Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[H][H].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>O.COCCO>[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:15](=[O:16])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)Cl)c1ccc(C#N)cc1
Reactant: OCc1cccnc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CN(C(=O)OCc1cccnc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.4 %

Procedure:
To a solution of 3-pyridylcarbinol (4.3 g., 0.0392 mole) in 200 ml. of ethylene glycol monomethyl ether (glyme) was added a 57% dispersion of sodium hydride in oil (1.7 g., 0.0392 mole). After the exothermic reaction had subsided and the evolution of hydrogen had ceased, a solution of N-methyl-N-(4-cyanophenyl)carbamoyl chloride in 30 ml. of glyme was added dropwise. A suspension formed and was stirred at room temperature for 18 hrs. The reaction mixture was poured into 700 ml. of water. The reaction product was extracted with methylene dichloride and the extract was dried over magnesium sulfate and concentrated. The residue was an oil which solidified. This was recrystallized from hexane to give 1.5 g. of solid melting at 82°-84.5° C. This solid is a 14.4% yield of 3-pyridylmethyl N-methyl-N-(4-cyanophenyl)carbamate.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].[Cl:12][C:13]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].Cl>C(O)C.O>[Cl:12][C:13]1[N:20]=[C:19]([S:11][C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Fc1ccc(S)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A solution of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of ethanol is added, under nitrogen, to a solution of 698 μL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of ethanol. The reaction medium is stirred at room temperature for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6-dichloronicotinonitrile in 30 mL of ethanol. The reaction medium is stirred for 2 hours at 0-5° C. 63 mL of a 0.1N HCl solution is added to stop the reaction. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2-chloro-6-(2,4-difluorophenylthio)-nicotinonitrile in the form of a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][CH:18]=1)=[O:13])[CH3:10].C1(C)C=CC=CC=1>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][C:18]=1[Br:1])=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(-c2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Br
Reaction time: 8 h
Yield: 56.5 %

Procedure:
N-Bromosuccinimide (1.22 g, 6.83 mmol) was added to a solution of ethyl-2-phenylthiophen-4-carboxylate (6.83 mmol) in acetic acid (10 mL) and stirred overnight. Toluene was added and the solvent was removed under vacuum. The product was purified by flash chromatography on silica, eluting with 0%-10% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.2 g). LCMS m/z 312.52 [M+H]+ R.T.=4.55 mins (Analytical Method 5).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>CO>[CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N1CCC(N)CC1
Yield: 79.3 %

Procedure:
t-Butyl-1-isopropylpiperidin-4-ylcarbamate (2.64 g, 10.9 mmol) obtained in Preparation Example (2-iii-1) was dissolved in methanol (20 ml) in a 250 ml vessel at 0° C., and trifluoroacetic acid (TFA; 4.06 ml, 54.5 mmol, 5 eq.) was slowly added thereto while stirring. The resulting mixture was reacted for 18 hrs. After the completion of reaction, the reaction product was concentrated under reduced pressure, subjected to azeotropic distillation with CHCl3 3 times, basified with 2N aqueous KOH solution (20 ml) and extracted with CHCl3 3 times. The organic layer was separated, washed with brine, dried, filtered and distilled under reduced pressure to obtain 1.23 g of the title compound as yellow oil (yield 79.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([CH:29]([CH3:31])[CH3:30])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.I[C:33]1[CH:38]=[CH:37][N:36]([CH3:39])[C:35](=[O:40])[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1([CH:29]([CH3:31])[CH3:30])[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:33]3[CH:38]=[CH:37][N:36]([CH3:39])[C:35](=[O:40])[CH:34]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: CC(C)C1(CCCO)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cn1ccc(I)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C1(CCCO)CCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1

Procedure:
A mixture of 6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 0.092 mmol), 4-iodo-1-methylpyridin-2(1H)-one (20 mg, 0.085 mmol), Pd(PPh3)2Cl2 (6 mg, 0.0085 mmol), and Cs2CO3 (2 N, 0.425 mL, 0.85 mmol) in 1,4-dioxane (2 mL) was refluxed for 3 h under N2. The reaction mixture was treated with EtOAc (20 mL) and water (20 mL), and the organic layer was dried and concentrated in vacuo. The residue was purified by preparative HPLC to give two isomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[OH:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.[CH3:21][C:22](=O)CC>>[CH2:21]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:8][CH3:9])=[O:19])[CH:14]=[CH:15][CH:16]=1)[CH3:22]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CCC(C)=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(OCC)c1
Temperature: 80 °C
Yield: 78 %

