Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](C1C=CC(O)=CC=1)([CH3:3])[CH3:2].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[CH3:13][C:11]1([CH3:14])[C:15]2[C:20](=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:1]([CH3:3])([CH3:2])[CH2:12]1
Reactant: CC(C)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
68 g (1/2 mol) of 4-isopropyl-phenol, 150 g (1 mol) of 4-tert.-butyl-phenol and 30 g of an acid activated Fuller's earth were stirred for 5 hours at 150°C. The substance which collected in the deep cooling condenser was isobutane. After removal of the catalyst by suction filtration, fractional distillation yielded 46 g of 1,1,3,3-tetramethyl-5-hydroxy-indane in addition to phenol.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]=[O:7].[CH3:8][C:9]1[C:18]2([CH2:20][CH2:19]2)[C@:17]([OH:22])([CH3:21])[C:15](=[O:16])[C:14]2[C:10]=1[C@@H:11](O)[C@@:12](CO)([CH3:23])[CH:13]=2>CC(C)=O>[CH3:23][C:12]1[CH:13]=[C:14]2[C:10](=[C:9]([CH3:8])[C:18]3([C@:17]([OH:22])([CH3:21])[C:15]2=[O:16])[CH2:20][CH2:19]3)[C:11]=1[CH2:6][OH:7]
Reactant: C=O
Reactant: CC1=C2C(=C[C@@](C)(CO)[C@@H]2O)C(=O)[C@](C)(O)C12CC2
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1=C(CO)C2=C(C)C3(CC3)[C@@](C)(O)C(=O)C2=C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.2 %

Procedure:
To a solution of 250 ml of 1M H2SO4 and 200 ml acetone was added 40 g paraformaldehyde (MW 30, 1.33 mol). The solution was heated to clear and was then allowed to cool to room temperature. 1 g illudin S (MW 264, 3.79 mmol) was added to the above solution. The mixture was stirred at room temperature for 72 h and was partitioned between ethyl acetate and water. The organic extracts were washed by saturated NaHCO3 and saline respectively to neutral. After being dried by MgSO4, the solution was concentrated and chromatographed to give 245 mg 14 (23.4%) and 226 mg HMAF (24.3%). 14 is a white crystal: mp 100.5-102.5; IR (KBr) 3469, 2966, 2858, 1703, 1656, 1596, 1172 cm−1; 1H NMR (CDCl3) δ 0.48 (m, 1H), 0.84 (m, 1H), 0.99 (m, 1H), 1.10 (s, 3H), 1.17 (m, 1H), 1.32 (s, 3H), 1.67 (s, 3H), 3.61 (s, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.96 (d, J=11.7 Hz, 1H), 4.56 (s, 1H), 4.75 (d, J=5.4 Hz, 1H), 4.91 (d, J=5.4 Hz, 1H), 6.52 (s, 1H); 13C NMR (CDCl3) δ 199.7, 141.4, 136.5, 135.9, 134.7, 90.0, 80.3 75.9, 70.8, 46.8, 32.3, 24.7, 22.5, 13.8, 8.9, 5.6; MS m/z 276 (M+), 217, 201, 173; HRMS for C16H20O4 calcd 276.1362. found 276.1364. UV λmax 305 nm (ε 3148).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>>[Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: CN(C)CCCl
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)c1
Product: Cc1cccc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2Br)c1

Procedure:
The title compound was prepared essentially as described in Example 117 except that the compound of Example 126 was reacted with 2-(N,N-dimethylamino)ethyl chloride. mp 71° C., NMR, IR, MS 464, 466.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.[Br:18]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Yield: 76.1 %

