Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[I:22]I.[F:24][C:25]([F:51])([F:50])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]1[CH:42]=[CH:43][N:44]=[C:37]1[C:36]([NH:45][CH2:46][CH2:47][CH2:48][OH:49])=[N:35]2>C(#N)C>[I:22][C:42]1[N:38]2[C:39]3[C:34]([N:35]=[C:36]([NH:45][CH2:46][CH2:47][CH2:48][OH:49])[C:37]2=[N:44][CH:43]=1)=[CH:33][C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:50])[F:51])=[CH:41][CH:40]=3
Reactant: II
Reactant: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2ccnc12
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2c(I)cnc12
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To a mixture protected from light of Selectfluor (103 mg; 0.29 mmol; 1.4 eq) and iodine (63 mg; 0.248 mmol; 1.2 eq) in acetonitrile (1.8 ml) stirred for 10 min under argon is added 3-({7-[2-(trifluoromethyl)phenyl]imidazo[1,2-a]quinoxalin-4-yl}amino) propan-1-ol (80 mg; 0.207 mmol; 1 eq) prepared as in example 5. The reaction mixture is stirred at rt overnight. Filtration of solid side-products, concentration, dissolution in ethyl acetate, washing with brine, aqueous sodium carbonate and water, drying (magnesium sulphate) and purification by prep CCM on silicagel (dichloromethane/methanol 95:5) affords the title product as an orange oil (88 mg; 0.17 mmol; 82%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])=[C:8]([CH3:23])[C:6]=2[N:7]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:37]=2)[CH:32]=[CH:31]1>>[OH:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:13]1[CH:20]=[CH:21][CH:22]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:35]4[CH:34]=[C:33]5[CH:32]=[CH:31][NH:30][C:38]5=[N:37][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH:12]=1
Reactant: Cc1c(-c2cccc(C(=O)NCCO)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1c(-c2cccc(C(=O)NCCO)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with ethanolamine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide (74 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 2.6 mg of 426. MS (Q1) 515.2 (M)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:18][OH:19])[CH2:9][O:10][CH:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].C1(C=CC(O)=CC=1)O.Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:9][O:10][CH:11]([C:12]([F:15])([F:14])[F:13])[CH:16]1[CH2:17][O:19][NH:18]2
Reactant: C=CC(OCC(=NO)c1ccccc1F)C(F)(F)F
Agent: Cl
Agent: Oc1ccc(O)cc1
Product: Fc1ccccc1C12COC(C(F)(F)F)C1CON2
Temperature: 128 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(1,1,1-trifluorobut-3-en-2-yloxy)ethanone oxime 4 (1.085 kg, 3.328 mol) in xylenes (6.9 L) was added hydroquinone (86.2 g, 0.8 mol) at rt. The solution was heated to 128° C. (internal temperature) for 18 h. The solution was cooled to rt, and hexanes (7.0 L) was added, followed by 4.0 M aq. HCl (2.4 L). The reaction mixture was stirred for 1 h, and filtered. To the solid was added water (2.0 L), methyl tert-butyl ether (7.0 L) and 25% wt. aq. NaOH (0.4 L). The aq. layer was extracted once with methyl tert-butyl ether (7.0 L), the organics were combined, washed with 27% aq. NaCl (2.0 L) and concentrated under vacuum to a black oil 5 (512.0 g, 56%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][C:17](O)=[O:18])[CH:11]=[C:12]([Cl:14])[CH:13]=1>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][OH:18])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: O=C(O)CCc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
LiAlH4 (1M in Et2O, 10 mL, 10 mmol) was slowly added to a solution of 3-(3,5-dichlorophenyl)-propionic acid (2.19 g, 10 mmol) in Et2O (50 mL). The reaction was heated at reflux for 2 h. The reaction was cooled to room temperature and 2 N NaOH (1 mL) and aqueous NH4Cl (satd., 3 mL) as room temperature and 2 N NaOH (1 mL) and aqueous NH4Cl (satd., 3 mL) as over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (25% EtOAc/hexanes) to afford 3-(3,5-dichlorophenyl)-propanol (640 mg). 1H NMR (400 MHz, CDCl3) δ 7.17 (m, 1H), 7.07 (m, 2H), 3.64 (m, 2H), 2.65 (t, 2H), 1.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[NH:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)[O:7][C:6]2=1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[NH:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:35]([C:32]4[CH:33]=[CH:34][C:28]5[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=5[CH:31]=4)=[O:36])[CH2:19][CH2:18]3)[O:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CN3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 7 and in analogy to Example 1 using trans-4-(6-methoxy-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:16]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O-])=[O:41])[N:35]=[CH:34]2)(=O)C.[NH4+].[OH-:44]>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:16]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:44][C:7]([CH3:12])([CH3:8])[CH3:6])=[O:41])[N:35]=[CH:34]2
Reactant: CC(=O)Oc1ccc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2c1
Reactant: [OH-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)c5cccnc5)c4)nc4ccc(O)cc34)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
A mixture of 5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.374 g, 0.607 mmol) and 28% NH4OH (0.45 mL) in MeOH (50 mL) was stirred at RT for 24 h. The volatiles were removed in vacuo and the residue was washed with Et2O to give the product tert-butyl 5-(6-hydroxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.318 g, 0.554 mmol, 91%).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH3:13])=[C:6]([S:14][CH3:15])[S:5][C:4]=1[C:16]#[N:17])[CH3:2].S(=O)(=O)(O)[OH:19]>>[CH2:1]([C:3]1[C:7]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH3:13])=[C:6]([S:14][CH3:15])[S:5][C:4]=1[C:16]([NH2:17])=[O:19])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCc1c(C#N)sc(SC)c1-c1oncc1C
Product: CCc1c(C(N)=O)sc(SC)c1-c1oncc1C
Temperature: 60 °C
Yield: 42 %