Procedure:
Potassium carbonate (65.3 g, 473 mmol) and iodoethane (25.5 mL, 324 mmol) were added to a stirred solution of 3-hydroxyphenylacetic acid (12.0 g, 79 mmol) in 2-butanone (125 mL). The resulting mixture was heated in an oil bath (80° C.) for 16 h and then allowed to cool. The mixture was concentrated and methylene chloride was added. The organic layer was washed with water, brine, and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give ethyl 3-ethoxyphenylacetate (12.7 g, 78%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(C=O)c1
Yield: 94.4 %

Procedure:
By the method of Example 1, Step F, 10.0 g (0.0819 mole) of 3-hydroxybenzaldehyde and 16.0 g (0.0982 mole) of methyl 2-bromopropionate were reacted in the presence of 13.6 g (0.0983 mole) of anhydrous potassium carbonate in 50 mL of N,N-dimethylformamide, yielding 16.1 g of methyl 2-(3-formylphenoxy)propionate as an orange liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.COCCNC.[CH3:56][C:57]([OH:61])([C:59]#[CH:60])[CH3:58]>>[OH:61][C:57]([CH3:58])([CH3:56])[C:59]#[C:60][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]([CH2:21][CH2:22][O:23][CH3:24])[CH3:20])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: C#CC(C)(C)O
Reactant: COCCN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: CNCCOC
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: COCCN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 20 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-(((2-methoxyethyl)(methyl)amino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with 2-methoxy-N-methylethanamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (20 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22](Cl)(=[O:24])[CH3:23].Cl>C1COCC1.O.C(Cl)Cl>[C:22]([NH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C#N)cc(Cl)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1c(C)cc(C#N)cc1Cl
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred solution of 4-amino-3-chloro-5-methylbenzonitrile (0.516 g, 3.1 mmol) in 10 mL of THF at room temperature was added 6.6 mL of 1.0 M NaHMDS in THF. The resulting reaction mixture was stirred at room temperature for 30 min., at which time acetyl chloride (3.1 mmol) was added. DCM (100 mL) and water (100 mL) were added to the reaction mixture after being stirred overnight, followed by the addition of 5 mL of 1.4 N HCl aqueous solution. Layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The extracts were combined and solvents were evaporated in vacuo. The residue was purified by flash chromatography (5-20% EtOAc/DCM) to give 0.220 g of 4-acetamido-3-chloro-5-methylbenzonitrile. 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 1 H), 7.46 (s, 1 H), 7.02 (s, 1 H), 2.31 (s, 3 H), 2.26 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:21][N:20]=3)[S:18][C:11]=12)[NH2:5].CC[N:34]([CH:38]([CH3:40])[CH3:39])[CH:35](C)C.ClC(Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>C1COCC1>[CH:38]1([NH:34][C:35]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:27][CH2:28][O:29][CH2:30][CH2:31]6)=[CH:21][N:20]=5)[S:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)=[O:44])[CH2:39][CH2:40]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cn4)sc23)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: NC1CC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
The solution of aniline 359 (136 mg, 0.312 mmol) and DIPEA (0.218 mL, 1.246 mmol) in THF (6 mL) was cooled to 0° C., and then triphosgene (46.2 mg, 0.156 mmol) was added and the reaction mixture was stirred for 1 h at 0° C. followed by an addition of cyclopropylamine (89 mg, 1.558 mmol). The reaction mixture was stirred at r.t. for an additional 3 hrs then concentrated, partitioned between water and ethyl acetate. A thick solid was formed which was isolated by suction filtration, rinsed with water and ethyl acetate, and dried in vacuo. This material was then purified using Gilson (eluent 20-95% MeOH/H2O, 1 h) to give the title compound 360 (30 mg, 0.058 mmol, 18.53% yield) as a white solid. 1 HNMR (DMSO-d6) d (ppm) 1H:HNMR 9.16 (s, br, 1H), 8.16 (d, 1H, J=1.6 HZ), 8.11 (d, 1H, J=5.4 Hz), 7.91 (s, 1H), 7.83 (d, 1H, J=8.2 Hz), 7.46 (dd, 1H, J1=2.1 Hz, J2=8.2 Hz), 7.34 (dd, 1H, J1=2.6 Hz, J2=13.9 Hz), 6.97-7.45 (m, 2H), 6.84-6.81 (m, 1H), 6.23 (d, 1H, J=4.7 Hz), 3.18 (t, 4H), 3.14 (s, 2H), 2.15-2.12 (m, 1H), 1.98 (m, 4H), 0.23-0.19 (m, 2H), 0.02-0.005 (m, 2H). MS: 520.4 (MH)+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-])=O)([CH3:3])[CH3:2]>[Pt].C(OCC)(=O)C>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19])([CH3:3])[CH3:2]
Reactant: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)OCCCNc1c(N)cnc2cccnc12
Reaction time: 2.5 h
Yield: 95.4 %

