Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].C([NH+](CC)CC)C.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[NH:27][N:26]=[N:25][N:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2nnn[nH]2)nn1
Temperature: 120 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-3-cyanopyridazine (reference example 13) (0.52 g, 1.34 mmol) in N-methylpyrrolidone (13 ml) was treated with sodium azide (403 mg, 6.1 mmol) followed by triethylammonium chloride (537 mg, 3.9 mmol) and the mixture stirred under argon for 7 hours at 120° C. The mixture was then poured into water and acidified to around pH2. It was then extracted twice with ethyl acetate and the combined organic extracts washed twice with water, dried and evaporated to give a solid. The solid was purified by MPLC, and triturated with a 1:1 mixture of diethyl ether/ethyl acetate to give the title compound as an off-white solid (275 mg, 48%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][CH2:17][OH:18])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5]1.CN(C=O)C.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>O>[CH2:31]([O:18][CH2:17][CH2:16][O:15][C:7]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][N:4]([CH3:3])[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: Cn1nc(-c2ccccc2)c(OCCO)c1-c1ccccc1
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
Sodium hydride (0.89 g, 57%, 0.02 mole) is added to a solution of 2-[(1-methyl-3,5-diphenyl-4-pyrazolyl)oxy]ethanol (5.9 g, 0.02 mole) and dry DMF (50 ml). The reaction mixture is stirred and heated to 80°-90°C. The stirred mixture is allowed to cool. This mixture is added to a solution of 1-bromoheptane (9 g, 0.05 mole) and dry FMD (75 ml). After heating at 80°-90°C for 4 hours, the stirred reaction mixture is poured into water.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][CH2:37][OH:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][CH2:37][OH:38])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CCO)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromoethanol (0.40 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 23%).
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]([Cl:16])([Cl:15])[F:14])=[CH:4]1.[F:17][C:18]([F:27])([F:26])[CH2:19][CH2:20][CH:21]([C:24]#[N:25])[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:15][C:13]([Cl:16])([F:14])[S:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:21]([CH2:20][CH2:19][C:18]([F:17])([F:26])[F:27])([C:22]#[N:23])[C:24]#[N:25])[CH:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(Cl)(Cl)Sc1cn(CCl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
0.61 g of 1-(chloromethyl)-3-{[dichlorofluoromethyl]thio}-1H-indole and 0.35 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.28g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of [(3-{[dichlorofluoromethyl]thio}-1H-indole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (44), hereinafter) shown by below formula.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16](C3C=CC(CN4CCOCC4)=CC=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[N:62]1([CH2:68][C:69]2[CH:70]=[C:71]([CH:74]=[CH:75][CH:76]=2)C=O)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:71]3[CH:74]=[CH:75][CH:76]=[C:69]([CH2:68][N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)[CH:70]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(CN5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 77 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Morpholin-4-ylmethyl-benzaldehyde were reacted to produce the title compound (77%). 1H NMR (d-chloroform): 8.78 (d, J=8 Hz, 1H), 8.20 (m, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.63 (m, 2H), 6.42-6.50 (m, 2H), 6.01 (s, 1H), 5.61 (s, 1H), 5.38 (t, J=8 Hz, 1H), 4.37 (d, J=13 Hz, 1H), 4.27 (d, J=13 Hz, 1H), 3.99 (m, 4H), 3.53 (m, 2H), 3.18 (s, 1H), 3.05 (m, 1H), 3.04 (s, 1H), 2.70 (d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 1.68 (d, J=9 Hz, 1H). MS: 480.09 (M+H). HPLC retention time: 1.81 minutes (G Method).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C1C=CC=CC=1>[C:16]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: OCCCCCCBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OCCCCCCBr
Yield: 65.2 %

Procedure:
Into a reactor, 30 g of 6-bromo-1-hexanol, 18.4 g of triethylamine, and 500 ml of benzene were charged, to which a solution of 16.5 g of acryloyl chloride in 200 ml of benzene was added dropwise, while stirring and cooling with ice, and stirred for 3 hours to give a reaction solution. The reaction solution was washed with a 3N-HCl and then with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was purified by the silica gel column chromatography (eluent; toluene) to give 25.4 g (Y., 65.1%) of 6-bromohexyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14][N:25]=[N+:26]=[N-:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCN=[N+]=[N-])N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 101.1 %

