Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=C)=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:35]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:35])=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c3ccccc3)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 0.08 mmol) in CH2Cl2 (15 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to move excess ozone. NaBH4 (12.2 mg, 0.32 mmol) was added to the mixture in portions at rt, and the mixture was stirred overnight at rt. The reaction was quenched by water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layer was combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-3-((S)-1-(4-(hydroxylmethyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 25%). 1H NMR (CDCl3): 0.00 (s, 4H), 0.09 (s, 2H), 0.87 (s, 8H), 1.28 (s, 4H), 1.53 (d, 3H), 1.98 (d, 2H), 3.53 (m, 2H), 4.25 (m, 1H), 4.98 (m, 1H), 4.61 (m, 1H), 5.71 (m, 1H), 6.90 (m, 1H), 7.12-7.38 (m, 10H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[CH3:11][NH:12][N:13]=[C:14](Br)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:3]([C:2]([F:10])([F:9])[F:1])=[C:4]([C:5]([F:8])([F:7])[F:6])[N:12]([CH3:11])[N:13]=2)=[CH:20][CH:19]=1
Reactant: CNN=C(Br)c1ccc(Cl)cc1
Reactant: FC(F)(F)C#CC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1nc(-c2ccc(Cl)cc2)c(C(F)(F)F)c1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
5.7 g (41 nmol) of gaseous hexafluoro-2-butyne were passed at below (-50)° C. into a suspension, cooled to (-70)° C., of 9 g (36 mmol) of α-bromo-4-chlorobenzaldehyde methylhydrazone in 100 ml of toluene. The mixture was subsequently heated to (-25)° C., and 8.4 g (83 mmol) of triethylamine were added dropwise at this temperature. After the mixture had been stirred for 2 hours at this temperature and for a further 16 hours at approx. 20° C., it as washed with water, dried over magnesium sulfate and finally concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[C:21](#[N:25])[CH2:22][C:23]#[N:24]>>[NH2:25][C:21]1[O:1][C:2]2[C:10]([CH:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Br:12])[CH:14]=3)[C:22]=1[C:23]#[N:24])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Reactant: O=Cc1cccc(Br)c1
Product: Cn1ccc2c3c(ccc21)C(c1cccc(Br)c1)C(C#N)=C(N)O3

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 3-bromobenzaldehyde (48 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 79 mg (80%) of white solids. 1H NMR (CDCl3): 7.36-7.31 (m, 2H), 7.21-7.16 (m, 2H), 7.06-7.01 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.57 (dd, J=3.0 Hz, J=0.9 Hz, 1H), 4.82 (s, 1H), 4.69 (brs, 2H), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:18]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:17])[CH:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:18]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCC1CCCCC1)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
66 g (263 mmole) 1-(2-Chloro-phenyl)-3-cyclohexyl-propan-1-one, 77.5 g (2.1 eq.) urotropine and 72.6 g (2.7 eq.) of acetic anhydride were placed in a 500 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 100 ml water and 100 ml 2M NaOH were added and the mixture was extracted two times with 200 ml dichloromethane each. The organic layer was washed two times with 100 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 150 ml volume and the solution was added dropwise over a period of 2.5 h to 660 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was poured onto approx. 500 g of ice and extracted three times with 150 ml dichloromethane each. The organic layer was washed twice with 150 ml of a saturated sodium bicarbonate solution and once with 100 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 5:1) to yield 40.0 g (61%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.42 (t, 1H, aromatic), 7.29 (d, 1H, aromatic), 7.24 (d, 1H, aromatic), 3.25 (dd, 1H, COCH), 2.71 (m, 2H, benzylic), 1.78-0.87 (m, 13H, aliphatic) ppm.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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:10]1([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cnccc1Br
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cnccc1-c1ccccc1
Temperature: 110 °C
Yield: 50.5 %

Procedure:
4-bromonicotinaldehyde (150 mg, 0.81 mmol), phenylboronic acid (98 mg, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (46.6 mg, 0.05 mmol) were mixed in dioxane (3.5 mL). Na2CO3 (2 M solution in water, 0.81 mL, 1.63 mmol) was added and the reaction mixture was stirred and heated in the microwave (110° C., 150 W) for 30 min. After addition of excess water followed by extraction with EtOAc, the combined organic layers were filtered (celite) and dried (MgSO4). Purification by flash chromatography (heptane/EtOAc, gradient 5-40% EtOAc) provided 4-phenylnicotinaldehyde (75 mg, 48%) as a dark yellow gum. ESI-MS [M+H]+=279.1.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.[CH:29]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30]1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[CH:29]1([N:32]2[CH2:37][CH2:36][N:35]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[CH:17][CH:16]=3)=[O:15])[CH2:34][CH2:33]2)[CH2:31][CH2:30]1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 22.5 °C

