Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)[CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:35])[CH3:34])[CH2:31][CH2:32]4)[CH:26]=3)=[C:4]2[CH:3]=1
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CNc1ncc(I)c2cc(Cl)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncc(-c2cnn(C3CCN(C(C)=O)CC3)c2)c2cc(Cl)oc12
Temperature: 95 °C
Yield: 99.1 %

Procedure:
A mixture of 2-chloro-4-iodo-N-methylfuro[2,3-c]pyridin-7-amine (125 mg, 0.405 mmol), 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (142 mg, 0.446 mmol), (1,1′-bis-(diphenylphosphine)-ferrocene)palladium dichloride (29.6 mg, 0.0405 mmol) and potassium carbonate (140 mg, 1.01 mmol) in 1,4-dioxane (1.35 mL) and water (0.58 mL) was heated to 95° C. for 20 h. The mixture was adsorbed directly onto a dry 5 g silica gel cartridge and purified by ISCO chromatography (0 to 10% methanol:ethyl acetate) to afford 150 mg (99%) of the title compound as a tan solid. 1H NMR (400 MHz, CD3OD): δ 8.06 (s, 1 H), 7.92 (s, 1 H), 7.82 (s, 1 H), 7.05 (s, 1 H), 4.74-4.60 (m, 1 H), 4.51 (tt, J=4.4, 11.5 Hz, 1 H), 4.14-4.00 (m, 1 H), 3.39-3.34 (m, 1 H), 3.05 (s, 3 H), 2.85 (td, J=3.0, 13.0 Hz, 1 H), 2.28-2.11 (m, 5 H), 2.11-1.89 (m, 2 H); MS (ESI): 374.11, 376.08 [M+H]+; HPLC tR=2.29 min (ZQ3, polar—4 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=O)=[CH:5][CH:4]=1.[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N:13]([CH2:14][CH2:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)[CH3:12])=[CH:5][CH:4]=1
Reactant: CNCCC1=CCCCC1
Reactant: COc1ccc(CC=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/N(C)CCC2=CCCCC2)cc1
Yield: 95.3 %

Procedure:
The solution of p-methoxyphenylacetaldehyde in 200 ml of toluene, prepared according to Example la), is added under reflux within one hour to a mixture of 78 g (55.5 mmol) of N-methyl-2-(cyclohexen-1-yl)ethylamine in 20 ml of toluene. After 1 hour under reflux there is obtained N-[(E)-p-methoxystyryl]-N-methyl-2-(cyclohexen-1-yl)ethylamine (yield 95.3%) dissolved in toluene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
A mixture of 6-hydroxy-1-tetralone (50.0 g, 308 mmol), K2CO3 (64.0 g, 434 mmol) and BnBr (58.0 g, 340 mmol) in DMF (400 mL) was stirred at 25° C. for 16 hours. The mixture was diluted in water (1000 mL), extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product as a brown solid (54.0 g, yield 69%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:22])[N:6]2[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:22])[N:6]2[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc2ccccc12
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Yield: 463.7 %

Procedure:
Using the procedure described in Example 1, Part E, 4-hydroxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole (796 mg, 2.8 mmol) was treated with 112 mg (2.8 mmol) of 60% NaH/mineral oil and then 0.27 mL (0.27 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane to give 450 mg (45% yield) of [[2-methyl-1-[(1-naphthalenyl)methyl]-1H-indol-4-yl]oxy]acetic acid methyl ester, 167-171° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7]3([O:32][C@H:8]3[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[NH2:33][CH2:34][CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1.C(O)CCC>COC(C)(C)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([C@H:8]([NH:33][CH2:34][CH2:35][C:36]3[N:40]=[CH:39][NH:38][CH:37]=3)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: NCCc1c[nH]cn1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H]3OC32C1
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H](NCCc3c[nH]cn3)[C@@]2(O)C1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
5,6α-epoxicholestan-3β-yl acetate (9.8 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-yl acetate as a white solid (7.5 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:15][CH2:16][CH:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC(NS(=O)(=O)c1ccccc1)c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(NC(CCN1CCC(Cc2ccccc2)CC1)c1ccccc1)c1ccccc1