Procedure:
To 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio)thiophene-2-carbonitrile (0.87 g, 3.3 mmol) was added conc. sulfuric acid (11 ml) and the mixture was heated at 60° C. for 1.5 hours. The reaction solution was allowed to cool down to room temperature, ice was added and then the mixture was extracted with ethyl acetate. The organic layer was washed (with water, saturated aqueous sodium hydrogen-carbonate and saturated aqueous sodium chloride, in turn), dried (over anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: chloroform/ ethyl acetate=1:0-3:1) and recrystallized from diethyl ether to afford 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio)thiophene-2-carboxamide (0.39 g, 42%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1Oc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(F)cnc1Oc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a stirred solution of methyl 5-fluoro-2-(4-fluorophenoxy)nicotinate (step 1, 2.63 g, 9.9 mmol) in methanol (50 mL) was added 2 N sodium hydroxide aqueous solution (10 mL). The reaction mixture was stirred at 40° C. for 3 h. After cooling, the pH value was adjusted to 4.0 by the addition of 2 N hydrochloric acid. The mixture was diluted with water (100 mL), and extracted with dichloromethane (100 mL×3). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated to afford 2.26 g (91%) of the title compound as off white solids: 1H-NMR (CDCl3) δ 8.25 (1H, dd, J=7.5, 3.1 Hz), 8.16 (1H, d, J=3.1 Hz), 7.16–7.13 (4H, m); MS (ESI) m/z 252 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:19].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:15]2[CH2:16][CH2:17][CH2:18][C@@:11]3([C:10](=[O:19])[N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])[CH2:13][CH2:12]3)[CH2:14]2)=[N:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC[C@]3(CCN(c4ccccc4Cl)C3=O)C2)nc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (40.0 mg, 0.000133 mol, prepared by using a procedure analogous to that used for the synthesis of example 92, steps 1-3), 2-chloro-5-nitropyridine (23 mg, 0.00015 mol), and potassium carbonate (55 mg, 0.00040 mol) in N,N-dimethylformamide (1.0 mL, 0.013 mol) was stirred at 120° C. for 1.5 hours. After cooling the reaction mixture to ambient temperature the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 387.1 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added platinum [5 wt. % (dry basis) on activated carbon, wet, Degussa type F101, RAW (Aldrich #330159), 15 mg] under an atmosphere of H2 (g) at rt for 2 h. The catalyst was filtered off from the mixture and the filtrate was concentrated in-vacuo to afford the product in quantitative yield. LC-MS: 357.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12](NN)=O.[C:16](=O)(O)[O-:17].[Na+]>Cl>[CH2:12]1[C:3]2=[C:4]3[C:9](=[CH:10][CH:11]=[C:2]2[NH:1][C:16]1=[O:17])[N:8]=[CH:7][CH:6]=[CH:5]3
Reactant: NNC(=O)c1c(N)ccc2ncccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C1Cc2c(ccc3ncccc23)N1
Yield: 45 %

