Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17](=[O:19])[NH2:18])[C:11]([NH2:20])=[C:10]2[C:21]#[N:22].[CH3:29]COCC>>[CH3:28][O:27][C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:25]=1[O:26][CH3:29])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17](=[O:19])[NH2:18])[C:11]([NH2:20])=[C:10]2[C:21]#[N:22]
Reactant: CCOCC
Reactant: COc1cc(Oc2ccc3c(c2)c(C#N)c(N)n3CC(N)=O)cc(OC)c1O
Product: COc1cc(Oc2ccc3c(c2)c(C#N)c(N)n3CC(N)=O)cc(OC)c1OC

Procedure:
Using the general method of selective demethylation described for Example 31 5-(3,5-dimethoxy-4-hydroxyphenoxy)-2-amino-1-carbamoylmethyl-1H-indole-3-carbonitrile (95 mg) was obtained as a beige solid from 5-(3,4,5-trimethoxyphenoxy)-2-amino-1-carbamoylmethyl-1H-indole-3-carbonitrile (150 mg; 0.37 mmol) after trituration with Et2O.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:11][C:12]2[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(Cl)c1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 3-(bromomethyl)-2,4-dichloropyridine (2.9 g, 12.3 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.2 g, 6.1 mmol), and triethylamine (1.3 mL, 9.3 mmol) in absolute ethanol (25 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness. The residue was dissolved in EtOAc (80 mL). The solution was extracted with water (3×50 mL) and 1 N NaOH (1×50 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/DCM), affording the title compound (475 mg, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.75 (s, 2H), 6.72 (s, 1H), 7.69 (d, 1H, J=5.3 Hz), 8.36 (d, 1H, J=5.3 Hz); M+ 357.
Reaction SMILES: C[O-].[Na+].C(OC(=O)C([O:10][CH2:11][CH3:12])=O)C.[N+:14]([C:17]1C=[CH:21][CH:20]=[CH:19][C:18]=1C)([O-:16])=[O:15].O>C(O)C>[N+:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=1[CH:11]=[O:10])([O-:16])=[O:15]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=Cc1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
383 g (7.1 mols) of sodium methylate are dissolved in ethanol and 985 g (6.75 mols) of oxalic acid diethyl ester and 925 g (6.75 mols) of 2-nitrotoluene are poured in. The mixture is heated under reflux for 30 minutes and is allowed to cool, 300 ml of ice water are next added cautiously and after the exothermic reaction has subsided 1,600 ml of water are added. After boiling additionally for 90 minutes under reflux, the mixture is steam-distilled until two phases no longer pass over. The organic phase is separated from the distillate and 310 g of 2-nitrotoluene are recovered from it. The residual aqueous phase of the distillate is filtered, 600 g of (anhydrous) sodium carbonate and 2,000 ml of toluene are added and the mixture is cooled to +3° C. 650 g of solid potassium permanganate are added over the course of 70 minutes and the reaction temperature is kept at between +2° and +6° C. The mixture is stirred for a further 45 minutes at +5° C and then warmed to 40° C, and 50% strength sulphuric acid is then added dropwise (gas being evolved). The exothermic reaction is kept at 35°- 40° C by cooling. Insoluble material is then filtered off and the toluene phase is separated from the filtrate. The filter residue is washed with hot toluene and the combined toluene phases are extracted by shaking with 15% strength sodium carbonate solution and with water and are then dried with the sodium sulphate. On concentrating the toluene phase in vacuo, 2-nitrobenzaldehyde is obtained as a viscous oil which crystallizes immediately on cooling. Melting point 40°- 41° C.
Reaction SMILES: CN(C)C=O.[I:6]N1C(=O)CCC1=O.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([F:26])[CH:21]=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]>O>[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([F:26])[C:21]([I:6])=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: COc1c(F)cc(C)c(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(N)c(C(=O)O)c(C)c(I)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
An N,N-dimethylformamide (14 ml) solution of N-iodosuccinimide (1.89 g, 8.4 mmol) was dropwise added to an N,N-dimethylformamide (14 ml) solution of 2-amino-4-fluoro-3-methoxy-6-methylbenzoic acid (I-29) (1.4 g), followed by stirring at room temperature for 2 hours and a half. Water was added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with aqueous saturated sodium thiosulfate solution and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (2:1) was concentrated under reduced pressure to obtain the entitled compound (1.77 g, 78%) as a brown solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([C@H:10]3[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[N:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([CH:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][OH:8])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C2(c3ncc(Br)s3)CO2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CC[C@H](C(CO)c2ncc(Br)s2)CC1

