Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[N:19][CH:18]=4)[C:10]=3[CH:9]=2)=[CH:6][C:5]([CH3:37])=[CH:4][N:3]=1.Cl.C[OH:40]>O1CCOCC1>[N:23]1([C:21]2[N:22]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:7]5[C:2]([OH:40])=[N:3][CH:4]=[C:5]([CH3:37])[CH:6]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[CH:18]=[N:19][CH:20]=2)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: Cc1cnc(F)c(-c2cc3c(cn2)cnn3-c2cncc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc(O)c(-c2cc3c(cn2)cnn3-c2cncc(N3CCCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-[6-[6-(2-fluoro-5-methyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2113 mmol; 106.6 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 164 as a by-product (18.7 mg, 22%). 1H NMR (400 MHz, DMSO) δ 9.89-9.85 (s, 1H), 9.25-9.20 (s, 1H), 8.64-8.60 (s, 1H), 8.56-8.52 (d, J=2.6 Hz, 1H), 8.41-8.38 (s, 1H), 8.08-8.05 (s, 1H), 7.33-7.30 (s, 1H), 3.95-3.84 (m, 4H), 2.99-2.93 (m, 2H), 2.71-2.66 (m, 2H), 2.15-2.13 (s, 3H), 1.88-1.81 (m, 2H); MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:19]2[C:20]3[O:40][CH2:39][O:38][CH:22]([CH:23]([N:30]=[CH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:21]=3[CH:41]=[CH:42][C:43]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[C:51]([O:53][CH3:54])=[O:52].[NH4+].[Cl-]>O1CCCC1.O>[C:51]([C:23]([CH:22]1[O:38][CH2:39][O:40][C:20]2[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:42]=[CH:41][C:21]1=2)([N:30]=[CH:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])([O:53][CH3:54])=[O:52]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)C#CC(N=Cc1ccccc1)C1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C#C[Si](C)(C)C)(N=Cc1ccccc1)C1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To diisopropylamine (700 mg.) in 15 ml. tetrahydrofuran at -78° under N2 was added 3.8 ml. of 1.64 M n-butyllithium dropwise. After 5 minutes, 3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne (3.378 g.; 6.74 mmol) in 15 ml. tetrahydrofuran was added dropwise (10 minutes). After an additional 5 minutes, methyl chloroformate (680 mg.) in tetrahydrofuran (10 ml.) was added dropwise (5 minutes). After 40 minutes at -78° the solution was warmed to 0° and the color lightened from deep red to orange. After 10 minutes at 0°, water (5 ml.) was added dropwise followed by 10% aqueous NH4Cl (30 ml.). The layers were separated and the mixture extracted as in the previous example, dried over Na2SO4 and concentrated to dryness to give 3-carbomethoxy-3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne (3.645 g.) as an orange foam; Mass spectrum M/e 559, large fragmentation peaks at 287 (base peak) and 272. ##STR13##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](SC)[C:5]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH2:19]([O:26][N:27]=[C:6]1[C:5]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NOCc1ccccc1
Reactant: CSC1=Nc2ccc(Br)cc2C12CCCCC2
Agent: Cl
Solvent: CO
Product: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Temperature: 45 °C