Procedure:
6-Aminoquinoline-5-carboxylic acid hydrazide was dissolved in 10 mL of 2 M hydrochloric acid and heated briefly on a hot plate. The reaction was neutralized by gradual addition of solid sodium bicarbonate and filtered. The collected product was dried under vacuum at 55° C. to give 416 mg (45%) of 1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one as a brown solid. Mass spectrum (negative ion chemical ionization): m/z=183 (60%). 1H NMR (DMSO-d6): δ3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)=[O:8])[CH2:2][CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Reaction time: 3 h

Procedure:
1.5 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 1.5 g of triethylamine were suspended in 10 ml of dichloromethane. Under ice-cooled and stirring condition, 1.4 g of p-toluenesulfonylchloride in 10 ml of dichloromethane solution was added dropwise to the suspension and the reaction was continued for additionally 3 hours at a room temperature, further continued for 1 hour under ice-cooled condition. The crystals formed in the reaction mixture were collected by filtration and recrystallized from chloroform-ether to obtain 1.4 g of 6-[4-(p-toluenesulfonyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 280°-282° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([OH:17])CO)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.I(O)(=O)(=O)=O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH:14]=[O:17]
Reactant: OCC(O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 8 h

Procedure:
To 115 g. of 1-(3-chloro-4-cyclohexylphenyl)-1,2-ethanediol in tetrahydrofuran (800 ml.) is added a solution of periodic acid (102 g.) in ether (750 ml.). The reaction mixture is stirred under nitrogen overnight. The reaction mixture is filtered and the filtrate is washed with water (3×200 ml) and placed over sodium sulfate. Removal of solvent gives a liquid residue which is then distilled to give 3-chloro-4-cyclohexylbenzaldehyde.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1)=[O:14])=[O:9]
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A mixture of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) and triethylamine (0.14 ml, 1 mmol) in dry acetone (10 ml) was stirred at room temperature for 30 minutes. A solution of 3-bromophtalide (213 mg, 1 mmol) in acetone (2 ml) was added under ice cooling, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered by suction, and the solvent was removed from the filtrate. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate, then with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (developing solvent: benzene:ether=49:1). The pale yellow second eluate was collected. After removing the solvent, the resulting oily product was crystallized with isopropyl ether to give the desired compound (159 mg, yield, 39%). m.p., 194°-195° C. (white crystals, recrystallized from benzene-n-hexane)
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(O)=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:2]
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)Cl)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of benzyl (2R)-2-(carboxymethyl)-4-methylvalerate (500 mg) in dry dichloromethane (10 ml) was added oxalyl chloride (0.2 ml) at 0° C. After the solution was stirred at the same temperature for 1 hour, the solvent was evaporated in vacuo to give benzyl (2R)-2-(chloro-carbonylmethyl)-4-methylvalerate (522 mg) as an oil.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[CH3:6][O:7][CH2:8][CH2:9][NH:10][CH3:11]>>[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH3:11])[CH:2]([CH3:1])[C:3]#[CH:4]
Reactant: CNCCOC
Reactant: C#CC(C)O
Product: C#CC(C)N(C)CCOC

Procedure:
In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and N-(Methoxyethyl)methylamine were converted to yield (2-Methoxy-ethyl)-methyl-(1-methyl-prop-2-ynyl)-amine as colorless oil, MS: 141 (M).
Reaction SMILES: C1(=O)[N:5]([O:6][CH:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])C(=O)C2=CC=CC=C12.[ClH:19]>>[ClH:19].[NH2:5][O:6][CH:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9]
Reactant: O=C1OCCC1ON1C(=O)c2ccccc2C1=O
Agent: Cl
Product: NOC1CCOC1=O

Procedure:
α-Phthalimidooxy-γ-butyrolactone (1.0 g, 4 mmol) was added to hydrochloric acid (1M, 10 mL) at reflux. After 5 min. at reflux for 5 min and the reaction was cooled down on an ice bath and filtered. The filtrate was evaporated to dryness. Toluene was added and residual water removed azeotropic distillation. 0.75 g of the desired material was obtained.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][Br:11])(=[O:8])[O:5]CC)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Br.C(O)C>[C:13]1([NH2:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCBr)OCC
Agent: Br
Solvent: CCO
Solvent: Nc1ccccc1
Product: O=P(O)(O)CCBr
Yield: 53.2 %