Procedure:
To a mixture of compound from step A (2 g, 8.61 mmol) and N-bromosuccinamide (1.84 g, 10.33 mmol) in carbon tetrachloride (50 ml) was added benzoyl peroxide (209 mg, 0.86 mmol) and the resulting mixture heated at reflux for 4 h. The reaction mixture cooled and filtered through celite, and filtrate evaporated. The residue purified by MPLC (Biotage Horizon: FLASH 40+s) eluent: 100% Hexanes (190 ml), gradient rising from 100% hexanes to 10% EtOAc in Hexanes (1000 ml), then 10% EtOAc in Hexanes (250 ml) to afford the title compound 2.04 g (76%). 1H NMR (CDCl3): 1.75 (s, 9H), 4.82 (s, 2H), 7.39 (m, 1H), 7.58 (m, 1H), 7.87 (d, J 8.0 Hz, 1H), 8.15 (d, J 8.5 Hz, 1H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([B:12](O)O)[CH2:9][CH2:10][CH3:11]>C(Cl)Cl.CCOCC>[CH2:8]([B:12]1[O:7][CH2:6][CH2:5][NH:1][CH2:2][CH2:3][O:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2′-azanediyldiethanol (26.12 g, 246 mmol) in DCM (250 ml) and ether (500 mL) was added n-butylboronic acid (25.4 g, 242 mmol) and molecular sieves (3 A, 4-6 mesh, 65 g). It was stirred at ambient temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting white solid was recrystallized with DCM/ether to provide white crystals as the title product. NMR (300 MHz, CDCl3): δ 0.47 (t, J=9 Hz, 2H), 0.88 (t, J=6 Hz, 3H), 1.20-1.37 (m, 4H), 2.82 (br, 2H), 3.24 (br, 2H), 3.95 (br, 4H), 4.27 (br, 1H). MS (DCI—NH3) m/z 172 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCNC1
Product: COC(=O)c1cccc(N2CCCC(COCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 79.4 %

Procedure:
Using 3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxymethyl]piperidine (62.2 mg, 0.185 mmol) and 3-(methoxycarbonyl)phenylboric acid (66.6 mg, 0.370 mmol), the same procedure was followed as in Example 2 to obtain 69.2 mg (79%) of the desired compound as a colorless oil.
Reaction SMILES: C(OC(=O)[N:7]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([NH:26][C:27]([CH3:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:30])[CH2:10][CH2:9]1)(C)(C)C.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([NH:26][C:27]([CH3:29])=[O:28])[CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:30])[CH2:10][CH2:9]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-acetamino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting solid was recrystallized in methanol-ethyl acetate to give 18 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-acetaminoquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:45])[C@@H:15]([NH:37]C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:46]>O1CCOCC1>[ClH:46].[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:45])[C@@H:15]([NH2:37])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1

Procedure:
A solution of 900 mg 4-[(S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester in 5 ml dioxane and 5 ml HCl (4 M in dioxane) was stirred for 3 h at RT. After this time the reaction mixture was neutralized with (Polystyryl-methyl)trimethylammonium bicarbonate, the suspension filtered, washed with ethyl acetate and the wash solutions evaporated to give the crude product. Yield: 760 mg.
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[CH:6]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=1[OH:37])([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[OH:22])[CH3:7].C(N(CC)CC)C>>[C:29]([C:27]1[CH:26]=[C:25]([C:33]([CH3:34])([CH3:36])[CH3:35])[C:24]2[O:37][Si:2]([CH3:4])([CH3:3])[O:22][C:9]3[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:8]=3[CH:6]([CH3:7])[C:23]=2[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2O[Si](C)(C)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Yield: 78.5 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 25.8 grams (0.20 mole) of dichlorodimethylsilane, 87.7 grams (0.20 mole) of 2,2'-ethylidene-bis(4,6-di-t-butylphenol) and 40.5 grams (0.40 mole) of triethylamine. Recrystallization from acetonitrile-toluene yields 77.7 g (79% yield) of product as white needles, mp 171°-177° C.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C>C1(C)C=CC=CC=1>[OH:5][CH2:4][C:3]1[C:2](=[O:1])[NH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccnc1O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=c1[nH]cccc1CO
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of 2-hydroxynicotinic acid (3-067-01) (5.0 g) in toluene (70 mL), and to the reaction mixture were added hexamethyldisilazane (HMDS, 19 mL) and chlorotrimethylsilane (TMSCl, 0.23 mL), and the reaction mixture was heated under reflux. After stirring for 2 h, the solvent was removed, and toluene was added to the residue. To the reaction mixture was added diisobutylaluminium hydride (DIBAL, 2 M toluene solution, 90 mL) at −78° C., after stirring for 4 h, the reaction was quenched with methanol. The insoluble substance was filtered off on Celite, and the filtrate was evaporated under reduced pressure. To the residue were added water and ethyl acetate, and the organic layer was separated, and then the aqueous layer was extracted with three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate, and evaporated to give 3-hydroxymethyl-2(11)-pyridone (7-008-01) (2.6 g, 59%) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][Sn:8]([CH3:11])([CH3:10])[CH3:9])=O)C.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:4]([CH2:6][CH2:7][Sn:8]([CH3:11])([CH3:10])[CH3:9])=[O:3])[NH2:13]
Reactant: NN
Reactant: CCOC(=O)CC[Sn](C)(C)C
Solvent: CCO
Product: C[Sn](C)(C)CCC(=O)NN
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A mixture of 8 g (30 mmoles) of 2-(ethoxycarbonyl)-ethyltrimethylstannane (compound 47), 5 ml of 95% hydrazine (150 mmoles) in 10 ml of ethanol was refuxed for 2 hours. The volatiles were removed at reduced pressure. Distillation of the crude product afforded 5.26 g of 2-(hydrazinocarbonyl)ethyltrimethylstannane, b.p. 92°-98° C. (0.07 mm), compound 42 of Table I. The infrared spectrum of the distillate showed the following characteristic absorptions: 3300 cm-1 (N-H), 1660 cm-1 and 1530 cm-1 ##STR22## and 760 cm-1 (--Sn(CH3)3). A gas chromatogram of the sample showed a single peak on a 6'×1/8" commercially obtained column packed with 10% on silicone gum rubber on silanized diatomaceous earth. The NMR spectrum exhibited the following proton absorptions: a broad singlet at 752 Hz (1 proton) assigned to N-H, a singlet at 388 Hz (2 protons) assigned to NH2, a triplet centered at 235 Hz (2 protons) assigned to ##STR23## a triplet centered at 98 Hz (2 protons) assigned to CH2 -Sn, and a singlet centered at 6 Hz (9 protons) assigned to Sn(CH3)3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:22]([F:23])([F:25])[F:24])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1F
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.101) (0.415 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.37 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1cc(F)ccc1F
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(F)ccc4F)cc3)c2cc1OC
Yield: 87 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) was dissolved in toluene (10 ml) with heat, 2,5-difluorophenyl isocyanate (120 μl) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and then washed with toluene to obtain 132 mg of the title compound (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[OH:16])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>CC(=O)CC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:23][CH:25]2[O:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(Cl)nn2)c(OCC2CO2)c1