Procedure:
5′-Bromo-2′-(methylthio)spiro[cyclohexane-1,3′-[3H]indole] (9.0 g, 28.98 mmol) and O-benzylhydroxylamine hydrochloride (13.8 g, 86.9 mmol) were combined in methanol (150 mL) and heated to 45° C. for 6 hours. Methanol was evaporated in vacuo. Ethyl acetate was added to the residue and this mixture was washed with ammonium chloride solution. Ethyl acetate was dried over magnesium sulfate, ethyl acetate collected evaporated in vacuo and the residue was flash chromatographed on alumina 90 (9:1 Hexane/EtOAc) to the desired product (6.5 g, 60%). 1H NMR (DMSO-d6, 300 MHz) δ 1.38-1.70 (m, 8H), 1.92-2.06 (m, 2H), 5.06 (s, 2H), 6.71 (d, 1H, J=8.26 Hz), 7.22-7.43 (m, 7H), 9.62 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:18])(OCOC)[C:11]([CH2:19][CH3:20])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[Cl-].[Cl-].C([Al+2])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.ClCCl>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:18])=[C:11]([CH2:19][CH3:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)OCOC
Agent: CC[Al+2]
Agent: CC[SiH](CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCC1=C(C)CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution mixture of 2.35 g of (1RS,4RS)-3-ethyl-4-methyl-4-methoxymethoxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether and 25 ml of dichloromethane was added under nitrogen stream and at -78° C. 1.4 ml of triethylsilane by drops, and the resulting mixture was stirred for 15 minutes. Thereafter, under the same conditions, 8.17 ml of 0.93 M hexane solution of ethylaluminum dichloride was added by drops and the resulting mixture was brought up to -10° C. over 1 hour. Thereafter, the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted with diethyl ether. The ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 1 g of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 53%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[OH-].[K+].I[CH2:15][CH2:16][CH2:17][CH3:18]>C(O)CCC>[CH2:15]([N:6]1[C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=[C:4]([O:10][CH3:11])[C:5]1=[O:9])[CH2:16][CH2:17][CH3:18]
Reactant: COc1cc(C)c(C)[nH]c1=O
Reactant: CCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCn1c(C)c(C)cc(OC)c1=O
Temperature: 85 °C
Reaction time: 24 h
Yield: 29.6 %

Procedure:
n-Butanol (13 mL) was added to a mixture of 5,6-dimethyl-3-methoxy-2-pyridone (1-004-06) (306 mg) and potassium hydroxide (157 mg). 1-Iodobutane (0.44 mL) was added to the suspension, and the reaction mixture was heated with stirring in an oil bath at 85° C. under nitrogen atmosphere. After 24 h, the reaction mixture was evaporated under reduced pressure, and the residue was dissolved in acetyl acetate and water. The reaction mixture was extracted twice with ethyl acetate, and once with water, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue (300 mg) was purified by silica gel column chromatography (Lobar column B, toluene/acetone (3/1)) to give 1-butyl-5,6-dimethyl-3-methoxy-2-pyridone (1-004-07) (124 mg, 29.6%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br.O>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:8][C:6]2=[S:7])[CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(N(CC2CC2)C(N)=S)cc1
Agent: Br
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=S)N2CC1CC1
Yield: 71.8 %

Procedure:
To a suspension of 2.36 g (0.01 mole) of N-cyclopropylmethyl-N-(p-methoxyphenyl) thiourea in 30 ml of toluene were added 1.21 g (0.011 mole) of benzaldehyde and 0.84 g (0.005 mole) of 48% hydrobromic acid. The resulting mixture was heated under reflux for 6 hours using a water separator. After cooling, the reaction mixture was washed with dilute hydrochloric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from isopropyl alcohol to give 2.33 g (72%) of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinethione, m.p. 146°-147° C.
Reaction SMILES: C([O:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=O)C.[C:14](Cl)(=O)C.C(=O)(O)[O-].[Na+].C([Si](C)(C)OCCCCC#CCO)(C)(C)C>CO>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]#[C:6][CH2:5][OH:4]
Reactant: CC(=O)OCC#CCCCC(=O)O
Reactant: CC(=O)Cl
Agent: CC(C)(C)[Si](C)(C)OCCCCC#CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC#CCO
Reaction time: 16 h
Yield: 92 %