Procedure:
A 100-L glass-lined reactor was charged with toluene (45.00 kg) and stirred at ˜20-25° C. To the stirring toluene was added 4-(4-morpholinylmethyl)benzoic acid hydrochloride (6.50 kg, 93.5%, 24.04 mol), 1-hydroxybenzotriazole monohydrate (2.32 kg, 15.13 mol), 1-cyclopropylpiperazine (3.50 kg, 27.07 mol) and acetonitrile (9.00 kg). The resulting off-white slurry was stirred under N2 at ˜20-25° C. for 40 minutes. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.50 kg, 27.07 mol) was added, followed by an acetonitrile (1.20 kg) rinse. After the addition, the reaction mixture was stirred at ˜20-25° C. overnight. Water (32.50 kg) and aqueous saturated sodium carbonate (19.50 L) were then added to the stirring suspension. The suspension was stirred for an additional 30 minutes. The resulting biphasic solution was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a 50% brine solution [water (19.50 L)/brine (19.50 L)]. To the stirred organic phase was then added anhydrous sodium sulfate (2.86 kg) and the resulting mixture was stirred at ˜20-25° C. for 1.5 hours. The solid sodium sulfate was filtered off and the filter cake was washed with acetonitrile (15.30 kg). The filtrate was transferred to a clean 100-L glass-lined reactor and stirred at ˜20-25° C. Water (0.47 kg) and 5/6N HCl in 2-propanol were added to precipitate the title compound as the corresponding bis-hydrochloride salt as a solid. The solid was filtered, washed with acetonitrile (10.2 kg) and dried (60 Torr, ˜40-45° C.) to a constant weight to yield the title compound as a white solid.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)[C:11](=[O:24])[N:10]([CH2:25][CH3:26])[C:8]=2[N:9]=1)=O.[ClH:27].[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(#N)C.C(O)C>[ClH:27].[NH:28]=[C:29]1[CH:34]=[CH:33][N:32]([C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[C:12]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=4)[C:11](=[O:24])[N:10]([CH2:25][CH3:26])[C:8]=3[N:9]=2)[CH:31]=[CH:30]1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(-n3ccc(=N)cc3)nc21
Temperature: 40 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 220 g (0.59 mol) of the product of Example 2, 2-methylsulfinyl-6-(3,5-dimethoxy-phenyl)8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, in 2 L of acetonitrile was added a solution of 100 g (0.765 mol, 1.3 eq) of 4-aminopyridine hydrochloride in 700 mL of ethanol. The mixture was heated to 40° C. and stirred for 6 hours. The mixture was then cooled to 24° C. and filtered to provide 256 g (99%) of 2-(4-imino-4H-pyridin-1-yl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]-pyrimidin-7-one hydrochloride; mp 295-300° C. (dec).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO.[Cl-].[Na+].O>[C:11]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
A solution of 6-bromoindole (2.0 g, 10.20 mmol) in anhydrous toluene (20 mL) under a nitrogen atmosphere was treated with Pd[P(Ph3)]4 (10% mol). After stirring the mixture for 30 min., phenylboronic acid (1.87 g, 15.30 mmol) in anhydrous EtOH (10 mL) was added followed by the addition of sat'd NaHCO3 (6 mL). The bi-phasic mixture was heated to reflux for 24 h. After cooling to room temperature, the mixture was added to a sat'd brine solution and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 CH2Cl2/heptane) to give the desired material as white powder (900 mg, 45%): 1H NMR (DMSO-d6, 300 MHz) δ 11.15 (br s, 1H), 7.58-7.66 (m, 4H), 7.41-7.47 (m, 2H), 7.36 (m, 1H), 7.26-7.31 (m, 2H), 6.42 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH2:18][CH:19]([OH:31])[CH:20]2[C:24](N3CCCC3)=[CH:23][C:22](=[O:30])[O:21]2)C(=O)OC(C)(C)C)=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:17][CH2:18][CH:19]([OH:31])[CH:20]3[O:21][C:22](=[O:30])[CH:23]=[C:24]23)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCC(O)C1OC(=O)C=C1N1CCCC1)Cc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C2C(O1)C(O)CCN2Cc1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
At room temperature, 176 mg (0.35 mmol) of tert-butyl [(6-chloropyridin-3-yl)methyl][3-hydroxy-3-(5-oxo-3-pyrrolidin-1-yl-2,5-dihydrofuran-2-yl)propyl]carbamate (cf. V-2) are stirred in a mixture of 7 ml of dichloromethane and 3.5 ml of trifluoroacetic acid for one hour. After concentration under reduced pressure, 10.5 ml of acetic acid are added to the residue, and the mixture is stirred at 100° C. for two hours. After concentration under reduced pressure, the residue is purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (99:1 to 80:20). This gives (a) 6 mg (6% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-7-hydroxy-5,6,7,7a-tetrahydrofuro-[3,2-b]pyridin-2(4H)-one as a mixture of diastereomers and (b) 30 mg (32% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-5,6-dihydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>C(O)(=O)C>[N:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CCN2CCCCC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(CCN2CCCCC2)cc1