Procedure:
4-Benzylpiperidine (54 μL, 0.30 mmol) was added to a stirred solution of N-(3-oxo-1-phenylpropyl)benzenesulfonamide (83 mg, 0.28 mmol) (Example 3 Step 4) in MeOH (1.0 mL) under N2 and sodium cyanoborohydride (40 mg, 0.62 mmol) added. After 4 h the reaction was quenched with water, applied to an SCX-2 cartridge and washed with MeOH and then 2 M NH3 in MeOH solution. The desired fractions were concentrated under reduced pressure and further purified by reversed phase prep-HPLC system to give the title compound as a residue (10 mg, 7%), after isolating the free base. 1H NMR (400 MHz, CDCl3) δ 1.3–2.0 (9H, m), 2.25–2.40 (2H, m), 2.59 (2H, d, J 6.9 Hz), 2.91 (2H, t, J 9.4 Hz), 4.50–4.54 (1H, m), 7.08–7.22 (8H,m), 7.27–7.36 (4H, m), 7.41–7.46 (1H, m), 7.64–7.69 (2H,m). MS (ES+) C27H32N2O2S requires: 448, found: 449 (M+H+)
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21]1=[O:32])[CH:25]=[CH:26][CH:27]=2.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:20]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21]1=[O:32])[CH:25]=[CH:26][CH:27]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCCCCCN1C(=O)c2cccc3cccc1c23)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxyamide 0.49 g, 1.5 mmol) was reacted with benzo[cd]indol-2(1H)-one (0.25 g, 1.5 mmol) in the presence of potassium carbonate (0.2 g, 1.4 mmol) to give 8-(2-oxo-2H-benzo[cd]indol-1-yl)-octanoic acid benzyloxyamide as an amorphous solid (yield 0.12 g, 19%; purified by column chromatography using silica gel and ethyl acetate:heptane=1:1 as an eluent). MS (M+H+)=417.
Reaction SMILES: O[Li].O.C([C@@H]1COC(=O)N1[C:17](=[O:35])[C@@H:18]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1.C[O:37]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:23]([O:22][C:21]([NH:20][CH2:19][C@H:18]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:17]([OH:35])=[O:37])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% 11202 (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes, and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The ice bath was allowed to slowly warm, and the reaction mixture was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added. The mixture was stirred for 5 minutes, and then warmed to room temperature and stirred an additional 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M-BOC+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Fe].C(O)C.O>[NH2:23][C:20]1[CH:21]=[CH:22][C:3]([Cl:2])=[C:4]([CH:19]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2Cl)CC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)ccc2Cl)CC1
Yield: 86.2 %

Procedure:
Iron (1.7 g, 26.7 mmol) and concentrated hydrochloric acid (0.2 mL) were added to ethanol/water (45 mL/45 mL), and refluxed for 1 hour. The mixed reaction solution was added with tert-butyl 4-(2-chloro-5-nitrobenzyl)piperazine-1-carboxylate (1.9 g, 5.34 mmol) obtained in <Step 1> above, and further refluxed for 1 hour. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The resulting filtrate was distilled under reduced pressure and dissolved in ethanol and chloroform/2-propanol=3/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (chloroform:methanol=30:1 (v/v)) to obtain the title compound (1.5 g, 86%).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[N:23]=1
Reactant: Cc1ccnc(N)n1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: Cc1ccnc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Yield: 20.2 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 2-amino-4-methylpyrimidine (8.0 g) as the starting materials, (S)-3-[(4-methylpyrimidin-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (3.0 g) is obtained in the form of white crystals, m.p.=179° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][C:28]=1[O:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][C:28]=2[O:38][CH3:39])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
1-(tert-Butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (40 g, 0.11 mol), (prepared as described for the starting material in Example 1), was added to a suspension of ethyl 4-hydroxy-3-methoxybenzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry DMF (200 ml). After stirring at 95° C. for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight at 5° C. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 4-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxybenzoate (35 g, 89%).
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)=[N:25][N:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:32][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[O:27][C:23]([CH3:22])=[N:24][N:25]=2)=[CH:34][CH:33]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Product: Cc1nnc(-c2ccc(Nc3ccc4ccccc4c3[N+](=O)[O-])cc2)o1
Yield: 70.5 %

Procedure:
1-Nitronaphthalen-2-yl triflate (1.67 g, 5.2 mmol) and 4-(5-methyl-[1,3,4]oxadiazol-2-yl)aniline (0.91 g, 5.2 mmol) were used in a process similar to Example 1(1) to give the titled compound (1.27 g, yield 71%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:28]2[CH:32]=[CH:31][NH:30][N:29]=2)[C:5]2[N:6]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH3:33][O-:34].[Na+].O>CO>[CH3:33][O:34][C:2]1[CH:3]=[C:4]([C:28]2[CH:32]=[CH:31][NH:30][N:29]=2)[C:5]2[N:6]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: NC1(c2ccc(-c3nc4c(-c5cc[nH]n5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(-c2cc[nH]n2)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 36 %

