Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:44])([F:43])[F:42])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1.BrCC>CN(C=O)C>[CH2:1]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:42])([F:44])[F:43])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCN1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)C1
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
N,N-Diisopropylethylamine (18.0 μL, 0.103 mmol) was added to a solution of 2-(2-(2-(2-((4-(Piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (39) (17 mg, 0.034 mmol) in DMF (5 mL). The mixture was stirred for 5 min then bromoethane (4.0 μL, 0.051 mmol) was added and stirring was continued for 24 h at room temperature. A further portion of bromoethane (4.0 μL, 0.051 mmol) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. The volatiles were evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. Filtration then removal of the solvent under reduced pressure afforded a beige solid which was purified by mass-directed preparative HPLC to afford the title compound (40) (6.2 mg, 36%) as a white solid; 1H NMR (400 MHz, d4-MeOH) δ 8.54 (s, 1H), 8.38 (dd, J=4.8, 1.5 Hz, 1H), 7.69-7.66 (m, 3H), 7.28-7.19 (m, 3H), 3.68 (s, 2H), 3.59-3.46 (m, 2H), 3.38-3.22 (m, partially obscured by d4-MeOH), 3.19-3.08 (m, 2H), 3.04-2.80 (m, 3H), 2.12-1.99 (m, 2H), 1.99-1.70 (m, 2H), 1.34 (t, J=7.3 Hz, 3H). LCMS Method C: rt=4.20 min, m/z=513.2 [M+H]+, 511.2 [M−H]−.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[Si:31]([O:38][CH2:39][C:40]1([CH:46]=O)[CH2:44][O:43][C:42]([CH3:45])=[N:41]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:46][C:40]2([CH2:39][O:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:44][O:43][C:42]([CH3:45])=[N:41]2)=[CH:27][CH:28]=1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1=NC(C=O)(CO[Si](C)(C)C(C)(C)C)CO1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=NC(C=Cc2ccc(Br)cc2)(CO[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (4-bromobenzyl)triphenyl-phosphonium bromide (6 mmol) in dry THF (25 mL) is added NaH (6 mmol) in portions. After stirring at room temperature for 30 min, a solution of 4-(t-butyidimethylsilanyloxymethyl)-2-methyl-4,5-dihydrooxazole-4-carbaldehyde (prepared according to Scheme 3 using well-known chemistry in the art) (5 mmol) in THF (10 mL) is added in one portion. The mixture is stirred at room temperature for 12 h. After concentration, the residue is treated with EtOAc/hexane (1/5) (100 mL) and the solid is filtrated. The filtrate is washed with brine and dried over Na2SO4. After concentration, the crude product is purified by column chromatography by EtOAc/hexane (1/5) to give the desired product as a colorless oil. MS: (ES+): 410.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14](Cl)(Cl)=[S:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:14]=[S:15])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: S=C(Cl)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(N=C=S)cc(OC)c1OC

Procedure:
A mixture of 3,4,5-trimethoxyaniline (440 mg; 2.4 mmol) in toluene (20 ml), thiophosgene (300 mg; 2.5 mmol) and triethylamine (500 mg; 5 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trimethoxyphenylisothiocyanate. To the crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (40 ml) and refluxed for 16 h. The solvent was evaporated and the residue resuspended in ethyl acetate filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 200 mg of the title compound. M.p. 172°-173° C. MS (70 eV): m/z 479 (M+, 0.1%), 254 (55), 225 (100), 209 (80), 182 (32).
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])([CH3:3])[CH3:2].[H][H].[CH3:15][C:16]([CH3:18])=O>[Pt]>[CH:16]([NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([CH2:5][O:4][CH:1]([CH3:3])[CH3:2])[CH:7]=1)([CH3:18])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)OCc1cccc(N)c1
Reactant: CC(C)=O
Agent: [Pt]
Product: CC(C)Nc1cccc(COC(C)C)c1
Temperature: 90 °C