Procedure:
A solution of 11 g=50 mmoles of 4-(piperidin-1-ylethyl)-anisole in a mixture of 50 ml of glacial acetic acid and 50 ml of 48% strength hydrobromic acid is boiled under reflux for 4 hours, the solution is evaporated in vacuo and the residue is recrystallized from ethanol. This gives 9 g of the hydrobromide, melting point: 265° C. The salt is dissolved in 30 ml of water and the free base is precipitated with concentrated aqueous ammonia solution and is filtered off. This gives 5.5 g (54% of theory), melting point: 168°-169° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:7]=2[CH:14]=1)#[N:2].[H-].[Na+].[CH:17]12[O:22][CH:18]1[CH2:19][CH2:20][CH2:21]2>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][N:8]([CH:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[OH:22])[C:7]=2[CH:14]=1)#[N:2]
Reactant: C1CC2OC2C1
Reactant: CC1(C)CNc2cc(C#N)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(C2CCCC2O)c2cc(C#N)ccc2O1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.0 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine followed by addition of 0.24 g of sodium hydride. The mixture was stirred at 70° C. for 1 hour and after cooling to room temperature, 0.5 ml of cyclopentene oxide was added. The mixture was stirred at 70° C. for 3 hours. The reaction mixture was then allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were recrystallized from ethyl acetate-hexane to give 0.53 g of 6-cyano-3,4-dihydro-4-(2-hydroxycyclopentan-1-yl)-2,2-dimethyl-2H-1,4-benzoxazine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[OH:19]O>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:19]
Reactant: Cc1ccc(CSc2c(O)cc(C)oc2=O)cc1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1ccc(CS(=O)c2c(O)cc(C)oc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
4-Hydroxy-6-methyl-3-(p-methylbenzylthio)-2-pyrone (10.5 g., 0.0400 mol), 30% hydrogen peroxide (5.14 g., 0.0440 mol), and 50 ml. glacial acetic acid were combined and stirred at room temperature for 20 hours. The reaction mixture was poured into 250 ml. ice-water and the recovered white precipitate was collected and dried. The solids were recrystallized from toluene to give 3.9 g. (35 percent) of the desired compound as a pale pink crystalline solid, m.p. 156°-158°C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.2 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (7 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a white solid (1.6 g, 96%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O.O1CCCC1>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[O:19][CH2:8]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CO2)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A suspension of 4.84 g. of sodium hydride (57% mineral oil dispersion) in 70 ml. of dry dimethyl sulfoxide is heated at about 65° C. under argon with stirring for 1 hour. Dry tetrahydrofuran (75 ml.) is added and the resulting solution is cooled to -5° C. Trimethylsulfonium iodide (19 g., 92.8 mmole) is added very slowly and stirring is continued for about 5 minutes. A solution of 12.6 g. (92.8 mmole) of p-methoxybenzaldehyde in 120 ml. of tetrahydrofuran is added and the temperature is maintained at -5° C. After addition is completed the mixture is allowed to warm to room temperature, poured into water and extracted with ether. The extract is washed with saturated sodium chloride solution, dried and evaporated to give p-methoxystyrene oxide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:16]1([CH2:15][NH:14][C:4]2[N:3]=[C:2]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:31][CH2:30]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:18][CH2:17]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCC2CC2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCC2CC2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-(cyclopropylmethyl-amino)-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 48a) was treated with the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropyl-amine at 100° C. to yield 2-(cyclopropylmethyl-amino)-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=412.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:14]=[CH:15]N(C)C)=[S:13])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br)[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[CH2:20][CH3:21])=[CH:15][N:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ccccc1C(=O)CBr
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Product: CCc1ccccc1C(=O)c1cnc(NCCCNC(=O)OC(C)(C)C)s1

Procedure:
The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-ethyl phenacylbromide according to the procedure described for Example 25. MS (m/e): 389.9 (MH+, 100%).
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[O:21][C:20]=2[CH3:32])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[O:21][C:20]=2[CH3:32])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccc(OC)cc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(Oc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methanol (601 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (365 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (1.0 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.0 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 12% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methoxy}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (362 mg, 38%).