Procedure:
A solution of about 50 g of diethyl-2-bromoethyl-phosphonate in about 255 ml of about 48% hydrobromic acid was kept at reflux (about 95°-100° C.) overnight. The solvent was removed under reduced pressure and the residue evaporated twice with toluene, giving a syrup. This syrup was dissolved in about 65 ml of about 99% ethanol, about 20 g of aniline was added dropwise and the solid was collected, washed with cold about 99% ethanol (at about 0° C.) and dried in vacuo, giving about 30.6 g of the desired reagent, mp 157°-158° C.
Reaction SMILES: [CH:1](/B(O)O)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCOCC1.Br[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1](/[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (E)-styrylboronic acid (289 mg, 1.95 mmol) in mixed solution of dioxane and water (4:1, 15 mL) were added tert-butyl 4-bromobenzoate (500 mg, 1.95 mmol), tetrakis(triphenylphosphine)palladium (225 mg, 0.2 mmol) and sodium carbonate (622 mg, 5.9 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once start material has been consumed, the mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=25:1) to give (E)-tert-butyl 4-styrylbenzoate (0.1 g, 18%). The product was used for the next step directly without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:11])=[CH:4][C:5]#[C:6][C:7]([CH3:10])([OH:9])[CH3:8].[CH3:12][C:13]([C:20]#[CH:21])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18].[Cl-]>>[OH:9][C:7]([CH3:10])([CH3:8])[C:6]#[C:5][CH:4]=[C:3]([CH3:11])[CH2:2][C:21]#[C:20][C:13]([CH3:12])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=CC#CC(C)(C)O)CCl
Reactant: C#CC(C)=CCCC(C)=O
Agent: [Cl-]
Product: CC(=O)CCC=C(C)C#CCC(C)=CC#CC(C)(C)O

Procedure:
A mixture of 446 mg (2.58 mmoles) of 6-chloromethyl-2-methyl-6-hepten-3-yn-2-ol and 7-chloro-2,6-dimethyl-5-hepten-3-yn-2-ol (produced in accordance with Example X), 264 mg (1.94 mmoles) of 6-methyl-5-octen-7-yn-2-one (produced in accordance with Example II), 539 mg (3.90 mmoles) of anhydrous potassium carbonate, 20 mg (0.20 mmoles) of cuprous chloride, and 46 mg (0.20 mmoles) of benzyltriethylammonium chloride in 2.00 mL of acetonitrile (HPLC-grade) was stirred vigorously at room temperature for 18 hours, during which time the mixture was maintained under a nitrogen atmosphere. Isolation of the product in the manner described in the procedure of Example III afforded 556 mg of material, proton NMR analysis of which indicated the presence of minor amounts of unreacted 7-chloro-2,6-dimethyl-5-hepten-3-yn-2-ol and 6-methyl-5-octen-7-yn-2-one, but not any of the nonconjugated allylic chloride (6-chloromethyl-2-methyl-6 -hepten-3-yn-2-ol) which presumably underwent the coupling reaction more readily. Removal of the C-9 components by evaporative fractional distillation in the presence of a small amount of powdered calcium carbonate, followed by distillation, afforded 211 mg (40% yield, not corrected for recovery of unreacted starting materials) of the two named C-18 ketones: boiling point 130°-145° C. (bath temperature, 0.25 mm).
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([CH2:17][C:18](O)=[O:19])=[C:11]([F:21])[CH:10]=2.COC(=O)CC1C(F)=C2C(=CC=1F)N=CC(Br)=C2.[NH2:40][NH2:41]>CO>[Br:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([CH2:17][C:18]([NH:40][NH2:41])=[O:19])=[C:11]([F:21])[CH:10]=2
Reactant: O=C(O)Cc1c(F)cc2ncc(Br)cc2c1F
Reactant: NN
Agent: COC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Solvent: CO
Solvent: O=S(Cl)Cl
Product: NNC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 402.6 %

Procedure:
SOCl2 (394 mg, 3.31 mmol) was added dropwise to a stirred solution of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid (500 mg, 1.65 mmol) in 12 ml of methanol at 0° C. under N2. After stirring for 2 hours at room temperature the solvent was evaporated and the crude (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester was used directly in the next step. To a mixture of (3-bromo-5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (2.29 g, 7.22 mmol) in methanol (100 mL) was added anhydrous hydrazine (2.31 g, 72.2 mmol). The mixture was heated at 55° C. for 4 hours. Additional anhydrous hydrazine (1.16 g, 36.1) was added and the mixture was heated at 55° C. for 2 hours. The reaction mixture was cooled to room temperature to give a white solid. The white solid was filtered and washed with cold methanol to obtain 2.1 g of the title compound (92% yield). MS: m/z 318 [M+H+]. 1H NMR (500 MHz. DMSO-d6): δ 1.99 (2H, s), 4.25 (2H, bs), 7.72 (1H, d), 8.74 (1H, s), 9.03 (1H, s), 9.35 (1H, s).