Procedure:
The crude acid 29 (6.333 g) was treated with a 1% solution of acetyl chloride in methanol (60 mL). After 16 h, sodium bicarbonate (1.966 g, 23.4 mmol) was added. The mixture was dried (MgSO4), filtered through celite and evaporated in vacuo. Purification by flash chromatography on silica gel (30-40% ethyl acetate/hexanes) gave 7-Hydroxy-hept-5-ynoic acid methyl ester 30 (3.022 g, 19.3 mmol, 92% from 7-tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(C=O)c1
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8acetyl -3-methylflavone (2.5 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 90-92° C., 1H-NMR (CDCl3)δ:2.20 (s, 3H); 3.84 (s, 3H); 4.74 (d, 2H, J=5.1 Hz); 5.1-5.3 (m, 2H); 5.91-6.02 (m, 1H); 6.96-7.18 (m, 4H); 7.31 (d, 1H, J=16 Hz); 7.32-7.35 (m, 1H); 7.36-7.43 (m, 3H); 7.55-7.59 (m, 2H); 8.34 (d, 1H, J=8.9Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][O:21][C@@H:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc([C@H]2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
1.417 g of 4-Bromobenzyl bromide and 0.617 g of (S)-2-Phenyl-morpholine in 11 mL of acetonitrile were stirred at room temperature and 1.567 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification by flash chromatography afforded 0.851 g of product. 68% yield ES MS m/z 331.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][N:11]([CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(C1C=CC(C2([Cl:56])CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1)(C)(C)C>>[Cl:56][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=2)[CH2:12][N:11]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1
Reactant: CC(C)(C)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Product: FC(F)(F)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
This compound was prepared from compound (30) using the procedure described for compound (10).
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:30])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]4[CH:22]([CH2:28][CH3:29])[CH2:23][C:24](=[O:27])[NH:25][N:26]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1.Cl>O1CCOCC1>[CH2:28]([CH:22]1[CH2:23][C:24](=[O:27])[NH:25][N:26]=[C:21]1[C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH:4]([CH3:30])[CH:3]=[O:2])=[CH:7][CH:8]=3)[O:13][C:14]=2[CH:20]=1)[CH3:29]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC(C)C(OC)OC)cc3)oc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC(C)C=O)cc3)oc2c1

Procedure:
54 mg (74 μmol) 6-{2-[4-(2,2-dimethoxy-1-methyl-ethoxy)-phenyl]-benzoxazol-6-yl}-5-ethyl-4,5-dihydro-2H-pyridazin-3-one, 200 μL (4 mmol/mL; 800 μmol) HCl and 5 ml dioxane are stirred for 40 min at 80° C. Then the mixture is extracted with EA, extracted twice with H2O and then with sat. saline solution. The solv. of the org. phase is eliminated i.V.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: CCOc1cc(C(N)CC(=O)OC)ccc1OC

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-ethoxy-4-methoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.77-6.86 (m, 3H), 4.30 (s, 1H), 3.85 (t, 2H, J=5 Hz), 3.79 (s, 3H), 3.62 (s, 3H), 2.59 (s, 2H), 1.85 (d, 2H, J=5 Hz), 1.40 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15])(=[O:4])[CH2:2][CH3:3].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:1](=[O:4])[CH2:2][CH3:3]
Reactant: ClCCCCBr
Reactant: CCC(=O)Nc1ccccc1NC(=O)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(=O)N(CCCCCl)c1ccccc1N(CCCCCl)C(=O)CC
Reaction time: 16 h
Yield: 12.6 %

Procedure:
To a suspension of 3.27 g (15 mmol) of 1,2-di-propionylaminobenzene, 4.32 ml (37.5 mmol) of 4-bromo-1-chlorobutane, and 0.96 g (3.0 mmol) of tetrabutylammonium bromide in 25 ml of toluene, 5.6 ml of 50% aqueous sodium hydroxide was added at room temperature, and the mixture was stirred for 16 hours. The organic layer was separated, washed with saturated aqueous sodium chloride, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: hexane/ethyl acetate =2 :1 to 1:1 to 1:2 to 1:4) to give 0.76 g of the desired product (12.6% yield, white crystals).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])=[CH:7][CH:6]=1)([OH:4])=[O:3].[OH2:17]>O1CCOCC1.[Fe]>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([C:2]([OH:4])=[O:3])=[CH:6][CH:7]=1)[C:12]([CH3:13])=[O:17]
Reactant: CC(=Cc1ccc(C(=O)O)cc1)[N+](=O)[O-]
Reactant: O
Agent: [Fe]
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(C(=O)O)cc1

