Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C[Si]([O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:32][C:31]([F:34])([F:33])[S:28]([O:30][CH2:12]/[CH:11]=[C:10]1/[CH:19]([C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[O:20][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)(=[O:29])=[O:27]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC#CCCC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(OC/C=C1\CCC(c2ccccc2)OC1c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and 4-chlorobenzaldehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. After being stirred for 1 hour at the same temperature, the reaction solution was slowly heated to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH:20](B1OB(C=C)OB(C=C)O1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][NH:8][C:5]2[N:6]=[N:7][C:2]([CH:20]=[CH2:21])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(CNc1ccc(Cl)nn1)c1ccc(F)cc1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Temperature: 140 °C
Yield: 41.8 %

Procedure:
To a 5 mL microwave reaction vial was added 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (123 mg, 441 μmol, 1.0 equiv), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (159 mg, 661 μmol, 1.5 equiv), Cl2Pd(dppf) (54 mg, 66 μmol, 0.15 equiv), potassium carbonate (182 mg, 1.32 mmol, 3 equiv), and dioxane (21 mL). The reaction was heated in a microwave reactor at 140° C. for 12 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-50% EtOAc/hexanes) to give 50 mg (46%) of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-vinylpyridazin-3-amine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[C:26]([Cl:28])[CH:27]=2)[O:21][CH:22]=1>>[Cl:28][C:26]1[CH:27]=[C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[S:24][CH:25]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cc(Cl)cs2)n1
Product: Clc1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 80 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(4-chloro-2-thienyl)oxazole to give 2-(4-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 80%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 69-70° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH3:34])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1
Reactant: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-hydroxytetrahydrofuran-3-yloxy)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1([CH2:16][CH2:17][CH2:18][OH:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCCCCBr
Reactant: OCCCc1ccccc1
Product: BrCCCCCCCOCCCc1ccccc1

Procedure:
(2.05 g) from 1,7-dibromoheptane (3.83 g) and 3-phenylpropanol (1.08 ml).
Reaction SMILES: [CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH:4]=[CH:3]1.[CH3:8][PH:9](=[O:11])[CH3:10]>C(OCCCC)(=O)C1C(=CC=CC=1)C(OCCCC)=O>[CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]1[P:9](=[O:11])([CH3:10])[CH3:8]
Reactant: C[PH](C)=O
Reactant: CP1(=O)C=CCC1
Solvent: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Product: CP(C)(=O)C1CCCP1(C)=O

Procedure:
116 g of 1-methyl-1-oxophospholine and 6 g of tert.-butyl perpivalate in dibutyl phthalate are added dropwise with stirring under an oxygen-free atmosphere to 234 g of dimethyl phosphine oxide. The reaction temperature is 75° to 80° C. The starting materials are then distilled off. The residue consists of 185 g of 1-methyl-1-oxophospholanyl dimethyl phosphine oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.C1COCC1.CCOC(/N=N/C(OCC)=O)=O>CO.ClCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH2:35][CH2:34][O:33][CH3:32])=[CH:7]2
Reactant: COCCO
Reactant: Oc1cnc2c(Cl)ccnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COCCOc1cnc2c(Cl)ccnc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
A round bottom flask under nitrogen environment was charged with 8-chloro-1,5-naphthyridin-3-ol (1.05 g, 5.8 mmol), 22.8 g of PS-Triphenylphosphine (loading: 2.2 mmol/g), 2-methoxyethanol (2.2 mL, 27.9 mmol), and THF (29.1 ml, 5814 μmol)/DCM (58.1 mL). Mixture cooled to 0° C. and to this was added DEAD (1.84 mL) dropwise via syringe. Reaction mixture allowed to stir at room temperature for 16 hours. Diluted with 50 mL of 10% MeOH/dichloromethane and resin bound reagent filtered. Filtrate concentrated under reduced pressure and purified by ISCO silica gel chromatography (10-30% EtOAc/Hexanes) to afford 8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine (770 mg, 55% yield) as white solid. MS [M+H]=238.9. Calc'd for C11H11ClN2O2=238.67.
Reaction SMILES: [F:1]F.[C:3]([O:6][C@@H:7]1[C@@H:13]([O:14]C(=O)C)[C@H:12]([O:18]C(=O)C)[C@@H:11]([CH2:22][O:23]C(=O)C)[O:10][C@@:8]1(C1C=CC=CC=1)S)(=[O:5])[CH3:4].II.[Na]>C(#N)C>[C:3]([OH:6])(=[O:5])[CH3:4].[C:3]([OH:6])(=[O:5])[CH3:4].[C:3]([OH:6])(=[O:5])[CH3:4].[C:3]([OH:6])(=[O:5])[CH3:4].[C@@H:8]1([F:1])[O:10][C@H:11]([CH2:22][OH:23])[C@@H:12]([OH:18])[C@H:13]([OH:14])[C@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@](S)(c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: FF
Agent: II
Agent: [Na]
Solvent: CC#N
Product: CC(=O)O
Product: OC[C@H]1O[C@@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 54 %

