Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[NH:25][C:24]2=[O:32])=[CH:19][CH:18]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CN(CCN(C)C)C>C1COCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[NH:25][C:24]2=[O:32])=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(-n3c(=O)[nH]c4cccnc43)cc2)nc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 50 °C
Yield: 34.5 %

Procedure:
A mixture of 3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg), 1 M TBAF in THF (6.3 mL), and TMEDA in THF (20 mL) was heated at 50° C. for 24 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/3 then AcOEt/MeOH=95/5). The obtained product was recrystallized from MeOH-iPr2O to give 3-[4-(1H-benzimidazol -2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg) as white crystals.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C@@H:18]([CH2:21]OS(C)(=O)=O)[O:17][C:16]=3[CH:27]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C@@H:18]([CH2:21][NH:2][CH3:1])[O:17][C:16]=3[CH:27]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN
Reactant: CS(=O)(=O)OC[C@@H]1COc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Solvent: CO
Product: CNC[C@@H]1COc2ccc(S(=O)(=O)c3ccccc3)cc2O1

Procedure:
A 2M solution of methyl amine in methanol (10 mL) and methansulfonic acid 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(S)-yl-methyl ester (0.87 g, 2.26 mmol) were heated in a microwave at 100° C. for 3 hours. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluting with dichloromethane—methanol; 98:2, v/v) to give (7-Benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-ylmethyl)-methyl-amine as a white solid (0.557 g; 77%), which was converted to a hydrochloride salt: MS (M)+ 319; m. p. 240.0-243.6° C., [α]=+40.5° (methanol; c=1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([F:32])=[N:34][CH:35]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccc(F)nc6)cn5n4)c3)c2)CC1
Yield: 19.5 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), 6-fluoronicotinic acid (61 mg, 0.438 mmol), oxalyl chloride (64 μL, 0.730 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (38 mg, 20%) was obtained as a pale-green powder.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].C(Cl)(=O)C>>[CH:1](=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH3:2]
Reactant: CCC1(O)c2ccccc2C=Cc2ccccc21
Solvent: CC(=O)Cl
Product: CC=C1c2ccccc2C=Cc2ccccc21

Procedure:
5-Ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene (13.7 g., 0.058 mole) is dissolved in 80 ml. of acetyl chloride and the solution heated to refluxing for 90 minutes. The acetyl chloride is evaporated under reduced pressure and the residue dissolved in benzene. After washing with alkali followed by a water wash, the benzene is removed and the product distilled under reduced pressure. The desired 5-ethylidene-5H-dibenzo[a,d]cycloheptene is obtained as the fraction boiling at 130°-135°C. (0.02 mm.). It crystallized on cooling. The compound was purified further by recrystallization from 95% alcohol.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C.C(Cl)Cl>[N:8]1([C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][OH:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrCCCCCBr
Reactant: N[C@@H](CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: OC[C@@H](c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 138.3 %

Procedure:
A suspension mixture of (R)-(-)-2-phenylglycinol(686 mg, 5 mmol), 1,5-dibromopentane (0.82 ml, 6 mmol), and K2CO3 (1.38 g, 10 mmol) in ethanol (15 ml) was refluxed with stirring for 23 h. After cooling down to rt, the white solid was removed by filtration and the filtrate was concentrated to give white solid oil mixture. This was suspended in CH2Cl2 (30 ml), washed with water and saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give 1.42 g of clear yellow oil. This was purified by column chromatography (silica gel: 50 g, CH2Cl1 /MeOH:30/1 to 20/1) to afford 955 mg (93%) of desired compound as clear light yellow oil.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[C@@H:18]([CH2:29][O:30]C(=O)C)[O:17][C@@H:6]1[S:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:6]1[O:17][C@H:18]([CH2:29][OH:30])[C@@H:19]([OH:25])[C@H:20]([OH:21])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCCc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@H](SCCCc2ccccc2)[C@@H](O)[C@@H](O)[C@@H]1O
Yield: 92.1 %

Procedure:
Compound 6 (500 mg) is deacetylated with sodium methoxide in methanol to give 7 (300 mg, 92%): m.p. 122°-123° C. (H2O); [α]D27 +185.4±0.9° (C, 1.06, methanol).
Reaction SMILES: [C:1]([C@:3]1([OH:24])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[CH:11]=[CH:10]3)#[CH:2].C(Cl)CCl.ClC1C=CC=C(C(OO)=[O:37])C=1.C(O)(C)(C)C>C(OCC)(=O)C>[C:1]([C@:3]1([OH:24])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[C@H:11]1[O:37][C@@H:10]31)#[CH:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
750 mg. of 17α-ethinyl-11β-fluoro-17β-hydroxy-4,6-androstadien-3-one in 50 ml. of ethylene chloride is combined with 1.2 g. of m-chloroperbenzoic acid in 5 ml. of tert.-butanol and 1 ml. of ethylene chloride. The mixture is agitated at room temperature for 21 hours. The solution is then diluted with ethyl acetate and washed successively with sodium bisulfite solution and water. In this way, 420 mg. of 17α-ethinyl-6α,7α-epoxy-11β-fluoro-17β-hydroxy-4-androsten-3-one is isolated. UV: ε239 = 16,300 (methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].Cl.[CH2:24](O)[CH3:25]>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([O:8][CH2:24][CH3:25])=[O:7])[CH3:2]
Reactant: CCO
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCC
Yield: 45.5 %

