Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2cc(Br)cnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To 5.06 g of 5-bromo-2,3-diaminopyridine 46 (Ryabukhin et al (2006) Synthesis 21:3715-3726; Oguchi et al (2000) J. Med. Chem. 43(16):3052-3066; Seki et al (1995) J. Hetero. Chem. 32(3):1071-73; Fray et al (1995) J. Med. Chem. 38(18):3524-35) was added 50 mL acetic acid under N2 and the reaction was heated to reflux overnight. Complete reaction was confirmed by LCMS. The solution was concentrated in vacuo and purified by flash chromatography (DCM/MeOH) to give 4.68 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine 51 (82% yield), which may also be prepared by the methods of Cee et al (2007) J. Med. Chem. 50(4):627-40; Itoh et al (1982) J. Hetero. Chem. 19(3):513-17. 6-Bromo-2-methyl-3H-imidazo[4,5-b]pyridine (4.68 g) in 150 mL THF was added to 0.63 g (1.1 eq) NaH in 10 mL THF under N2 at −78° C. The reaction was stirred at −78° C. for 30 minutes followed by the addition of 3.86 g of SEM-Cl(1.05 eq) and allowed to warm up to room temperature. The reaction was stirred at room temperature 4.5 hours and complete reaction was confirmed by LCMS. The reaction was quenched with water followed by the addition of NaCl (not saturated) and the two products extracted with EtOAc and concentrated in vacuo. The two regioisomers were separated by flash chromatography (EtOAc/Hexanes) to give 2.84 g 6-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 and 1.94 g 6-bromo-2-methyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 53 (63% overall yield). 6-Bromo-2-methyl-34(2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 (2.08 g) was dissolved in 50 mL toluene followed by the addition of 2.32 g (1.5 eq) of bis(pinacolato)diboron, 0.24 g (0.05 eq) of PdCl2(dppf), and 1.79 g (3.0 eq) of KOAc. The reaction mixture was heated to 95° C. under N2 and let stir overnight. Complete reaction confirmed by LCMS. The mixture was cooled to room temperature, rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give 1.83 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 54 (77% yield). MS (Q1) 390.2 (M)+
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:19].C(=O)(O)[O-].[Na+]>CO>[O:19]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
13.5 g of tert-butyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 ml methanol, and 28.3 g phthalic acid monoperacid magnesium salt and 8.62 g sodium bicarbonate were added thereto, and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered through Celite, and the resulting filtrate was evaporated. Ethyl acetate was added to the resulting residue which was then washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and subjected to silica gel column chromatography to give 12.2 g of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH3:9][C:10]1[N:11]([C@H:16]2[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:12]([CH3:15])=[CH:13][CH:14]=1.C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH3:15][C:12]1[N:11]([C@H:16]2[CH2:20][C@@:19]([CH2:2][CH3:3])([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:10]([CH3:9])=[CH:14][CH:13]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CC[C@]1(C(=O)OC)C=C[C@@H](n2c(C)ccc2C)C1
Reaction time: 0.67 h
Yield: 82 %

Procedure:
A −40° C. solution of 2M (in THF/ethylbenzene/heptane) LDA (68 ml, 138 mmol) in tetrahydrofuran (120 ml) was treated with methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (14.02 g, 63.9 mmol) while keeping the temperature less than −33° C. The cold reaction was stirred for 40 minutes and then a solution of ethyl iodide (13.63 g, 87.4 mmol) in tetrahydrofuran (5 ml) was added slowly while keeping the temperature less than −33° C. The reaction was stirred with the cold bath in place for four hours and allowed to slowly warm. The reaction was poured into NH4Cl soln (300 ml), then extracted with ethyl acetate (2×200 ml), washed with brine dried over MgSO4, and concentrated under reduced pressure. The resulting brown oil was passed through a column of silica gel with 10% ethyl acetate/hexanes to give methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1-carboxylate as a brown oil (12.96 g, 82%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[C:15]1([C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(N=[N+]=[N-])c1sc2ccccc2c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2-(1-Azidoethyl)-3-phenylbenzo[b]thiophene (211 mg, 0.76 mmol) was dissolved in a mixture THF (4 mL) and water (0.27 mL) and triphenylphosphine (237 mg, 0.91 mmol) added. The mixture was stirred at RT for 1 h then additional triphenylphosphine (237 mg) was added. The reaction mixture was stirred at RT for 1 h then the reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% MeOH in DCM) affording the title compound as a white solid (160 mg, 83%). 1H NMR (CDCl3, 400 MHz): δ 7.84 (1H, dd, J=7.63, 1.55 Hz), 7.52-7.27 (8H, m), 4.56-4.44 (1H, br), 1.76 (2H, s), 1.47 (3H, d, J=6.21 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:22]3[C:21](=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: 3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]2)=[CH:5][C:4]=1[F:20].[O:23]=[C:24]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][N:25]1[C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=1.[Cl-].[Li+].O>CN1CCCC1=O>[O:23]=[C:24]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][N:25]1[C:31]1[CH:36]=[CH:35][C:34]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]3)=[CH:5][C:4]=2[F:20])=[CH:33][N:32]=1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: O=C1CC(CO)CN1c1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(N4CC(CO)CC4=O)nc3)c(F)c2)CO1