Procedure:
N4-(3-Isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine (4.2 g, 14.5 mmol), platinum on carbon (1.1 g of 5%), and ethyl acetate (100 mL) were placed in a hydrogenation flask. The mixture was shaken under a hydrogen pressure of 50 psi (3.5 Kg/cm2) for 2.5 hours. The reaction mixture was filtered and the catalyst was washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 3.6 g of N4-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamine as a bright yellow oil. 1H NMR (300 MHz, CDCl3): δ8.70 (dd, J=4.1,1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (dd, J=8.4,1.6 Hz, 1H), 7.37 (dd, J=8.4, 4.1 Hz, 1H), 5.99 (broad s, 1H), 3.98 (broad s, 2H), 3.63-3.55 (m, 5H), 1.87 (pentet, J=6.2 Hz, 2H), 1.17 (d, J=6.1 Hz, 6H); MS (EI): m/e 260.1630 (260.1637 calc'd for C14H20N4O).
Reaction SMILES: C(S[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)C.Cl[C:25]1C=CC=C(C(OO)=O)[CH:26]=1.[Na].[S:36]([O-:40])([O-])(=[O:38])=S>C(Cl)(Cl)Cl>[CH2:25]([S:36]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=1)(=[O:40])=[O:38])[CH3:26]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.25 g) and chloroform (3 ml), 3-chloroperbenzoic acid (purity: not less than 65%, 0.43 g) was added under ice-cooling, and then heated to room temperature, and stirred for 1 hour. To the reaction mixture, chloroform was added under ice-cooling, and then saturated aqueous sodium, thiosulfate solution was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, then saturated trine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crystal was washed with hexane, then methyl-tert-butyl ether to give 0.27 g of 2-(2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 6).
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:4])#[N:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34](Br)[CH:35]=[CH2:36]>C1COCC1>[C:1]([C:3]([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])([CH2:36][CH:35]=[CH2:34])[CH3:4])#[N:2]
Reactant: C=CCBr
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reaction time: 0.12 h

Procedure:
To (±)-tert-butyl 4-(1-cyanoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 156-A) (0.82 g, 2.61 mmol) in THF (13.04 ml) at −78° C. was added LiHMDS (1M in hexane, 3.13 ml, 3.13 mmol) and stirred for 7 minutes. At this point, allyl bromide (0.563 ml, 6.52 mmol) was added and the reaction stirred for 2 hours at −78° C. Reaction was then quenched with a saturated solution of aq. ammonium chloride and diluted with DCM. The layers were separated and the organic layer was dried over Na2SO4 and concentrated to an oil that was absorbed onto silica and purified via FCC (0-30% EtOAc:heptanes) to give the title compound. MS (ESI+) m/z 355.4 (M+H).
Reaction SMILES: [OH-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]3[C:15]([OH:16])=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)S[C:10]=32)=[CH:5][CH:4]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]3[C:10](=[C:24]([C:23]([O:27][CH3:28])=[O:26])[CH:25]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]3=[O:16])[C:11]=2[CH:12]=1
Reactant: C#CC(=O)OC
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccc(Cl)cc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2

Procedure:
(ba) 4.2 g of 9-chloro-2-phenyl-5,6-dihydro-3-hydroxythiazolo[2,3-a]isoquinolinium hydroxide (internal salt) were heated under reflux for 4 hours in 100 ml of toluene together with 1.32 ml of methyl propiolate. After concentration in vacuo, the residue was chromatographed on silica gel with toluene/acetone (9:1). There was obtained methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] quinolizine-1-carboxylate of m.p. 139°-141° (from ethyl acetate).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[OH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>>[CH3:13][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:3][CH2:2][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1
Reactant: CCC(=CCCC(C)=CCBr)CC
Reactant: Oc1ccc2c(c1)OCCC2
Product: CCC(=CCCC(C)=CCOc1ccc2c(c1)OCCC2)CC