Procedure:
A solution in DCM (0.7 mL) of ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]cyclohexanecarboxylate (30 mg, 0.082 mmol) from Step 2 was treated with trifluoroacetic acid (0.266 mL, 1.665 mmol) and triethylsilane (0.128 mL, 1.665 mmol) and left at 45° C. 16 h. The volatiles were removed under reduced pressure and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2-hydroxyethyl]cyclohexanecarboxylate which was used as such without further characterization. MS ESI calc'd. for C14H20BrNO3S [M+H]+ 362, 364, found 362, 364.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:32]([O:35][CH2:36][CH2:37]Br)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([O:35][CH2:36][CH2:37][N:18]1[C:19]2=[N:20][C:21]([CH3:25])=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:34])[CH3:33]
Reactant: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2ccc(C)nc21
Temperature: 60 °C
Reaction time: 16.5 h
Yield: 69.1 %

Procedure:
To a solution of 6.8 g of the compound of Example 2 in 50 ml of dimethylformamide are added 4.1 g of potassium carbonate and 5 g of 2-bromoethyl acetate, and the mixture is stirred at 60° C. for 16.5 hours. The reaction mixture is poured into ice-cold water, and the precipitate is extracted with ethyl acetate. The extract is washed with water, dried and concentrated, and then the residue is recrystallized from hexane to give 5.9 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-methyl-1H-pyrazolo[-3,4-b]pyridine as pale yellowish green crystals, melting at 101.5°-103° C.
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=[O:3].[CH3:9][O:10][C:11](=[O:29])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[N:14][C:13]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:18][C:16]1[CH:15]=[N:14][C:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:9](=[O:3])[O:10][C:11](=[O:29])[C:12]=2[CH:17]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(Cl)cnc1NCc1ccc(OC)cc1
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)cnc32)cc1
Yield: 90.9 %

Procedure:
Trichloromethyl chloroformate (5.40 mL, 44.82 mmol) was added slowly to a solution of 5-chloro-2-(4-methoxy-benzylamino)-nicotinic acid methyl ester (72) (12.5 g, 40.75 mmol) in dioxane and refluxed for 4 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was recrystallized by ether to yield 11.80 g (91%) of 6-chloro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (73) as white solids. MP: 173° C.; 1H-NMR (DMSO-d6): 3.71 (s, 3H), 5.25 (s, 2H), 6.85 (m, 2H), 7.33 (m, 2H), 8.49 (d, J=2.8 Hz, 1H), 8.82 (d, J=2.8 Hz, 1H); EIMS: 319 (M+1).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nnc(C(F)(F)F)s3)(CC1)CC2
Yield: 16.4 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (57.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (12.0 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[N:6][C:7]([S:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([C:20]3([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:14]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=O.Cl.[NH2:29][OH:30]>>[CH3:1][C:2](=[N:29][OH:30])[C:4]1[CH:5]=[N:6][C:7]([S:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([C:20]3([O:26][CH3:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:14]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(S(=O)(=O)c3ccc(C(C)=O)cn3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(S(=O)(=O)c3ccc(C(C)=NO)cn3)c2)CCOCC1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 50, 6-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]pyrid-3-yl methyl ketone was reacted with hydroxylamine hydrochloride to give 6-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]pyrid-3-yl methyl ketone oxime in 96% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[CH:10]=NO.[OH2:14]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:13])[C:10]2=[O:14]
Reactant: O=C(C=NO)Nc1ccccc1F
Reactant: O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(F)cccc2C1=O
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
A solution of N-(2-fluorophenyl)-2-(hydroxyimino)acetamide (35.0 g, 192 mmol) in sulfuric acid (150 mL) was heated and stirred at 70° C. for 45 minutes. The solution was allowed to cool to room temperature and poured into iced water, and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crystals were collected by filtration to give the title compound (14.6 g, 46% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[N:8]([CH2:18][CH3:19])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)[CH3:19]
Reactant: CCOC(=O)c1cn(CC)c2ccc(I)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(I)ccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 106.4 %

Procedure:
1,4-Dihydro-1-ethyl-6-iodo-4-oxo-quinoline-3-carboxylic acid ethyl ester (7.5 g, 0.02 mol) was suspended in THF (75 mL), NaOH (2 equiv.) solution in water (75 mL) was added and the mixture was stirred at 80° C. for 24 hours. After THF was evaporated, the solution was acidified to pH 5 using HCl. The obtained precipitate was filtrated off and dried under reduced pressure yielding the title compound (7.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:16](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)c2ccccn2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
According to Scheme 1 Method B: 3-Methoxyaniline (1.62 mmol, 0.18 mL) was added to a solution of picolinic acid (1.62 mmol, 0.20 g), EDCI.HCl (2.44 mmol, 0.47 g), Et3N (3.25 mmol, 0.45 mL), hydroxybenzotriazole (1.95 mmol, 0.30 g) in DCM (6 mL) at room temperature. The reaction mixture was stirred at 50° C. for 12 hours. The organic phase was washed with a saturated solution of NaHCO3 and with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to afford N-(3-methoxyphenyl)picolinamide (1.46 mmol, 0.33 g, 90%) as an orange liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH:30]=[CH2:31])[CH:26]=[CH2:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:29][CH:30]=[CH2:31])[CH:26]=[CH2:27]
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1csc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Yield: 65.3 %