Procedure:
To the autoclave described in paragraph (b) was charged 4.95 grams (0.03 mole) of the 3-(isopropoxymethyl)aniline prepared in paragraph (b) of this Example and 0.5 gram of 5 percent platinum on carbon hydrogenation catalyst in 230 milliliters of anhydrous acetone. The autoclave was then sealed, the stirrer was turned on, and the temperature was brought up to and maintained at about 90° C. The autoclave was charged with hydrogen gas to a pressure of 100 psi (the valve to the hydrogen cylinder being left open). After 25 hours the autoclave was cooled, broken open, and the contents removed and filtered. The filtrate was concentrated on a rotary evaporator at 55° C., leaving a brown liquid. NMR analysis indicated the brown liquid to be impure. Consequently, the brown liquid was purified by distillation at a pressure of 1.5 millimeters of mercury. A first cut (1.56 grams) was collected at 90° C. to 117° C., which also proved to be quite impure. A second substantially purer cut (1.15 grams) was collected at 118° C. to 122° C., which later was identified by NMR spectroscopy as N-isopropyl 3-(isoproxymethyl)aniline.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]([N:23]3C=CN=C3)=[O:22])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:28].[CH3:29][CH:30]([CH3:36])[CH2:31][C:32]([NH:34]N)=[O:33]>C1COCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]([NH:23][NH:34][C:32](=[O:33])[CH2:31][CH:30]([CH3:36])[CH3:29])=[O:22])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:28]
Reactant: CC(C)CC(=O)NN
Reactant: Cc1cc2c(cn1)cc(-c1cc(NC(=O)n3ccnc3)ccc1C)c(=O)n2C
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=O)NNC(=O)CC(C)C)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 18 (0.08 mmol) was dissolved in THF (0.5 mL) and 3-methylbutanehydrazide (12 mg, 0.1 mmol) was added at rt. The reaction mixture was stirred at rt for 1 h to yield the crude N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-2-(3-methylbutanoyl)hydrazinecarboxamide 26, which was used without purification after removal of THF. MS m/z 422.2 (M+1).
Reaction SMILES: CN1CCOCC1.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].[NH:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18](ON1C(=O)CCC1=O)=[O:19]>CN(C=O)C>[NH:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
1.4 ml (11 mmol) of N-methylmorpholine are added to 1.15 g (10 mmol) of proline in 50 ml of DMF. The mixture is cooled with an ice bath, 3.06 g (10 mmol) of Boc-Gly-OSu are then added and the pH is adjusted to between 6 and 7 throughout the reaction (14 h) by successive additions of small amounts of N-methylmorpholine (this substance is used as a proton acceptor). The DMF is evaporated off and the evaporation residue is taken up with AcOEt; after precipitation in petroleum ether and then filtration, the expected product is collected.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:12]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(CCCO)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(CCCO)n2)sc2ccccc12
Yield: 15 %

Procedure:
6-(3-Hydroxypropyl)-2-pyridinecarbonitrile (2.2 g, 13.6 mmol) and methyl thiosalicylate (3.7 g, 22.0 mmol) were dissolved in toluene (15 ml), and triethylamine (3.0 ml, 21.7 mmol) was added thereto. The reaction mixture was refluxed for 30 hrs and subjected to a silica gel (170 g) column chromatography. The fractions eluted with ethyl acetate were collected and concentrated to give the titled compound (0.61 g, 15%) as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:26][C:27]([O:29]CC)=[O:28])[C:6]([CH3:25])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]=1[CH3:9].[Li+].[OH-]>C1COCC1.CO.O>[OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:26][C:27]([OH:29])=[O:28])[C:6]([CH3:25])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]=1[CH3:9]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)N3CCCC3)cc2)c(C)c1CCO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(S(=O)(=O)N3CCCC3)cc2)c(C)n(CC(=O)O)c1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Ethyl 2-(2-(2-hydroxyethyl)-3,5-dimethyl-4-(4-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (20 mg, 0.045 mmol) in THF (2.0 ml), MeOH (0.500 ml) and water (0.50 ml) was stirred and LiOH (4.27 mg, 0.178 mmol) was added. The resulting mixture was stirred at 25° C. for two hours. The solvent was then removed and water was added, followed by 1 N HCl. The solvent was again removed, MeOH was added, and the resulting solution purified by preparative HPLC to give 12 mg of a light blue solid (12 mg, 0.029 mmol, 64.0% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 (d, 2H), 7.19 (d, 2H), 4.57 (s, 2H), 3.76 (s, 2H), 3.66 (t, 2H), 3.18-3.15 (m, 4H), 2.76-2.73 (m, 4H), 2.03 (s, 3H), 1.78 (s, 3H), 1.70-1.66 (m, 4H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a mixture of 9-pentyl-3-phenyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (30 mg, 0.093 mmol) in THF (30 mL) was added N-bromosuccinimide (19.9 mg, 0.112 mmol). The mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified using preparative LCMS to yield the desired product (8.7 mg, 23.3% yield). LCMS calculated for C17H18BrN6O (M+H): 401.1. found 401.1, 403.1
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[NH:11][C:10](=O)[NH:9][C:6]2=[N:7][CH:8]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[NH:11][C:5]2[C:6]([N:9]=1)=[N:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2
Reactant: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cnc2nc(Cl)[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one from step (c) above (161 mg, 0.789 mmol) in POCl3 (5 mL) was heated at 95° C. for 16 h. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting oily residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to give the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 222 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:13])([P:9]([OH:12])(=[O:11])[OH:10])[P:5]([OH:8])(=[O:7])[OH:6].[OH-].[Na+:15]>O>[NH2:1][CH2:2][CH2:3][C:4]([OH:13])([P:5]([OH:8])(=[O:6])[OH:7])[P:9]([O-:12])(=[O:10])[O-:11].[Na+:15].[Na+:15]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCC(O)(P(=O)([O-])[O-])P(=O)(O)O