Procedure:
Following the procedure of Example 1, 1-bromo-3-methyl-7-ethyl-2,6-nonadiene and 7-hydroxy-chromane are reacted to form 7-(3-methyl-7-ethyl-2,6-nonadienyloxy)-chromane, nD20 = 1.5342.
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cr](Cl)(O)(=O)=[O:14].N1C=CC=CC=1>ClCCl.C(OCC)C>[CH2:1]([C:5]1=[CH:11][C:10](=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[Cr](=O)(O)Cl
Reactant: CCCCC1(O)C=CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC1=CC(=O)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (Z)-1-butylcyclohept-2-enol (2 g, 11.9 mmol) dissolved in dichloromethane (60 mL) was pyridine chlorochromate on basic alumina (20 wt. %, 25.7 g, 23.8 mmol). The resulting reddish solution was stirred at room temperature for 2 h until determined to be complete by TLC. The mixture was diluted in 100 mL diethyl ether and stirred for 1 h after which it was poured over filter paper that was subsequently washed with the ether. The filtrate was partially concentrated (30 mL) and passed through a Florisil column with ether (100 mL). The resulting colorless solution was concentrated and purified by flash chromatography (5% Et2O/Pentane) to provide a colorless oil (920 mg, 47% yield). IR (film) 3477, 2933, 2864, 1662, 1458, 1421, 1375, 1344, 1322, 1267, 1201, 1124, 1103, 1048, 937, 875, 855 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.89 (s, 1H, COCH), 2.58-2.53 (m, 2H, COCH2), 2.41-2.38 (m, 2H, HC═CCH2), 2.18 (t, 2H, J=6.91 Hz, HC═CCH2(CH2)2CH3), 1.80-1.74 (m, 2H, COCH2CH2), 1.50-1.40 (m, 2H, HC═CCH2CH2), 1.38-1.25 (m, 2H, HC═C(CH2)2CH2CH3), 0.90 (t, 3H, J=7.18 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 204.4, 162.4, 128.2, 42.1, 40.8, 32.5, 29.7, 25.1, 22.4, 21.2, 13.9; HRMS (EI+) exact mass calculated for [M]+ (C11H18O) requires m/z 166.1358, found m/z 166.1359.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][CH:26]([C:30]#[CH:31])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[OH:25][CH:26]([C:30]#[CH:31])[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: C#CC(O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (75 mg, 0.23 mmol) in 0.78 ml CH2Cl2 were added successively 2-hydroxybut-3-ynoic acid (30 mg, 0.30 mmol), BOP (134 mg, 0.30 mmol), and triethylamine (36 mg, 49 μL, 0.35 mmol). The mixture was stirred at 0° C. for 30 minutes. Purification via silica gel chromatography using 0-100% ethyl acetate/hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)but-3-yn-1-one. (LC/MS: m/z 403.5 (M+H)+ at 2.34 min (10% O-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C=O.[C:32](O)(=O)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[CH2:32][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Agent: C=O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nc3n(c2CN2CCOCC2)CCS3)cc(C(C)(C)C)c1O

Procedure:
A mixture of 1.65 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole, 1.8 g of morpholine, 1.7 g of an aqueous 35% formaldehyde solution, 1.5 ml of acetic acid, and 10 ml of dioxane was refluxed for 6 hours. The reaction mixture was concentrated udner reduced pressure and to the residue was added 20 ml of an aqueous 10% potassium carbonate to precipitate crystals, which were recovered by filtration and recrystallized from methanol to provide 0.85 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-morpholinomethyl-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[B:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)=[CH:4][CH:5]=1)([OH:11])[OH:10]
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A suspension of (4-bromomethylphenyl)boronic acid (2.00 g, 9.31 mmol), thiomorpholine 1,1-dioxide (1.50 g, 11.1 mmol), and potassium carbonate (2.60 g, 18.8 mmol) in acetone (25 mL) was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature and the volatiles were evaporated. The residue was suspended in saturated aqueous ammonium chloride (100 mL). The aqueous phase was decanted from the waxy solid, rinsed with water (50 mL), and decanted again. The waxy solid was dissolved in methanol (50 mL), filtered to remove insoluble salts and evaporated to obtain 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide as a tan foam (2.48 g). The recovered material was crude by 1HNMR but was used without further purification.