Temperature: 110 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
In 14 ml of 1-methyl-2-pyrrolidone was dissolved 1.8 g of (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide. The solution was added 1.03 g of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 0.55 g of lithium chloride and 0.15 g of dichlorobistriphenylphosphine palladium (II) at room temperature and then stirred at the temperature of 110° C. for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. After being washed with brine, the organic layer, thus separated, was dehydrated, filtered, concentrated in vacuo and purified by column chromatography thereby to obtain (S)-3-(4-(2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide 410 mg. Yield 21%.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[F:7][C:8]1([F:42])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]3([C:20]([NH:22][C:23]4[N:24]=[C:25]([C:33]5[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=5)[C:36](Cl)=[O:37])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:21])[CH2:19][CH2:18]3)=[CH:16][C:10]=2[O:9]1>ClCCl>[F:42][C:8]1([F:7])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]3([C:20]([NH:22][C:23]4[N:24]=[C:25]([C:33]5[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=5)[C:36]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:37])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:21])[CH2:18][CH2:19]3)=[CH:16][C:10]=2[O:9]1
Reactant: O=C(Cl)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Reactant: CN(C)CCO
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To N,N-dimethylethanol amine (921 mg, 1.04 mL, 10.3 mmol) in dichloromethane (5 mL) was added a solution of 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoyl chloride in dichloromethane (5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (20 mL) and was washed with 1N HCl (20 mL) and saturated NaHCO3 (20 mL). The organics were dried over Na2SO4 and evaporated to yield 2-(dimethylamino)ethyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (1.30 g, 90%/). ESI-MS m/z calc. 559.6. found 560.3 (M+1). Retention time 1.72 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18]C(OC)=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC(=O)OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 83.7 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-6-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (500 mg, 0.80 mmol) and potassium carbonate (222 mg, 1.6 mmol) in methanol (5 mL) was stirred at room temperature overnight. A small amount of water was added, and the methanol was removed in vacuo. Additional water (20 mL) was added and the aqueous mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with a saturated sodium bicarbonate solution (10 mL), brine (10 mL), and then dried over sodium sulfate, filtered and concentrated in vacuo to give 412 mg crude product. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded 378 mg of the title compound (84%): MS m/z 565 (M+ +1), 582 (M+ +18); 1H NMR (CDCl3) δ 7.08 (C8, s, 1H), 6.52 (C5, s, 1H), 1.15 (C2-Me, d, 3H, J=6.0 Hz).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]=[N+:19]=[N-:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22](C)=O>>[CH:1]([N:14]1[CH2:15][CH:16]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(n3ccnn3)C2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 1.05 g (3.98 mmol) of N-benzhydryl-3-azidoazetidine in 50 ml of acetone cooled to -78° C. in a steel reaction vessel was bubbled 36 g of acetylene. The sealed reaction vessel after warming up to room temperature was heated at 80° C. for 17 hr. The solution was then cooled to room temperature, filtered and evaporated to yield the crude product which after chromatography over silica gel (2.5% methanol chloroform) yielded 0.88 g (76%) of the desired product as a solid, m.p. 167°-168° C. 1H NMR (CDCl3) δ: 7.88 (S, 1H), 7.73 (S, 1H), 7.55-7.07 (m, 10H), 5.35-5.1 (m, 1H), 4.53 (S, 1H), 3.76 (t, 2H), 3.5 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.S([O-])(O)(=O)=O.I[CH2:17][CH3:18].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:17][CH3:18])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: CCI
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C#N)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