Procedure:
70.0 kg of 3-amino-1-hydroxypropane-1,1-diphosphonic acid are suspended while stirring in 140 liters of demineralised water. The suspension is heated to 65°-70° and 59.9 liters, (79.5 kg) of 30% aqueous sodium hydroxide solution are added at such a rate that the temperature of the reaction mixture rises to approximately 85° with the formation of a clear solution. The pH value of the solution should be between 7.2 and 7.5. It can be finely adjusted if necessary by the addition of small amounts of 30% sodium hydroxide solution or of 3-amino-1-hydroxypropane-1,1-diphosphonic acid. The solution is cleared by filtering through a filter that is coated with a small quantity of diatomaceous earth and has been preheated to 75°-80° into a vessel preheated to the same temperature. The solution is inoculated, and, while stirring, cooled in the course of 2 hours to 20°-25°, 70 liters of 96% ethanol are added in the course of a further 2 hours while stirring, the mixture is then cooled to 0°-5° in the course of 1 hour and the reaction is completed by stirring at this temperature for at least 1 hour. The mother liquor is then centrifuged off and the residue is washed in portions with a mixture of 25 litres of ethanol and 45 litres of demineralised water. The whole is centrifuged thoroughly and dried in a vacuum cabinet at 35°-40° until the weight is constant (approximately 24 hours). Disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is obtained in the novel crystal form containing water of crystallisation (modification E), the IR spectrum of which is identical to that of the product obtained according to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([O:27][CH:28]3[CH2:32][CH2:31]CO3)[C:19]([O:23][CH:24]([F:26])[F:25])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.CN([CH:36]=[O:37])C>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([O:27][CH:28]3[CH2:32][CH2:31][O:37][CH2:36]3)[C:19]([O:23][CH:24]([F:25])[F:26])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: CN(C)C=O
Reactant: FC(F)Oc1ccc2c(Cl)nncc2c1OC1CCCO1
Agent: [H-]
Agent: [Na+]
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OC1CCOC1
Yield: 43.5 %

Procedure:
A solution under nitrogen of 3,5-dichloro-4-methyl-pyridine (457 mg, 2.82 mmoles) in dry DMF (10 ml) was portionwise added with 60% NaH (113 mg, 2.82 mmoles) and, after 1 hour at room temperature, was dropwise added, at a temperature <10° C., with 1-chloro-6-difluoromethoxy-5-(tetrahydrofuran-2-yloxy)-phthalazine (296 mg, 0.937 mmoles), obtained as described in example 53, in dry DMF (10 ml). After 2 hours at room temperature the mixture was poured into a 0.4M buffer at pH=7 (50 ml), extracted in ethyl acetate (2×50 ml) and the organic phase was washed with water, anhydrified and concentrated under vacuum. The residue was chromatographed (eluent:benzene/ethyl acetate 1:1, then ethyl acetate only), then crystallized from ethyl ether/benzene to give 180 mg of the title product (yield: 43.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#N)=[CH:24][CH:23]=1.CC[O:32]CC>>[F:15][C:4]1[CH:3]=[C:2]([C:26]([C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)=[O:32])[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Reactant: CCOCC
Agent: [Li]CCCC
Product: O=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To an oven-dried round-bottomed flask cooled at −78° C., was added 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (7.20 g, 24.82 mmol) in anhydrous ether (300 mL) under Argon, and the mixture was stirred at −78° C. for 10 min. n-BuLi (2.5 M in hexanes, 11.5 mL, 28.75 mmol, 1.16 eq) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 45 min. An Et2O solution (20 mL) of 4-fluorobenzonitrile (3.06 g, 25.29 mmol, 1.02 eq) was added dropwise. The resulting reddish solution was stirred at −78° C. for 2 h. The reaction mixture was quenched by adding 1N HCl (200 mL), and the dry ice-acetone bath was removed. The resulting slurry was stirred at room temperature for 1 h followed by the addition of Et2O (100 mL). The organic layer was separated, and then washed with sat'd NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (EtOAc/hexanes=0 to 30%) to give (3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methanone as slightly tan oil (7.20 g, yield: 86.9%). 1H NMR (400 MHz, CDCl3) δ ppm 7.85-7.80 (m, 2H), 7.40-7.37 (m, 2H), 7.20-7.14 (m, 3H), 5.92 (tt, J=52, 2.8 Hz, 1H); LC-MS (ESI) 335.31 (M+H), retention time=3.81 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: C(C1C=CC=CN=1)=C.[OH:9][C:10]1C=C(O)C=CC=1CC1C=C(Cl)C=C(CC2C=CC(O)=CC=2O)C=1O.[CH2:35]=[O:36].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>>[CH2:10]([C:42]1[CH:43]=[C:38]([Cl:37])[CH:39]=[C:40]([CH2:35][OH:36])[C:41]=1[OH:44])[OH:9]
Reactant: Oc1ccc(Cl)cc1
Reactant: C=O
Reactant: Oc1ccc(Cc2cc(Cl)cc(Cc3ccc(O)cc3O)c2O)c(O)c1
Agent: C=Cc1ccccn1
Product: OCc1cc(Cl)cc(CO)c1O