Procedure:
Elemental fluorine gas (3.4 mmol diluted to a 10% solution in nitrogen) was bubbled slowly through a mixture of phenyl-1-thio-β-D-glucopyranoside tetraacetate (0.75 g, 1.7 mmol) and iodine (0.86 g, 3.4 mmol) in dry acetonitrile (15 ml). After the addition of fluorine was complete the solution was poured into 10% sodium metabsulfite and extracted with dichloromethane. The organic layer was washed sequentially with 10% sodium bicarbonate and water, dried (MgSO4) and evaporated to a thick yellow syrup. 19F nmr analysis of the product mixture showed the presence of both anomers with ratio α:β=1:6. Purification of the product mixture by column chromatography on silica gel with ethyl acetate: petroleum ether (1:1) as eluant yielded pure β-D-glucopyranosyl fluoride tetraacetate (320mg, 54%) as white crystals; m.p. 87°-88° C. from ether [lit. 89° C.]; [α]D +20.8 (lit., [α]D 20.0); RF 0.52; (Found: C, 47.7; H, 5.55. Calc. for C14H19O9F: C, 48.0, H, 5.4%); δH (400 MHz, CDCl3, Me4Si) 2.04, 2.05, 2.10, 2.11 (each 3H, s, CH3 groups), 3.90 (1H, d d d, J4,5 9.4, J5,6a 4.8, J5,6b 2.8, H-5), 4.22 (1H, d d, J6a,6b 12.4, J5,6b 2.8, H-6b), 4.27 (1H, d d, J6a,6b 12.4, J5,6a 4.4, H-6a), 5.11 (1H, m, H-2), 5.21 (2H, m, H-3,4), 5.37 (1H, d d, 1JH,F 52.4, JH1,H2 5.4, H-1); δC (100 MHz, CDCl3, Me4Si) 20.6 ppm and 20.7 (s, CH3 groups overlapping), 61.7 (s, C-6), 67.4 (s, C-4), 71.1 (d, 2JC,F 28.6, C-2), 71.8 (d, 3JC,F 8.4, C-3), 72.0 (d, 3JC,F 4.2, C-5), 106.2 (d, 1JC,F 219.7, C-1), 169.1, 169.3, 170.0 and 170.6 (s, C=O groups); δF (235 MHz, CDCl3, Me4Si) -141.88 ppm (d d, 1 JH,F 53.0, 2JH,F 12.5, F-1); r/z (Cl+, NH3) 331 (M+ -F, 100%)
Reaction SMILES: [N:1]([C:4]1C=CC(C(OC)=O)=[CH:6][CH:5]=1)=[C:2]=[O:3].Cl.[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][OH:25])=[CH:21][CH:22]=2)[CH2:17][NH:16]1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)CN1>>[OH:25][CH2:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[CH2:15][N:16]([C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:26][C:34]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:3])[CH2:17]2
Reactant: c1ccc2c(c1)CNC2
Reactant: OCc1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccc(N=C=O)cc1
Agent: Cl
Product: O=C(NCCCCc1ccccc1)N1Cc2ccc(CO)cc2C1

Procedure:
The title compound was prepared as described in Example 1A, substituting (4-isocyanatobutyl)benzene for methyl 4-isocyanatobenzoate and isoindolin-5-ylmethanol hydrochloride for isoindoline. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32-7.12 (m, 8H), 6.32-6.24 (m, 1H), 5.16 (t, J=5.6 Hz, 1H), 4.54 (bs, 4H), 4.49 (d, J=5.7 Hz, 2H), 3.14-3.05 (m, 2H), 2.64-2.54 (m, 2H), 1.63-1.39 (m, 4H); MS (ESI(+)) m/e 325 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.[CH2:10]([C:13]1[C:21]2[O:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:26][CH2:27][CH2:28][CH2:29]Br)[CH2:11][CH3:12]>>[CH3:1][CH:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:29][CH2:28][CH2:27][O:26][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([C:22]([F:24])([F:25])[F:23])=[N:19][O:20][C:21]=3[C:13]=2[CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[CH2:3]1
Reactant: CC1CC(=O)NC(=O)N1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CC(C)NC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
6-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione was prepared as for Example 10 from 6-methyldihydropyrimidine-2,4(1H,3H)-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](O)(=O)[CH3:11].[N:14]([O-])=O.[Na+].COC(OC)CC(=O)C>[Zn].CCCCCCC>[CH2:7]([O:6][C:4]([C:3]1[NH:14][C:10]([CH3:11])=[CH:9][CH:2]=1)=[O:5])[CH3:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)O
Agent: COC(CC(C)=O)OC
Agent: [Na+]
Agent: [Zn]
Solvent: CCCCCCC
Product: CCOC(=O)c1ccc(C)[nH]1
Temperature: 0 °C
Reaction time: 48 h
Yield: 13.6 %