Procedure:
To a suspension of 2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)benzoic acid (16.4 g, 0.05 mol, see EP 812 845) in ethanol (160 mL) was added concentrated hydrochloric acid (12.5 mL, 0.15 mol), which gave a solution on stirring. The solution was heated to reflux for 25 hours and then allowed to cool. It was concentrated under vacuum to give an orange oil which gave crystals on cooling. These were collected by filtration to give 13.7 g of crude product, which was purified by recrystallisation in acetonitrile to give 8.1 g of product as fine white crystals (45.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:17]=[C:16]([N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=3[N:28]=[C:27]2[CH:37]([F:39])[F:38])[N:15]=1>C1COCC1.C(O)(=O)C.O>[F:39][CH:37]([F:38])[C:27]1[N:26]([C:16]2[N:17]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:19]=[C:14]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[N:15]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=2[N:28]=1
Reactant: Nc1cncnc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cncnc2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To 0.207 g (2.18 mmol) of 5-aminopyrimidine in THF (4 mL) was added 0.96 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture stirred for 10 min. A solution of 0.260 g (0.66 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent, followed by chromatography on silica eluting with hexanes/EtOAc (1:1) gave a yellow powder. Recrystallization from ethanol/CH2Cl2 gave 0.068 g (20% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amine: mp 293-295° C.; 1H NMR (CDCl3) δ 9.07 (s, 2H), 9.01 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.48 (t, JHF=53.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.95-3.90 (m, 4H), 3.82-3.81 (m, 4H); Anal. Calcd. for C20H19F2N9O2: C, 52.75; H, 4.2; N, 27.7. Found: C, 52.9; H, 4.2; N, 27.7%.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[CH2:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([Cl:19])=[O:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1Cc1ccccc1

Procedure:
To a solution of α-phenyl-o-toluic acid (4 g, 18.28 mmol) in dry CH2Cl2 (30 mL) was added thionyl chloride (5 mL, 68.50 mmol), followed by a drop of dry DMF. The reaction mixture was refluxed for 5 hr. The solvent and excess SOCl2 was removed in vacuo to give 2-benzyl-benzoyl chloride 18 as a pale yellow oil which was used directly in next step.
Reaction SMILES: [C:1]([C:9]1[C:10]([O:20]C(=O)C)=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:29]O>>[CH3:29][O:18][C:16](=[O:17])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[OH:20])[CH3:19]
Reactant: CC(=O)Oc1c(C(=O)c2ccccc2)cccc1C(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1O
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 2-(3′-benzoyl-2′-acetoxyphenyl)propionic acid (1) (6.2 g) in methanol (35 ml) was added wish concentrated H2SO4 (0.3 ml). The mixture was stirred at room temperature for 15 hours until disappearance (1) and of the reaction intermediates. The solvent was evaporated off under vacuum and the residue was dissolved in ethyl acetate (30 ml) and washed with water. The organic layer was treated with a NaOH solution (100 ml), and the basic phase was acidified with 4N HCl and extracted with ethyl acetate (2×25 ml). The collected organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum. The crude product (4.3 g) was dissolved in isopropyl ether (5 ml) and the slightly yellow precipitate was filtered. n-Hexane (25 ml) was added to the residue and the mixture was stirred overnight. After filtration, 3.2 g of (2) were obtained (0.11 mol; 70% yield starting from 4) as a whitish solid (melting point 108-111° C.).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1.Cl>O>[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH:13]1[S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9]
Reactant: O=S([O-])c1ccccc1
Reactant: CC1C=CC(=O)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1CCC(=O)CC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
Benzenesulfinic acid sodium salt (3.0 g) was added to a solution containing 1.52 g of 4-methyl-2-cyclohexene-1-one and 9 ml of water. 1N Hydrochloric acid (18 ml) was added dropwise to the resulting solution. After stirring at room temperature for 24 hours, the crystals so precipitated were filtered and washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 4-methyl-3-(phenylsulfonyl)-cyclohexan-1-one (m.p.: 71–74) was obtained in the form of white crystals. Yield: 72%
Reaction SMILES: [CH:1]1([CH2:12][CH2:13][C:14](O)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH2:12][CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCC1CCCCCCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCC1CCCCCCCCCC1

Procedure:
The starting material 3-cycloundecylpropan-1-ol is obtained as follows: hydroxymethylcycloundecane is reacted with thionyl chloride to give chloromethylcycloundecane, which is reacted with malonic acid diethyl ester in the presence of sodium ethylate to give (cycloundecylmethyl)-malonic acid diethyl ester, which, after saponifying the ester group and decarboxylating the corresponding malonic acid, gives 3-cycloundecylpropionic acid. 3-Cycloundecylpropionic acid is reduced with lithium aluminum hydride in tetrahydrofuran to give 3-cycloundecylpropanol.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][CH:5]=1.Cl.[NH2:27][OH:28].C[O-].[Na+].CO>CN(C=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:23]1[C:24]2[N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][OH:28])=[O:2])=[CH:5][CH:6]=3)[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CCn2c3ccccc3c3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccc(CCn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.6 %