Procedure:
A stirred mixture of 3-chloro-6-(2-hydroxy-4-methoxyphenyl)pyridazine (0.1 mole), potassium carbonate (0.3 mole) and epibromohydrin (0.4 mole) in butan-2-one was heated under reflux overnight. The filtered solution was evaporated to give an oil which was purified by elution with mixtures of chloroform-methanol on a silica column to give 3-chloro-6-[2-(2,3-epoxypropoxy)-4-methoxyphenyl]pyridazine m.p. 111°-112° (ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[N-:34]=[N+:35]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN1c2ncc(CCc3cccc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(CCc3cccc(N=[N+]=[N-])c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
8-[2-(3-Aminophenyl)ethyl]-2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.22 g, 0.54 mmol) was dissolved in 0.55 mL of concentrated hydrochloric acid. Water (2.8 mL) was added and the solution was cooled to 0° C. producing a precipitate. A solution of sodium nitrite (0.19 g, 2.75 mmol) in 8 mL of water was added dropwise. After 20 min, a solution of sodium azide (0.27 g, 4.15 mmol) in 3 mL of water was added in the dark. After 15 min, the product was extracted with ethyl acetate. Purification by flash chromatography, eluting with ethyl acetate/hexanes, and recrystallization (ether/petroleum ether) afforded 0.17 g of the title compound, m.p. 104°-105° C.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:16]O>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:3]([C:4]([O:6][CH3:16])=[O:5])=[CH:7][CH:8]=[CH:9][NH:10]1
Reactant: CO
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc[nH]c1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
To a flask is added 2-hydroxynicotinic acid (10 g, 72 mmol), concentrated H2SO4 (2 mL) and MeOH (400 mL), followed by toluene (80 mL). The reaction mixture is heated to reflux overnight with a Dean-Stark trap. After cooling to RT, the mixture is filtered and the filtrate is concentrated. The residue is dissolved in DCM (200 mL), neutralized with saturated aqueous NaHCO3 to pH 7 and extracted with DCM (200 mL) for three times. The combined organic phases are dried and concentrated to give the desired product (8.2 g, 74% yield). MS (m/z): 153.9 (M+H).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[Br:10][CH2:11][C:12](Br)=[O:13]>ClCCl.O>[Br:10][CH2:11][C:12]([N:3]1[CH2:4][CH:5]2[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:13]
Reactant: O=C(Br)CBr
Reactant: C1CC2CCC1CNC2
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 3-azabicyclo[3.2.2]nonane (1.25 g) in dichioromethane (20 ml) and water (0.75 ml) was added dropwise a solution of bromoacetyl bromide (2.02 g) in dichloromethane (10 ml) at, 5°-10° C. The mixture was allowed to warm to room temperature and stirred for 1 hour at the same temperature. The reaction mixture was washed with a saturated sodium bicarbonate aqueous solution (10 ml) and a brine (10 ml). The organic layer was dried over magnesium sulfate. Filtration and evaporation gave N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (1.15 g). The compound was used in a following reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:30])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][CH2:22]1)#[CH:20]>>[OH:30][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][CH2:22]1
Reactant: C#CC1(O)CCc2cccnc21
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCc4cccnc43)ccc1OCC2