Procedure:
To a solution of 1-{4-[6-chloro-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine that was prepared in a manner analgous to that described for Example 19 (0.14 g, 0.32 mmol) and sodium methoxide (0.051 g, 0.95 mmol, 3.0 equiv) in MeOH (0.8 mL) was irradiated in a microwave apparatus at 120° C. for 90 min. The resulting mixture was added to water 10 mL. The aqueous mixture was extracted with DCM (3×15 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 2.5 min, 50% hexane/50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give an oil which was triturated with MeOH to give 1-{4-[6-methoxy-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutanamine (0.052 g, 36%):
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:11](=[O:21])[C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:13][C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[I-].[K+]>>[CH2:22]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:11](=[O:21])[C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:13][C:6]3=[CH:5][C:4]=2[CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCBr
Reactant: CC1(c2ccccc2)Sc2cc3cc(O)ccc3n2C1=O
Agent: [I-]
Agent: [K+]
Product: CCCCCCOc1ccc2c(c1)cc1n2C(=O)C(C)(c2ccccc2)S1
Yield: 92.5 %

Procedure:
To a solution of 7-hydroxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one (2.86 g), n-hexyl bromide (1.76 g) and a small amount of potassium iodide, and the mixture was heated and refluxed for 33 hours. The reaction mixture was allowed to cool. Then insoluble matter was filtered. The solvent was evaporated off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (diluting solvent: n-hexane/ethyl acetate=9:1) to give 3.4 g (yield: 93%) of 7-hexyloxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3-(2H)-one.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[CH2:33]O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[Br:20][CH2:33]/[CH:32]=[CH:31]/[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1cccc(/C=C/CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(/C=C/CBr)c1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine (1.47 g, 5.6 mmol) in acetonitrile (35 ml) at 0° C. was added dropwise over 5 minutes a solution of bromine (0.88 g, 5.6 mmol) in acetonitrile (5 ml) at a rate such that the temperature was kept between 5° C. and 10° C. The mixture was then allowed to warm to room temperature, then to this was added dropwise a solution of (E)-3-(3-nitrophenyl)-2-propen-1-ol (Preparation 21, 1 g, 5.6 mmol) in acetonitrile (5 ml). The mixture was warmed to 65° C. for 40 min, cooled to room temperature, and poured onto diethyl ether (150 ml). The mixture was concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with hexane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, and the residue recrystallised from cyclohexane to give the title compound as a very pale yellow solid (0.82 g, 61%).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:16]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:16])=[CH:13][CH:14]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Product: NC(=O)c1ccc(N2CCNCC2)cc1
Yield: 19.5 %

Procedure:
To 8.0 g (0.04 mole) of 4-(1-piperazinyl)benzonitrile was added, with stirring, 50.0 ml (0.87 mole) of 93% sulfuric acid over a 15 min period. The mixture was stirred overnight and the resulting suspended amide was collected by filtration, rinsed with water, and allowed to air dry. The solid was recrystallized from absolute ethanol to give 1.6 g (20%) of white solid, m.p. 240°-243° C.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:30]1[CH2:43][O:42][C:37]23[O:38][CH2:39][CH2:40][O:41][C:32]2([C@:33]2([CH2:56][CH2:55][C@H:54]4[C@@H:44]([CH2:45][C:46](=[CH2:57])[CH:47]5[C@:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]5)[C@@H:35]2[CH2:36]3)[CH3:34])[O:31]1>>[CH2:40]1[CH2:39][O:38][C:37]23[O:42][CH2:43][CH2:30][O:31][C:32]2([C@:33]2([CH2:56][CH2:55][C@H:54]4[C@@H:44]([CH2:45][C@H:46]([CH:57]=[CH2:1])[CH:47]5[C@:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]5)[C@@H:35]2[CH2:36]3)[CH3:34])[O:41]1
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 70 %

Procedure:
17,17-Bis(ethylendioxy)-6α-vinylandrostane was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane (Prepn. 14) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 13). The crude was purified by flash chromatography (SiO2, n-hexane/EtOAc 88/12). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.47 (1H, m), 4.91 (2H, m), 3.94-3.73 (8H, m), 2.00-0.67 (21H, m), 0.88 (3H, s), 0.83 (3H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[C:18]([Cl:17])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1c(Cl)cccc1Cl
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3c(Cl)cccc3Cl)c21
Yield: 83.5 %

Procedure:
The title compound (cis/trans=21:79) was prepared as a pale yellow powder in 83.5% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 2,6-dichlorobenzyl alcohol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23]C(=O)C(F)(F)F)=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].O1CCOCC1.[OH-].[Na+]>CO>[NH2:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]([C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:14][CH2:15][CH2:16]2
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NC(=O)C(F)(F)F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(N)ccc32)cc1

Procedure:
16 g of 1-[3-(4cyano-phenyl)propionyl]-6-trifluoracetylamino-1,2,3,4-tetrahydro-quinoline are dissolved in 70 ml of methanol and 50 ml of dioxan and stirred with 200 ml of 1N sodium hydroxide solution for 2 hours at 40° C. Then the mixture is extracted with methylene chloride, the organic phase is dried over sodium sulphate and concentrated by evaporation.