Procedure:
An aqueous alkaline dispersion useful as a polyester tire cord dip, the solids of the dispersion consisting essentially of a major amount by weight of a rubbery vinyl pyridine copolymer and an minor amount by weight of a heat reactable 2,6-bis(2,4-dihydroxy phenyl methyl)-4-chlorophenol composition made by the process of first reacting about 2 mols of formaldehyde with 1 mol of parachloro phenol to provide 2,6-dimethylol-4-chlorophenol which then is reacted with about 2 mols of resorcinol to give the heat reactable bis(dihydroxy phenylmethyl) chlorophenol composition.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[S:22][CH:23]=[CH:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28](O)=O)=[C:16]2[CH2:15]1.[OH2:31]>CN(C)C=O>[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[S:22][CH:23]=[CH:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([CH2:28][C:18]3[CH:19]=[C:20]4[C:11](=[CH:23][CH:24]=3)[C:12](=[O:31])[NH:8][C:1]4=[O:2])=[C:16]2[CH2:15]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Reactant: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cc3ccc4c(c3)C(=O)NC4=O)ncn2-c2ccsc2C1=O
Reaction time: 0.5 h
Yield: 47 %

Procedure:
3.39 g (20 mmol) of 1,1'-carbonyldiimidazole were added in one portion at room temperature to a solution of 5.27 g (20 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid in 50 ml of dimethylformamide and the mixture was stirred at 50° for 30 minutes. Subsequently, 4.47 g (20 mmol) of phthaloylglycinamide oxime were added in one portion and the mixture was stirred at 110° for 15 hours. The dimethylformamide was evaporated in a high vacuum and the residue obtained was treated with 150 ml of water. Extraction with methylene chloride (twice), drying with sodium sulfate, filtration and evaporation yielded a reddish residue, which was subsequently chromatographed (silica gel, methylene chloride/methanol 20:1). After recrystallization from acetonitrile there were obtained 4.21 g (47%) of 5-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione as pale brown crystals of m.p. 245°-246°.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([NH2:15])=[N:12][NH:13][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(=O)[CH2:17][C:18]([CH3:20])=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:14]=[N:13][N:12]3[CH:16]=[CH:17][C:18]([CH3:20])=[N:15][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1n[nH]cc1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccn2ncc(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 1.0 g (4.47 mmol) of 4-benzenesulphonyl-1H-pyrazol-3-ylamine and 0.6 ml (5.37 mmol) of ethyl acetoacetate in 8 ml of acetic acid was heated at reflux for 1.5 hrs. The reaction solution was cooled to RT and evaporated. The residue was partitioned between CH2Cl2 and H2O and the aqueous phase was washed three times with 150 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 20:1) yielded 0.91 g (70%) of 3-benzenesulphonyl-5-methyl-pyrazolo[1,5-a]pyrimidine as beige crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 13%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.014 g, 30%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.61 (s, 2H) (NCH2-pyridyl and C6H4CH2N), 3.71 (br s, 4H, piperazine N(CH2)2), 7.39 (dd, J=5.30, 8.2 Hz, pyridine 5-H), 7.47 (d, J=8.2 Hz, 2H) and 8.12 (d, J=8.7 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.78 (d, J=6.9 Hz, 1H, pyridine 4-H), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.50, 4.6 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.5 Hz, 1H, pyridine 2-H), 13.42 (br s, 1H, imidazo[4,5-b]pyridine N—H);