Procedure:
The title compound was prepared similarly according to Procedure E by reacting 10-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide with 7-ethynyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol. 1H NMR (500 MHz, DMSO) δ 2.30-2.43 (1H, m), 2.54-2.61 (1H, m), 2.83-2.95 (1H, m), 2.96-3.07 (1H, m), 4.49 (4H, s), 6.21 (1H, br. s.), 7.03 (1H, d, J=8.51 Hz), 7.14 (1H, br. s.), 7.24-7.36 (2H, m), 7.57 (1H, br. s.), 7.73 (1H, d, J=7.41 Hz), 7.80 (1H, s), 8.46 (1H, d, J=4.26 Hz), 8.53 (1H, d, J=2.05 Hz); LC-MS: m/z=387.10 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Oc1cccc(Br)c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCCN2CCCC2)c1
Reaction time: 48 h
Yield: 43.1 %

Procedure:
3-bromo-phenol (5.34 g, 30.9 mmol, 1 equiv), 1-(2-chloro-ethyl)-pyrrolidine (5.24 g, 30.9 mmol, 1 equiv) and potassium carbonate (K2CO3) (34 g, 24.7 mmol, 8 equiv) were weighed out into a 500 mL round bottom flask, were diluted with 150 mL DMF and stirred for 2 days. The contents were poured onto ethyl acetate water mixture and extracted once. The organic layer was separated, washed with brine and dried over sodium sulfate (Na2SO4). Filtration followed by concentration provided crude product as a pale yellow oil. Column chromatography (1:9 ethyl acetate/hexanes) provided desired product as a yellow oil (3.6 g, 43% yield). 1H NMR (DMSO-d6): δ 1.65-1.69 (m, 4H), 2.72 (s, 1H), 2.75 (t, J=5.8 Hz, 2H), 2.88 (s, 1H), 4.06 (t, J=5.8 Hz, 2H), 6.95 (dd, J=8.35 Hz, 1H), 7.11 (d, J=7.7, 1H), 7.13-7.14 (m, 1H), 7.22 (t, J=8.1 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]([CH2:15][OH:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:30][S:31]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[OH:16][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][S:31]([CH3:30])(=[O:32])=[O:33])=[CH:40][CH:39]=2)[C:3]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][C:5]=1[C:18]([F:21])([F:20])[F:19])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CC(CO)NC(=O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CC(C)CC(CO)NC(=O)c1cc(-c2ccc(NS(C)(=O)=O)cc2)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-(1-hydroxymethyl-3-methyl-butyl)-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinamide and 4-methanesulfonylaminophenylboronic acid as starting materials, MS (ISP) 567.2 (M)+.
Reaction SMILES: [Na].C(=O)(O)O.[NH2:6][C:7]([NH2:9])=[NH:8].[NH:10]([CH:17]=[C:18]([C:33]#N)[CH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[C:23]([NH:24]C=O)=[C:22]([O:31][CH3:32])[CH:21]=1)C1C=CC=CC=1>O>[NH2:8][C:7]1[N:9]=[C:17]([NH2:10])[C:18]([CH2:19][C:20]2[CH:21]=[C:22]([O:31][CH3:32])[C:23]([NH2:24])=[C:27]([O:29][CH3:30])[CH:28]=2)=[CH:33][N:6]=1
Reactant: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC=O
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [Na]
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Reaction time: 2 h

Procedure:
A solution of 1.84 g. of sodium in 200 ml. of absolute alcohol was treated with 14.4 g. of guanidine carbonate and 8.9 g. of 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-formanilide and refluxed for 20 hours. Then, 200 ml. of water were added and the alcohol was removed under vacuum. After standing at room temperature for 2 hours, the crystals formed were removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine having a melting point of 215°-216° C.