Procedure:
To a 4-neck 22 L round bottom flask equipped with an overhead stirrer, liquid addition funnel, nitrogen inlet and an internal temperature probe was charged ethyl 3-oxobutanoate (1952 g, 15.0 mol) and glacial acetic acid (5 L). The resulting solution was cooled to 0° C. with an ice water bath and an aqueous solution of sodium nitrite (1242 g, 18.0 mol, 1.2 eq, in 1875 ml of water) was added slowly (4.5 h) not allowing the internal temperature above 10° C. The homogeneous red solution was allowed to warm to ambient and stirred for 48 h. The solution color changed from light red to yellow. Reaction vessel was then placed in a heating mantle, fitted with a reflux condenser and acetylacetaldehyde dimethyl acetal (1982 g, 15.0 mol, 1 eq) was added in one portion (the top of the reflux condenser was left open to air to allow for the rapid gas evolution during the addition of the zinc). Zinc (dust, 2156 g, 33 mol, 2.2 eq) was added in portions (at a rate such that gas evolution was controlled) over 4 h. The addition of zinc brought the reaction to reflux and after addition the dark red solution was heated at reflux for an additional 1.5 h. Contents of the reaction were poured hot into a 50 L container with 20 kg of ice and allowed to stir for 16 h. Resulting suspension was filtered, dried in convection oven and recrystallized with hot heptane yielding a light yellow solid (312 g, 13.6% yield).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1C#N.[C:10](=[O:13])([O-])[O-:11].[K+].[K+].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.Cl>C1(C)C(C)=CC=CC=1.O.C(OCC)(=O)C>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:10]([OH:11])=[O:13])[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccnc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)c1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
In 500 ml of ortho-xylene, 100 g of 2-chloronicotinonitrile, 108.82 g of anhydrous potassium carbonate, and 133.83 ml of 4-amino-1-benzylpiperidine were together stirred for 24 hrs under reflux. This reaction mixture was cooled to room temperature, added with 500 ml of ethyl acetate and 1,000 ml of pure water, and adjusted to a pH of about 2-3 with conc. HCl. The aqueous fraction thus formed was obtained, washed again with 300 ml of ethylacetate, and adjusted to a pH of about 9-10 with sodium hydroxide in an ice bath while stirring. After completion of addition of sodium hydroxide, the fraction was stirred for an additional 1 hr, filtered, washed with water, and hot air dried to afford 137.4 g of the title compound (yield: 71.5%). 1H NMR (CDCl3) δ 8.26 (dd, 1H), 7.63 (dd, 1H), 7.36-7.28 (m, 5H), 6.59 (m, 1H), 5.0 (d, 1H), 4.14-3.97 (m, 1H), 3.53 (s, 2H), 2.88 (d, 2H), 2.22 (t, 2H), 2.1-1.98 (m, 2H), 1.68-1.47 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([F:11])[CH:3]=1.[CH3:12]OS(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[Na+].C1N2CCN(CC2)C1.C[N:39]([CH:41]=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:9])[C:41]#[N:39])=[C:4]([F:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: N#CCc1ccc(Br)cc1F
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: C1CN2CCN1CC2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Br)cc1F
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A 2-L, 3-neck flask was charged with (4-bromo-2-fluorophenyl)acetonitrile (100.91 g, 0.4715 mol), MeOTs (156 mL g, 1.034 mol), DMF (400 mL) and THF (400 mL). The headspace was purged with nitrogen and the solution was cooled to −10° C. The NaOtBu (96.58 g, 1.005 mol) was divided into 4 equal portions that were added separately to the reaction to control the exotherm. Five minutes after the fourth and final charge an aliquot was removed and analyzed by HPLC, verifying reaction completion. The cold bath was removed, and the reaction allowed to stir without cooling (internal temp=4° C.). The flask was then charged with DABCO (13.02 g, 0.116 mol) to consume the remaining MeOTs. After 30 min an aliquot was removed and analyzed by HPLC, showing no detectable MeOTs. The flask was charged with H2O (400 mL) and hexanes (400 mL) and the mixture added to a separatory funnel. The phases were mixed well and then separated. The aqueous phase was re-charged to the separatory funnel and re-extracted with hexanes (200 mL). The organic phases from the first two extractions were combined and transferred back to the separatory funnel and washed twice with H2O (200 mL). The phases were separated and the organic layer was added to a 2-L, 3-neck flask set up for distillation. The solution was distilled under vacuum (400 torr with an internal temperature of about 50° C.) until no significant solvent distillation occurred. An aliquot of the solution was removed and analyzed by 1H NMR to record the amount of solvents present. The solution of product was held overnight and used without further processing in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([CH3:13])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[CH3:22][NH2:23]>C(O)C>[CH3:22][NH:23][C:1]1[N:2]=[CH:9][N:8]=[C:7]2[N:6]([CH3:13])[N:5]=[C:4]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: CN
Reactant: CCOC=Nc1c(C#N)c(-c2ccc([N+](=O)[O-])o2)nn1C
Solvent: CCO
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 10.0 grams of 4-cyano-5-ethoxymethyleneamino-1-methyl-3-(5-nitro-2-furyl)-pyrazole, and 100 millilitres of a 33% solution of methylamine in ethanol was heated at reflux for 30 minutes and cooled. The crystalline solid precipitated was collected, washed with ether and dried. Recrystallisation from dimethylformamide gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine, having melting point 280° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 40 g (184 mmol) of 5-bromo-1-indanone in 500 mL of methanol in a water bath was added 16.2 g of sodium borohydride portionwise, keeping the reaction temperature below 40° C. The water bath was removed and the reaction mixture stirred at ambient temperature for 2 h and then quenched by the addition of 100 mL of water. The methanol was removed in vacuo, and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with two portions of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated to give a yellow solid which was used without further purification. Mass spectrum (MS): m/z 195, 197 (M+1-H2O), 116 (M+1-H2O-HBr).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]#[N:24])[CH:18]=[CH:19][CH:20]=1)=O.N1CCCCC1.O>C(Cl)(Cl)Cl>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:13][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][C:23]#[N:24])[CH:16]=1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Reactant: N#CC=Cc1cccc(C=O)c1
Solvent: O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(C=CC#N)c2)c(=O)o1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 5.24 g of 3-acetyl-4-hydroxy-6-methyl-2H -pyran-2-one, 4.90 g of 3-(3-formylphenyl)-2-propenenitrile and 1.92 g of piperidine in 40 ml of chloroform was heated under refluxing for 35 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooling to room temperature, the reaction mixture washed successively with 10% hydrochloric acid, and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. Precipitated crystals were filtered, and the crystals were subjected to silica gel column chromatography to obtain 4.05 g of 4-hydroxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a)] as a pale yellow crystal.
Reaction SMILES: [CH2:1]([S:4][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:11])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[CH2:1]([S:4][C@H:5]1[N:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCS[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCS[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1CC(=O)OC
Reaction time: 18 h