Procedure:
Concentrated hydrochloric acid (367 ml) was added dropwise to a mixture of 1-(4-carboxyphenyl)-2-nitroprop-1-ene (61.17 g) and iron powder (61.17 g) in dioxan (500 ml) at reflux. The heating was continued for 1 hour at the end of addition. The solution was cooled, water added, the dioxan evaporated and the residue extracted with chloroform and dried (MgSO4). Removal of the solvent gave a solid which was recrystallised from ethyl acetate to give 26 g of the title compound. τ (d6DMSO) 7.83 (3H, s), 6.14 (2H, s), 2.69 (2H, d, J=9 Hz), 2.05 (2H, d, J=9 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:13][CH:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrBr
Reactant: CCOC(=O)C(=O)CCCCCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)C(Br)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 6-chloro-2-oxohexanoate (2.9 g, 15 mmol) in carbon tetrachloride (30 mL) was added bromine (0.85 mL, 16.5 mmol) and stirred at rt for 1 hour. The reaction mixture was diluted with EtOAc, washed with Na2S2O3 solution, water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes to provide the desired product ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) in 95% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.25 (1H, dd), 4.29 (2H, q), 3.71 (2H, t), 2.16 (1H, m), 1.91 (1H, m), 1.29 (3H, t).
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[O:6]=[C:7]1[O:13][C@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[C:10]([OH:11])=[C:8]1[OH:9]>O>[O:6]=[C:7]1[O:13][C@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[C:10]([O-:11])=[C:8]1[OH:9].[Sr+2:5].[O:6]=[C:7]1[O:13][C@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[C:10]([O-:11])=[C:8]1[OH:9]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O

Procedure:
Bramley apples were preserved as in Example 12a, except that the preservative solution contained 14.68 grams of strontium carbonate, 35 grams ascorbic acid, 765 g water, having pH of 5.3, to provide a 5.44% % (w/w) strontium ascorbate solution.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:25]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.10 g (0.60 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one in 1.5 mL DMF were combined with 0.10 g (0.70 mmol) potassium carbonate and stirred for 15 min at RT. Then 0.10 g (0.60 mmol) 4,6-dichloropyrimidine were added to the reaction mixture and stirred overnight at RT. Then water was added and the precipitate formed was suction filtered, washed and dried i. vac.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13](=[O:28])[C:12]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:29][CH2:30][CH3:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23](=[O:24])[NH:1][C:2]([CH2:5][OH:6])([CH2:3][OH:4])[CH3:7])=[CH:26][CH:27]=1)[C:13](=[O:28])[C:12]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:29][CH2:30][CH3:31]
Reactant: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc21
Reactant: CC(N)(CO)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)NC(C)(CO)CO)cc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
A solution of 0.172 g of 2-amino-2-methylpropane-1,3-diol in 2 ml of DMF is added at RT to a mixture of 0.374 g of the compound obtained in step B of EXAMPLE 241, 0.25 g of triethylamine, 0.364 g of BOP and 5 ml of DCM and the reaction mixture is stirred for 3 hours at RT. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed twice with a 5% solution of potassium carbonate, with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using an AcOEt/DCM mixture (80/20; v/v) as the eluent to give 0.18 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=138°-141° C.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (4.0 g, 0.021 mol) in dichloromethane (25 ml) was added dropwise to a stirred solution of chlorosulphonic acid in dichloromethane (25 ml) at −70° C. under argon. After warming to room temperature, the reaction was stirred for 18 h before being quenched in ice/water (200 ml). The resulting mixture was extracted with ethyl acetate (3×100 ml), dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (2.74 g, 45%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15](COCC[Si](C)(C)C)[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:6]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[F:34][C:2]([F:1])([F:33])[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:6]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](NCC(F)(F)F)C3)ccnc21
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)[nH]c1nccc(N3CC[C@H](NCC(F)(F)F)C3)c12
Temperature: 60 °C
Yield: 4.3 %

Procedure:
(S)-4-(3-(2,2,2-trifluoroethylamino)pyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (156 mg, 0.32 mmol) was dissolved in 1,4-dioxane (0.4 mL) and then treated with 48% HBr(aq) (0.4 mL) and heated at 60° C. for 20 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a yellow solid (5.0 mg, 5%). 1H NMR (400 MHz, d6-DMSO) δ 8.81 (s, 1H), 8.47 (s, 1H), 8.15 (d, J=5.8, 1H), 6.43 (d, J=5.8, 1H), 3.95 (m, 1H), 3.81 (m, 1H), 3.68 (m, 1H), 3.60-3.50 (m, 2H), 2.81 (m, 1H), 2.14 (m, 1H), 2.02-1.88 (m, 1H). LCMS (Method D): RT=7.71 min, M+H+=361.0.