Procedure:
To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-bromopropyl]benzenesulfonamide (1.64 g, 3.27 mmol) in THF/H2O (20/4, 24 mL) was added sodium azide (2.13 g, 32.7 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was extracted with ether (3×60 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 1.38 g of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzenesulfonamide as a colorless oil in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:4]/[C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10]
Reactant: CC(C)=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1c(Cl)cccc1Cl)/C=C/c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(73) To a 0.33 M solution of 2,6-dichlorobenzaldehyde (1.75 g, 10 mmol) and acetone (290 mg, 5 mmol) in 30 ml of ethanol was added 5 ml of 40% potassium hydroxide at 10° C. After stirring for 18 hr at room temperature, a solid precipitated and was filtered. The precipitate was recrystallized from ethanol to afford 1.46 g (78.5%) of pale yellow, cotton-like flakes: mp 154.0-154.4° C. (lit. mp 145-146° C., Unterhalt, Arch. Pharm., 1978, 311, 262-267). 1H NMR (250 MHz) δ 7.85-7.79 (d, 2 H), 7.40-7.36 (d, 4 H), 7.26-7.19 (d, 2 H), 7.24-7.18 (m, 2 H); 13C NMR (62.7 MHz) 189.1, 137.6, 135.4, 133.3, 132.5, 130.2, 129.1 ppm.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[CH:20]=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:24])N.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+]>O1CCOCC1.O>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20]([OH:24])=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carbaldehyde G1 (0.55 mmol) in dioxane (6.8 mL) and water (2.4 mL), sulfamic acid (0.9 mmol) and sodium dihydrogen phosphate (2.33 mmol) were added. The mixture was cooled to 0° C. and sodium chlorite (0.95 mmol, dissolved in the minimum amount of water) was added. Other two additions of an equal amount of oxidant were made during 24 h of stirring, then the reaction was filtered and the solid product was washed with water and dried, resulting in 94% yield of the title compound. ESI (+) MS: m/z 289 (MH+); MS (ES−) 287. 1H NMR: 7.35-7.41 (m, 1H), 7.45-7.56 (m, 4H), 7.96 (d, J=9.00, 1H), 8.58 (d, J=9.00, 1H), 8.68 (d, J=5.17, 1H), 8.78 (d, J=5.17, 1H), 9.57 (s, 1H), 11.47 (bs, 1H), 13.54 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:12]([C:3]2[C:2]([OH:1])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:14])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc2ccccc2cc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc2ccccc2cc1O

Procedure:
Using 3-hydroxynaphthalene-2-carboxylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([OH:19])=[C:16]([C:20]#[N:21])[C:15](=[O:22])[NH:14][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:17]([OH:19])=[C:16]([C:20]#[N:21])[C:15](=[O:22])[NH:14][C:13]=3[S:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1c(O)c2c(-c3ccc([N+](=O)[O-])cc3)csc2[nH]c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1c(O)c2c(-c3ccc(N)cc3)csc2[nH]c1=O
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(4-nitrophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.054 g, 0.173 mmol) and ammonium chloride (0.007 g, 0.138 mmol) in ethanol: water mixture (2:1, 24 mL) was added iron powder (0.097 g, 1.73 mmol) in a single portion. The reaction mixture was heated at reflux for 16 hours, cooled to room temperature, filtered and the filtrate concentrated under reduced pressure. The residue was taken up in DMSO/MeOH and purified by RP-HPLC. MS (ESI) m/e 281.7 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 11.65 (br s, 1H), 7.31 (d, 2H), 6.88 (d, 2H), 6.74 (s, 1H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([O:23][CH3:24])=[O:22].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Methyl androst-4-ene-3-one-17β-carboxylate (10 g, 30.3 mmol, prepared according to Rasmusson, et al., J. Med. Chem. 27 1960 (1984)) and chloranil (8.95 g, 36.4 mmol) in 700 ml t-butanol was heated at reflux for 3.5 hours then cooled and filtered. The filtrate was concentrated and the residue taken up in 700 ml chloroform and washed successively with 4×150 ml water, 3×150 ml saturated sodium bicarbonate, 3×150 ml 5% sodium hydroxide, 3×150 ml brine, dried over sodium sulfate, and concentrated to yield methyl androst-4,6-diene-3one-17β-carboxylate as a dark foam (7.0 g, 70%).
Reaction SMILES: [CH3:1][OH:2].[Br:3][C:4]1[CH:11]=[C:10](F)[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[CH:11]=[C:10]([O:2][CH3:1])[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Br)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methanol (0.28 mL, 6.9 mmol) and 4-bromo-2,6-difluorobenzonitrile (1500 mg, 6.88 mmol) in THF (34 mL) was added NaHMDS (6.88 mL, 1.0 M in THF, 6.88 mmol) at 0° C. The reaction mixture was stirred at rt overnight, and diluted with brine, extracted with EtOAc. The organic layer was dried, and evaporated. The crude product was purified by column chromatography (0-30% EtOAc/Hex) to give 4-bromo-2-fluoro-6-methoxybenzonitrile.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]1([NH:22][S:23](Cl)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:16]1([NH:22][S:23]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:11][CH2:12]2)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)Nc1ccccc1
Reactant: BrCCCCCCOC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1)N1CCC(OCCCCCCBr)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 135.2 %

Procedure:
A solution of 3 g (10 mmol) 4-(6-Bromo-hexyloxy)-piperidine hydrochloride and 3.44 g (18 mmol) of Phenylsulfamoyl chloride in 100 ml dry CH2Cl2 was treated with 6.95 ml (49.9 mmol) of triethylamine. The reaction was stirred for 4 h at RT, diluted with CH2Cl2 and washed with water. The organic phase was dried (MgSO4) and evaporated to yield 5.67 g (quantitative) of 4-(6-Bromo-hexyloxy)-piperidine-1-sulfonic acid phenylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24].CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][CH2:14][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COc1ccccc1CCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCc2ccccc2OC)cc1