Procedure:
To a stirred solution of 1.76 g of 4(R)-allylthio-3(S)-[1(R)-{dimethyl-{2-methylprop-2-yl}silyloxy}ethyl]azetidin-2-one in 60 ml of dry dimethylformamide were added 3.52 g of finely ground potassium carbonate and 0.6 ml of methyl bromoacetate. After 18 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The separated organic layer was washed with water and dried over magnesium sulphate. Evaporation in vacuo afforded a crude product which was chromatographed on silica gel. Elution with ethyl acetate/hexane mixtures afforded 1.56 g of the title compound as a pale yellow oil.
Reaction SMILES: C(N=C=O)CCCCC[N:7]=C=O.[C:13]([O:18][CH2:19][CH2:20]O)(=[O:17])[C:14](C)=[CH2:15]>>[C:13]([OH:18])(=[O:17])[CH:14]=[CH2:15].[NH2:7][C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C=NCCCCCCN=C=O
Reactant: C=C(C)C(=O)OCCO
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
A urethane acrylate was synthesized as in the Examples using 336 g (four equvalents) of hexamethylene diisocyanate and 533 g (4.1 moles) of hydroxyethyl methacrylate.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH:17]([O:19]C)[CH2:16][N:15]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH2:14]2)=[CH:9][CH:8]=1)[CH3:6].C(=O)(O)[O-].[Na+].O>ClCCl>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][N:15]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH2:16][CH:17]([OH:19])[CH2:18]2)=[CH:9][CH:8]=1)[CH3:6]
Reactant: CCc1ccc(C2CC(OC)CN(C(=O)N3CCOCC3)C2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(C2CC(O)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and at 0° C., 4.6 ml of a boron tribromide solution (1 molar in dichloromethane, 4.6 mmol, 2 eq.) were added to a solution of 890 mg (2.3 mmol) of 4-{[3-(4-ethylphenyl)-5-methoxypiperidin-1-yl]carbonyl}morpholine in 22 ml of dichloromethane. The reaction mixture was stirred at RT for 2 h, then poured onto ice, neutralized with solid sodium bicarbonate and, after addition of water and phase separation, extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water with 0.1% trifluoroacetic acid/acetonitrile gradient). Yield: 314 mg (43% of theory)