjusted to 5.5 by addition of 5N HCl and stirred for 48 hrs at RT under an inert atmosphere. The solvent was removed under reduced pressure and the crude was taken-up in AcOEt (150 ml). The organic layer was washed with NaHCO3 (10 ml) and with brine (10 ml) and was dried over MgSO4. The solvent was removed under vacuo to give the expected 4-(methyl-propyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (106 mg, 82% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[Na+].[Na+].CB1OB(C)OB(C)O1.[OH-].[Na+]>C(COC)OC.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>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH3:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of 0.30 g (0.78 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 6, intermediate) in 15 mL dimethoxyethane was added 9 mg tetrakis(triphenylphosphine)palladium. After 20 min. 0.25 g (2.35 mmol) sodium carbonate in 8 mL water and 132 μl (0.94 mmol) trimethylboroxine were added and the reaction was stirred at 100° C. for 3 h. The reaction was cooled to room temperature then poured into 1M aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel with ethyl acetate:n-hexane (1:2) as eluant to give the product as a light yellow oil (66.0%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cc(Cl)ccc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2,5-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.14 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:9][CH2:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[C:7]=2[CH:8]=1
Reactant: COc1ccc(CCc2ccccc2C(=O)O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 50 ml of a methylene chloride solution containing 1.80 g (7.0 mmol) of 2-[2-(4-methoxyphenyl)ethyl]benzoic acid were added 1.83 ml (13 mmol) of trifluoroacetic anhydride and 0.8 ml (6.3 mmol) of boron trifluoride ethyl ether complex and the mixture was stirred at room temperature for 5 hours.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH:7]=[CH:6]1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6]1
Reactant: COCCn1ccc2nccc(Sc3ccc([N+](=O)[O-])cc3)c21
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COCCn1ccc2nccc(Sc3ccc(N)cc3)c21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A sealed vial was charged with 1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine (0.147 g, 0.446 mmol) and methanol (5 mL). Tin (II) chloride dihydrate (0.504 g, 2.23 mmol) was added and the reaction was stirred at 50° C. for 3 hours. The reaction was concentrated and dissolved in DCM. The solution was washed with saturated sodium bicarbonate solution, which was extracted with DCM. The combined organic layers were washed with water, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-10% DCM:MeOH) to afford 4-(1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridin-7-ylthio)benzenamine as an orange oil that solidified under high vacuum. MS: M+H+=300.1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[N+:15]([O-:9])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc2ccccc21
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A solution of 72% 3-chloroperbenzoic acid (97.8 g (0.408 mol) dissolved in 1 L DCM, dried on sodium sulphate and filtered off) was added dropwise to a solution of 85.0 g 0.41 mol) 3-bromoquinoline in 100 mL DCM cooled to 5° C. Care was taken to ensure that the temperature of the reaction mixture did not rise above 10° C. After the addition had ended the mixture was stirred for 5 h, then a solution of 72% 3-chloroperbenzoic acid (25.0 g, 0.104 mol) dissolved in 200 mL DCM, dried on sodium sulphate and filtered off) was again added dropwise and the mixture was stirred overnight at RT. Saturated aqueous sodium carbonate solution was added, the phases were separated and the organic phase was dried on sodium sulphate. The solution was filtered through activated charcoal and then evaporated down i. vac.
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C>>[CH2:14]([O:13][CH:4]1[CH2:5][CH:6]2[CH2:7][CH:8]1[CH:9]=[CH:10]2)[CH2:15][CH2:16][CH3:17]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=COCCCC
Product: CCCCOC1CC2C=CC1C2