Procedure:
A mixture of 14.5 g. of ethyl p-aminobenzoate, 10 g. of 1-bromo-3-(o-methoxyphenyl)propane and 50 ml. of hexamethylphosphoramide is heated at 130° C. for 15 hours, cooled and diluted with 20 ml. of water. The mixture is chilled, diluted with 50 ml. of cold ethanol:H2O (1:1) and filtered. The solid is washed with three 50 ml. portions of cold ethanol-water (1:1) and with water to give crystals, m.p. 106°-109° C. Recrystallization from ethanol (100 ml.) gives yellow crystals, m.p. 111°-113° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=O)OC(C)(C)C)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.ClC1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>Cl.O>[CH3:29][Si:2]([CH3:30])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][N:33]=4)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(N3CC[C@@H](Nc4ccc(C#N)cn4)C3)ncnc21
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A solution of (R)-tert-butyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (700 mg, 1.61 mmol) in HCl (in MeOH, 6 N, 5 mL) was stirred at ambient temperature for 3 hours. The volatiles were removed under reduced pressure. The residue was dissolved in DMSO (3 mL). 6-chloronicotinonitrile (323 mg, 2.41 mmol), KI (10 mg, 0.06 mmol) and DIPEA (311 mg, 2.41 mmol) were then added. The reaction mixture was stirred at 120° C. for 14 h, cooled to ambient temperature, diluted with H2O (20 mL), and extracted with EtOAc (3×40 mL). The combined extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 436 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[ClH:22]>C1C=CC=CC=1.CCOCC>[ClH:22].[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])=[O:5])[CH3:18]
Reactant: CCNCC
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCBr
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 1.5 g of 3-bromo-2'-acetyl-6'-methylpropionanilide in 20 ml of benzene was added 0.8 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol gave 3-(diethylamino)-2'-acetyl-6'-methylpropionanilide hydrochloride having a melting point of 124° to 126° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19].CCCCCC>CN(C=O)C>[CH2:22]([O:21][C:18]([C:19]1[O:10][C:7]2[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH3:11])[C:4]=2[CH:5]=1)=[O:20])[CH3:23]
Reactant: Cc1c(Br)ccc(O)c1C=O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc2c(C)c(Br)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-Bromo-6-hydroxy-2-methyl-benzaldehyde (6.8 g, 0.032 mol)) in anhydrous DMF (50 ml) was added potassium carbonate (13.1 g, 0.095 mol) and cooled to 0° C. Bromo ethyl acetate (7.1 ml, 0.063 mol) was added slowly. The reaction mixture was stirred for one hour at 0° C. The completion of the reaction was confirmed by TLC. The reaction mixture was then heated to 100° C. and maintained for 2 hours. After cooling to room temperature, ice water (250 ml) was added and the mixture was stirred for 20 minutes. The solid separated was filtered, washed with water (100 ml) and dried under vacuum, to get crude product. Column chromatography using 2/5 ethyl acetate/hexane yielded 5-Bromo-4-methyl-benzofuran-2-carboxylic acid ethyl ester (6.2 g, 69.6%)
Reaction SMILES: CS([C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=2[N:9]=1)(=O)=O.[NH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[O:34][CH3:35])=[O:25])[CH2:20]1>>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=1[C:24]([N:21]1[CH2:22][CH2:23][C@@H:19]([NH:18][C:5]2[S:6][C:7]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=3[N:9]=2)[CH2:20]1)=[O:25]
Reactant: CS(=O)(=O)c1nc2cc(C(F)(F)F)ccc2s1
Reactant: COc1cccc(OC)c1C(=O)N1CC[C@@H](N)C1
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](Nc2nc3cc(C(F)(F)F)ccc3s2)C1

Procedure:
In analogy to the procedure described for example 202, step 4, the title compound was prepared from 2-methanesulfonyl-5-trifluoromethyl-benzothiazole and ((R)-3-Amino-pyrrolidin-1-yl)-(2,6-dimethoxy-phenyl)-methanone (Intermediate 5). (M+H+) 452.2.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[O:8][C:9](=[O:20])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O-:19])=[O:18])[CH:11]=2.[Na+].[CH3:22]O>O>[CH3:6][C:7]1[O:8][C:9](=[O:20])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH3:22])=[O:18])[CH:11]=2
Reactant: Cc1cc2ccc(C(=O)[O-])cc2c(=O)o1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2cc(C)oc(=O)c2c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Concentrated sulfuric acid (3 mL) was added to a mixture of sodium 3-methyl-1-oxo-1H-isochromene-7-carboxylate (1.69 g) and methanol (50 mL), and heated under stirring in an oil bath at 60° C. for 2 days. The reaction mixture was returned to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain methyl 3-methyl-1-oxo-1H-isochromene-7-carboxylate (1.0 g).