Procedure:
A suspension of 1.0 g (0.00275 mol) of 3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 50 ml of tetrahydrofuran was treated wth 4.1 ml (0.033 mol) of diallylamine. After stirring at reflux for 18 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.76 g (66%) of 3-(4-diallylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 125-127°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)CCC>O1CCCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: C1CCOC1
Product: O=C(c1ccco1)c1cc([N+](=O)[O-])ccc1Cl
Yield: 78.7 %

Procedure:
To a mixture of 2-chloro-5-nitrobenzoyl chloride(5.50 g, 0.0250 mol) and tetrahydrofuran is added 2-tributylstannylfuran (10.1 g, 0.0275 mol) followed by dichloro-bis-triphenylphosphine palladium (0.540 g, 0.00075 mol). The resultant mixture is stirred overnight at room temperature and concentrated in vacuo. The resultant oil is chromatographed on silica gel with methylene chloride-hexanes to afford the title compound as a bright yellow solid (4.95 g, 78.7%, mp 93-96° C.) which is identified by IR and NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-t-butyldimethylsilyloxypyrrolidine (42.23 g) in dry dichloromethane (422 ml), boron trifluoride etherate (103.54 g) was added at room temperature, and the resultant mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate solution and water and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28](OC)=[O:29])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:37][NH:38][CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([N:38]([CH3:39])[CH3:37])=[O:29])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Product: C[C@@H](c1ccc(-c2cncc(C(=O)N(C)C)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate following a procedure analogous to that described in Example 71 Step 3 using dimethylamine in place of ammonia. LC-MS Method 2 tR=1.086 min, m/z=506.3; 1H NMR (CDCl3) 0.87 (m, 1H), 1.21-1.37 (m, 4H), 1.64 (m, 1H), 1.98 (m, 2H), 2.22 (m, 1H), 2.35 (m, 1H), 2.54 (m, 1H), 2.65 (m, 1H), 3.05 (m, 3H), 3.15 (m, 4H), 3.45 (m, 2H), 5.63 (m, 1H), 7.03-7.18 (m, 4H), 7.34 (m, 2H), 7.49 (m, 2H), 8.06 (m, 1H), 8.58 (m, 1H), 8.81 (m, 1H).
Reaction SMILES: C1C=CC(C[O:8][C:9]([C@@H:11]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:10])=CC=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42](Cl)(=[O:44])=[O:43])=[C:37]([CH3:46])[C:36]=1[CH3:47].[OH-].[Na+]>ClCCl>[NH:22]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([S:42]([C:38]2[C:37]([CH3:46])=[C:36]([CH3:47])[C:35]([O:34][CH3:33])=[CH:40][C:39]=2[CH3:41])(=[O:44])=[O:43])[CH:14]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)n2cc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c3ccccc32)c(C)c1C

Procedure:
In the same manner as Example 5, Z-Trp-OBZl (15.0 g, 35 mM) and 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride were reacted in dichloromethane (500 ml) in the presence of sodium hydroxide (17.8 g, 0.44 M). The reaction product was then hydrolyzed with an aqueous solution of sodium hydroxide to give Z-Trp(Mtr)-OH. Yield 19.0 g (98.4%); m.p. 71°-74° C.; [α]D24 -41.6° (c=0.9, DMF).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=3)[CH2:30][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)nn1C(C)(C)C

Procedure:
103 mg (97%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(3,4-dichlorophenyl)piperazine (52 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH:16](O)[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][O:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.CCOCC>[C:19]([O:23][C:24]([N:26]([CH:16]([CH3:17])[CH:15]=[CH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[O:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(O)/C=C/c1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C=Cc1cccc(Oc2ccccc2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
(-)-(E)-1-3(-Phenoxyphenyl)but-1-en-3-ol from step (d) (2.6 g), N,O-bis(t-butoxycarbonyl)hydroxylamine (2.65 g), and triphenylphosphine (4.25 g) were taken up in toluene (30 ml) and cooled to -78° C. under N2. A solution of DEAD (2.9 g) in toluene (10 ml) was then added and the mixture allowed to warm to room tempterature. 40/60 pet.ether (60 ml) was added to precipitate Ph3P=O as a dark gummy mass. The mother liquor was decanted off and stripped to give a tan/orange oil which was eluted through a silica gel column using methylene chloride. The eluate was stripped to give a pale yellow oil which was eluted through a second silica gel column using ether/methylene chloride/40-60 pet.ether (1:1:8) and the eluate stripped to give the desired product as a colourless oil which was dried under high vacuum. Yield 1 97 g.