Procedure:
Dicyclopentadiene was heated with butyl vinyl ether to form the Diels-Alder product of 5-butoxy-2-norbornene. The product was then purified by vacuum distillation.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:12](=CC=O)[CH:11]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:36][CH2:37][OH:38]>>[CH2:1]([O:8][CH:9]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C:12](=[C:37]([OH:38])[CH3:36])[CH:11]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:28])[CH3:29])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C)[Si](C)(C)OC1CC(OCc2ccccc2)CC(O[Si](C)(C)C(C)(C)C)C1=CC=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)=C1C(O[Si](C)(C)C(C)(C)C)CC(OCc2ccccc2)CC1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of Compound 31 (288 mg, 0.587 mmol, 31a:31b=ca. 1:2) in EtOH (1 mL) cooled to 0° C. was added NaBH4 (26.6 mg, 0.704 mmol). After, the reaction mixture was stirred for 1 h at 0° C., into the reaction mixture was poured ice water, and extracted with AcOEt. The organic layer was washed with saturated brine, and dried over anhydrous MgSO4. Solvents were removed in vacuo, and the residue was purified by silica gel column chromatography (10 g; 15% AcOEt/hexane) to yield Compound 32 (283.3 mg, 98%) as a mixture of two stereoisomers. The ratio of the stereoisomers constituting the mixture was ca. 2:1. It was impossible to know whether the major product was aS*,2R,6R isomer or aR*,2R,6R isomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:14][CH2:15][OH:16])[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30]>C(#N)C.O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=1)[C:29]([N:10]1[CH2:11][CH2:12][O:13][C@:8]([CH2:14][CH2:15][OH:16])([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9]1)=[O:30]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCC[C@@]1(c2ccc(F)cc2)CNCCO1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(F)cc2)C1
Yield: 102.8 %

Procedure:
2-[(2R)-2-(4-Fluorophenyl)morpholin-2-yl]ethanol (1.76 g, 7.82 mmol) and triethylamine (1.32 mL, 9.38 mmol) were dissolved in a mixed solvent of acetonitrile (18 mL) and water (0.9 mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (1.48 mL, 8.21 mmol) in toluene (8.2 mL) was added dropwise with stirring under ice cooling, and then the mixture was further stirred under the same conditions for 5 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude 2-[(2R)-4-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorophenyl)morpholin-2-yl]ethanol (3.74 g) as a colorless oily substance.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[C:12](O)[CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[C:14]([O:4][CH3:1])[CH:15]=1
Reactant: CCCC(=O)c1ccc(Br)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCC(=O)c1ccc(Br)cc1OC
Yield: 67.7 %

Procedure:
Potassium carbonate (9.07 g) and methyl iodide (3.92 ml) were added to a solution of the compound of Example B220 (13.30 g) in acetone (75 ml), and this reaction mixture was stirred while heating under reflux for 4 hours. The reaction mixture was filtered through celite, ether was added to remove insoluble material by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (9.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:29])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=1)[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC.Br[Si](C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[Cl:29][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([Cl:1])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:26]([CH3:27])[CH3:28])[CH:19]=1)[CH2:5][P:6](=[O:7])([OH:10])[OH:13]
Reactant: CCOP(=O)(Cc1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1)OCC
Agent: BrB(Br)Br
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(CP(=O)(O)O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a solution of diethyl 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzylphosphonate (0.59 g, 1.28 mmol) in CH2Cl2 (10.0 mL) at −30° C. was added bromotrimethylsilane (2.53 mL, 19.2 mmol). The reaction mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (25.0 mL), cooled to −78° C. and to it was added BBr3 (19.0 mL, 19.0 mmol, 1.0 M solution in CH2Cl2). The reaction mixture was stirred at −78° C. for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into ice, concentrated and extracted with ethyl acetate. The organic layer was washed with water (20 mL×2), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford 3,5-dichloro-4-(3′-iso-propyl-4′-hydroxyphenoxy)benzylphosphonic acid as a brown solid (0.20 g, 40%): mp: 178-181° C.; LC-MS m/z=391 [C16H17Cl2O5P−H]−; 1H NMR (300 MHz, DMSO-d6): δ 9.08 (s, 1H), 7.48 (s, 2H), 6.72 (m, 2H), 6.25 (m, 1H), 3.18 (m, 1H), 3.00 (d, J=21.0 Hz, 2H), 3.11 (m, 1H), 1.14 (d, J=6.0 Hz, 6H); Anal. Calcd for (C16H17Cl2O5P+0.2 C4H8O2+0.5H2O): C, 48.30; H, 4.73. Found: C, 48.69, H, 5.16.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][OH:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate and TEA in CH2Cl2 at 0° C. was added dropwise a solution of MsCl. The mixture was stirred for 2 h. The mixture was washed with water and dried over Na2SO4. The organic phase was distilled off to give the crude product (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-(methylsulfonyloxy)butyl)-2,2-dimethyloxazolidine-3-carboxylate (6.2 g). 1H NMR (CDCl3, 400 MHz) δ 0.06 (s, 6H, 0.89 (s, 9H), 1.46 (s, 12H), 1.50 (s, 3H), 1.53 (m, 3H), 2.94 (s, 3H), 3.49 (m, 2H), 3.50 (m, 2H), 3.7 (m, 2H), 3.9 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[NH2:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: COc1cc(N)cc(F)c1
Agent: Br
Product: COc1cc(F)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 63.9 %