A solution of 3-bromophenylacetonitrile (8.12 g) in dichloromethane (150 mL) at room temperature was treated sequentially with tetrabutylammonuim hydrogen sulfate (14.1 g), iodoethane (10 mL), and 15% NaOH (35 mL), stirred for 4 hours, and separated. The aqueous phase was extracted with dichloromethane, and the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% dichloromethane/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[C:15]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)#[N:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:11]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[C:15]#[N:16])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8-Chlorotheophylline (20 g, 93.19 mmol) was dissolved in 800 ml of DMF and 2-cyanobenzyl bromide (18.28 g, 93.19 mmol), potassium carbonate (12.88 g, 93.19 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was suspended in 900 ml of water and 900 ml of EtOAc, and compound (1A) was collected by filtration of the suspension. The layers in the mother liquor were separated and the aqueous layer was extracted with 3×500 ml of EtOAc. The combined organic layers were washed with 1×500 ml of water, and the solvent was evaporated to give compound (1A) as white crystals. Combined yield: 28.6 g (93%). Mp. 222.5-223.7° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)C(C)C)(C)C.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (130 mg, 0.5 mmol, 1 eq) and N,N-diisopropylethylamine (0.26 mL, 3 eq) in anhydrous dichloromethane (10 mL) at room temperature was added dropwise cyclopropane carbonyl chloride (0.26 mL, 3 eq). After the reaction mixture was stirred at ambient temperature for two hours, it was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (with 10% THF added). The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:30) to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide as a white powder in amount of 51 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[C:5]2[CH2:18][CH:19]([CH2:21][OH:22])[O:20][C:4]=2[CH:3]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[C:5]2[CH2:18][CH:19]([C:21]([OH:25])=[O:22])[O:20][C:4]=2[CH:3]=1
Reactant: OCC1Cc2c(cc(Cl)c3c(-c4ccccc4F)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2c(cc(Cl)c3c(-c4ccccc4F)noc23)O1
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A portion (4.3 g) of the 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol obtained in Example 22 was dissolved in 120 ml of acetone. To the solution, a mixture of chromium (VI) oxide (6.5 g), water (15 ml) and concentrated sulfuric acid (9.3 g) was added dropwise under stirring. The stirring was continued at room temperature for 2 hours, then the mixture was left to stand overnight. The insolubles were filtered off by suction, and the solvent was distilled off. Water was added to the residue, followed by extraction with ether. The ether layer was washed with water and dried, and the solvent was distilled off. The residue was recrystallized from acetone/water to yield 2.7 g of 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:21])=[O:4].C[O-].[Na+].I[CH2:26][CH3:27]>CO>[CH3:1][O:2][C:3]([C:5]1([CH2:26][CH3:27])[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:21])=[O:4]
Reactant: COC(=O)C1CC(CCOCc2ccccc2)CCC1=O
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C(=O)OC)CC(CCOCc2ccccc2)CCC1=O
Reaction time: 48 h

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90 EC in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0 EC and acidified with HCl. The solution was warmed to 40 EC for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0 EC and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1csc(CBr)n1

Procedure:
2-Methyl-4-thiazolecarboxylic acid ethyl ester (1 g) (Liebigs Ann. Chem. 1981, 623), N-bromosuccinimide (1.04 g) and a catalytic amount of benzoyl peroxide in chloroform (25 ml) was heated at reflux for 20 hours. After cooling, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 40% ethyl acetate in isohexane to give the product as an oil. Yield 0.5 g.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19](F)[CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([S:4][CH:2]([CH3:3])[CH3:1])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (1.5 mL), potassium carbonate (3 g) and N,N-dimethylformamide (20 mL), 4-chloro-2-fluoronitrobenzene (2.5 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 4-chloro-2-isopropylsulfanyl-1-nitrobenzene (3.30 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][N:13]1[CH:21]([CH2:22][CH2:23]O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:25]>C(Cl)Cl>[CH3:12][N:13]1[CH:21]([CH2:22][CH2:23][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)c2ccccc2C1CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCC2c3ccccc3C(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
p-Toluene sulfonyl chloride (2.3 g, 12.1 mmol) is added to a solution of TEA (3.5 g, 34.5 mmol) and 1,3-dihydro-2-methyl-3-(2-hydroxyethyl)-2H-isoindol-1-one (2.2 g, 11.5 mmol) in 50 mL of CH2Cl2 at room temperature under argon. The mixture is stirred at room temperature overnight and washed with water (3×50 mL). The organic layer is dried over Na2SO4 and evaporated to give an oil which is chromatographed in ethyl acetate over silica gel to give 1.5 g (38% yield) of 1,3-dihydro-2-methyl-3-(2-tosylethyl)-2H-isoindol-1-one.