Procedure:
4-(2-Carbazol-9-ylethyl)benzoic acid methyl ester (27) (0.15 g, 0.46 mmol) and hydroxylamine hydrochloride (0.19 g, 2.7 mmol) were placed under argon and dissolved in DMF (3 mL). To this was added a 25% sodium methoxide solution in methanol (0.79 g, 3.6 mmol) which resulted in immediate precipitation of a white solid. The reaction was stirred for 24 h at room temperature after which it was taken up in 20 mL ethyl acetate and 20 mL of saturated sodium bicarbonate. The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude extract was purified by HPLC to yield the title compound (10 mg, 7%) as an off-white solid. 1H NMR (400 MHz, DMSO): δ 11.14 (br, 1H), 8.14 (d, 2H, J=7.8 Hz), 7.62 (m, 4H), 7.40 (m, 4H), 7.18 (t, 2H, J=7.6 Hz), 4.62 (t, 2H, J=7.0 Hz), 3.11 (t, 2H, J=7.6 Hz). 13C NMR (100 MHz, DMSO): δ 140.2, 129.4, 127.3, 126.1, 122.5, 120.7, 119.2, 109.7, 44.1, 34.7. ESI-HRMS (m/z): [M−H]− calcd. for C21H18N2O2, 329.1298. found, 329.1273. Analytical HPLC: Purity=100%, tR=9.13 min, Method B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>CO.O>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:30])[CH3:29]
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: CC(C)(N)CO
Solvent: O
Solvent: CO
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)(C)CO
Yield: 30 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (25 mg, 30%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=C(C)[N+:13]([O-])=[CH:14][C:15]=1[CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:11]=[C:10]([O:9][CH3:8])[C:15]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][N:13]=1)(=[O:7])[CH3:6]
Reactant: CCCCc1c[n+]([O-])c(C)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCc1cnc(COC(C)=O)cc1OC

Procedure:
20.4 g (0.2 mol) of acetic anhydride are added dropwise to a solution of 19.5 g (0.1 mol) of 4-methoxy-5-n-butyl-2-picoline-N-oxide in 100 ml of toluene over the course of 15 minutes, whilst stirring. Thereafter the mixture is heated for 8 hours under reflux. After evaporation to dryness in vacuo, the mixture is rendered alkaline with 2 N aqueous sodium carbonate solution and is extracted with ether. The ether phases are combined, dried with sodium sulphate, filtered and evaporated. Distillation of the residue in a bulb tube in a high vacuum at 120° yields 2-acetoxymethyl-4-methoxy-5-n-butyl-pyridine.
Reaction SMILES: [K].[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3].[CH3:21]I>CN(C)C=O>[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[N:8]([CH3:21])[C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3]
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 40 ml of dimethylformamide were added 5.0 g of the potassium salt of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 1) and 11.9 g of methyl iodide; the mixture was stirred at room temperature for 16 hours. The mixture was then poured into 150 g of ice water and extracted with benzene. The benzene extract was washed with ice water and then dried over potassium carbonate. After removing the benzene, the residue was chromatographed through a column of silica gel (eluent, ethyl acetate), giving 2.7 g of Compound 2, mp 137° - 142° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:35]5[CH2:36][CH2:37][N:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(C)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 0.04 h
Yield: 21.8 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), 1-Isopropyl-piperazine (164 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 2.5 min under the irradition of microwave. The mixture was filtered over celite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 80 mg of 243. (yield=22%). 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.50-7.44 (m, 1H), 7.09-6.99 (m, 4H), 6.46 (d, J=8.8 Hz, 1H), 4.18-4.12 (m, 2H), 3.42-3.40 (m, 3H), 3.05-3.03 (m, 2H), 2.12-2.06 (m, 2H), 1.56-1.50 (m, 3H), 1.10-1.04 (m, 3H). LC-MS (ESI): m/z=509 [M+H]+
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][C:39]([CH3:42])=[N:40][N:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:38][C:39]([CH3:42])=[N:40][N:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1nnc(Br)s1
Product: Cc1nnc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)s1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-bromo-5-methyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI−): m/z=496 [M+HCOO]−.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[N:20]=1>O1CCCC1>[CH:1]([NH:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[N:20]=1)=[O:3]
Reactant: O=CO
Reactant: NCCSc1ccc2nccn2n1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNCCSc1ccc2nccn2n1
Reaction time: 1 h

Procedure:
On the other hand, 5.52 g of formic acid is added to 12.25 g of acetic anhydride at room temperature and the mixture is stirred at 45°-50° C. for 1 hour. After cooling, 60 ml of tetrahydrofuran and 5.83 g of the above-prepared crystals of 6-(2-aminoethylthio)imidazo[1,2-b]pyridazine are added and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure and the residue made basic with a saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals are collected by filtration to give 2.83 g of 6-(2-formylaminoethylthio)imidazo[1,2-b]pyridazine as colorless crystals melting at 148° to 151° C.