Procedure:
3-fluoro-5-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-fluoro-5-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 63%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.50 (d, 3H), 2.74 (bs, 3H), 2.94 (bs, 3H), 3.50-3.63 (m, 4H), 3.61 (s, 3H), 3.68-3.79 (m, 4H), 4.94-5.03 (m, 1H), 5.60 (s, 1H), 5.87 (dd, 1H), 5.88 (s, 1H), 5.93 (ddd, 1H), 6.63 (d, 1H), 7.57 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)[CH3:22])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:21]([NH:20][C:14]2[N:13]=[C:12]([C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:32])[F:1])[C:4]4=[N:11][CH:10]=3)[C:17]([C:18]#[N:19])=[CH:16][N:15]=2)[CH3:22])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc(N)cc1
Yield: 18.1 %

Procedure:
83 mg of the 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-{[(1S)-1-(4-nitrophenyl)ethyl]amino}pyrimidine-5-carbonitrile [103-1] was dissolved in a mixture solvent of 2 mL of ethanol and 3 mL of tetrahydrofuran, then 40 mg of 10% palladiumcarbon catalyst was added, and stirred overnight at room temperature in a hydrogen atmosphere. The insolubles were filtered through celite and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin-layer chromatography, and 14 mg of 2-{[(1S)-1-(4-aminophenyl)ethyl]amino}-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-5-carbonitrile [103-2] was obtained as pale yellow amorphous.
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].Cl>CC(OC)(C)C>[C:20]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:9]=[C:10]([CH3:11])[CH3:12])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(C)=CC(C)CCCCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)OCCCCCC(C)C=C(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
13 g (76 mmol) of 6,8-dimethylnon-7-enol (2), 10.8 g (107 mmol) of triethylamine and 200 ml of t-butyl methyl ether (MTBE) are placed in a 500 ml round-bottomed flask equipped with a thermometer and with a dropping funnel. Cooling is carried out to 5° C. and 8.4 g (107 mmol) of acetylchloride diluted in 20 ml of MTBE are added without exceeding a bulk temperature of 10° C. The mixture is stirred at ambient temperature for 14 hours. Cooling is carried out at 5° C. and neutralization is carried out with 100 ml of a 10% hydrochloric acid solution. The phases are separated and the organic phase is washed once with 100 ml of saturated aqueous NaHCO3 solution and then with aqueous saline solution to neutrality. The organic phase is dried and filtered, and the solvent is evaporated under reduced pressure. The acetate is purified by a distillation under reduced pressure (B.p.: 58° C./0.4 torr). The yield is 76%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1cccc(C2=CCC3(CC2)OCCO3)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Fc1cccc(C2CCC3(CC2)OCCO3)c1

Procedure:
The compound (17) was dissolved in a mixed solvent of toluene (150 ml) and Solmix (150 ml) and 3.48 g of Pd/C was added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 61.9 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4,5]decane (18). The yield based on the compound (17) was 88.1%.