Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[O:13])[CH:3]=1.[OH:14][C:15]1([CH2:28][SH:29])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:13]=[C:4]1[C:5](=[O:12])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:29][CH2:28][C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Reactant: O=C1C=C(Cl)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloronaphthalene-1,2-dione (1.0 g, 5.2 mmol) and tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (1.348 g, 5.45 mmol) in acetonitrile (20 mL) was added potassium carbonate (2.16 g, 15.6 mmol). The reaction was stirred at room temperature for 2 hours. To the reaction mixture was then added EtOAc (40 mL) and the reaction mixture filtered through celite. The solvent was then removed under reduced pressure. The crude foamy residue was dissolved in EtOAc (40 mL) and the solvent once again removed under reduced pressure. To the crude foamy solid was added EtOAc (7 mL) and the reaction mixture stirred for 10 min. An orange solid separated out. Diethyl ether (20 mL) was then added and the solution was left in the refrigerator to ensure that most of the product crashed out. The solid was filtered and washed with diethyl ether to afford the product as an orange solid. The mother liquor was concentrated under reduced pressure and purified by flash column chromatography (SiO2, 40% EtOAc in hexanes) to recover the product (1.66 g, 80%) as an orange solid. M.p.=156-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.2-8.14 (m, 1H), 7.9-7.86 (m, 1H), 7.72-7.66 (m, 1H), 7.61-7.55 (m, 1H), 6.50 (s, 1H), 4.05-3.85 (m, 2H), 3.25-3.1 (m, 2H), 3.19 (s, 2H), 1.9-1.7 (m, 5H), 1.47 (s, 9H); LCMS: 404 [M+H].
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:7]=1[O:8][C:9]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1>C(OCC)(=O)C>[Cl:5][C:6]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:7]=1[O:8][C:9]([CH:17]([OH:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1Cl

Procedure:
In this example, 0.49 g (0.0129 mole) of sodium borohydride was added portion-wise to a mixture containing 20 ml of methanol and 4.5 g (0.0129 mole) of 3-[2-(2,4-dichlorophenoxy)-3-oxo-4,4-dimethylpent-1-enyl]pyridine at 0° C. with stirring. The mixture was stirred at 0° C. for 15 minutes, then quenched by the addition of water. The mixture was then diluted with more water and then extracted twice with methylene chloride. The methylene chloride extracts were washed with water twice, dried over magnesium sulfate, filtered, then concentrated under vacuum affording a foam. The foam was dissolved in ethyl acetate, then chromatographed by flash column chromatography (silica gel) eluting with hexane and ethyl acetate mixtures. The product fractions were combined, concentrated and the residue recrystallized from methanol and water affording white crystals of the title compound mp 79.0°-81.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:25])=[CH:5][CH:4]=1.C1COCC1.CO.[Li+].[OH-]>O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)CCC(=O)N2Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CCc3cc(CCC(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a stirred solution of ethyl 3-(1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanoate (0.76 g, 2.07 mmol) in 1:1 THF/methanol (20 mL) was added a solution of LiOH (0.26 g, 6.21 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 3 h. Solvents were concentrated and the reaction mixture was acidified with citric acid solution to pH 6. Solid was filtered and dried to afford 3-(1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid as a pale brown solid (0.6 g, 86%). 1HNMR 400 MHz, DMSO-d6: δ 2.46-2.51 (m, 2H), 2.65-2.87 (m, 4H), 2.89 (t, J=16.00 Hz, 2H), 3.71 (s, 3H), 5.05 (s, 2H), 6.85-6.87 (m, 3H), 6.96-6.99 (m, 1H), 7.08 (s, 1H), 7.14-7.16 (m, 2H), 12.08 (s, 1H). LCMS: RT 2.023 min; LCMS (ES-API), RT; 0.81 min; m/z 340.0 [M−H]−.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].ClC[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Na].C(O)C>[O-]CC>[C:1]([NH:4][C:5]([C:29]1[CH:30]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:28]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1cccc(CCl)c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1cccc(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Temperature: 0 °C

Procedure:
Diethyl acetamidomalonate (2.60 g) and ethyl 3-(chloromethyl)phenoxyacetate (Robertson, J. Chem. Soc. 1933), 492; U.S. Pat. No. 3,933,895) (2.39 g) were dissolved in ethanolic ethoxide (prepared from sodium (230 mg) and absolute ethanol (10 ml) and the mixture refluxed for 19 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract evaporated. The residual gum was crystallised from ether/hexane to give diethyl acetamido-(3-ethoxycarbonylmethoxyphenyl)malonate as white prisms, m.p. 98.5°-101.5°. This derivative (1.90 g) was refluxed with 10% aqueous hydrochloric acid (25 ml) for 31/2 hours and the cooled solution was evaporated to dryness in vacuo. The residual white solid was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol 815 ml) and thionyl chloride (1.64 g). The resulting solution was set aside at room temperature for 18 hours, refluxed for 1 hour, cooled, and poured into ice-water, adjusting the pH to 9-10 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated, giving ehtyl 2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate as a colourless oil, which was used without further purification in Examples 20 and 21.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(C(C)C)cc2)oc1C)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
0.28 g (1.0 mmol) rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) and 0.30 g (1.2 mmol) 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole were dissolved under argon in 5.0 ml N,N-dimethylformamide; 0.048 g (1.1 mmol) sodium hydride (55% in mineral oil) were added and the reaction mixture then stirred for 48 hours at ambient temperature. It was then diluted with water and extracted with ether. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.32 g (67%) of rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:38]3[C:33](=[CH:34][C:35](I)=[CH:36][CH:37]=3)[CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[C:26]([CH:12]([O:14][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]=[CH:32]3)[C@H:2]([CH2:3][O:4][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH2:1])[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Product: N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1

Procedure:
(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-[(phenylmethoxy)methyl]benzeneethanamine is synthesized in analogy to the sequence previously described in example 1: commercially available Boc-Ser(Bn)-OH is transformed into its Weinreb-amide. Reduction to the aldehyde with LiAl4, reaction with 3-fluorophenylgrignard, cleavage of the tert.-butyloxycarbonyl protecting group, liberation of the amine from the hydrochloride and etherification with 1-(4-fluorophenyl)-5-iodo-1H-indazole gives the desired amine. This amine (123.3 mg, 0.25 mmol) is dissolved in 10 mL of dichloromethane. Triethylamine (0.084 mL, 0.61 mmol) and 0.028 mL (0.3 mmol) 2-methoxyacetylchloride are added. The reaction mixture is stirred overnight at r.t., then diluted with dichloromethane, washed with water and brine and dried over Na2SO4. After filtration the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 79.1 mg (55.9%) of the title compound as a mixture of stereoisomers are isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)C(C)(C)C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 103b), the acylation of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester with pivaloyl chloride yielded the title compound as a white solid; MS: m/e=376 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C([N:20]=[C:21]=[S:22])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([NH:1][C:21]([NH2:20])=[S:22])[CH2:3][CH2:4]2
Reactant: NN1CCc2cc(Cl)ccc21
Reactant: O=C(N=C=S)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)NN1CCc2cc(Cl)ccc21

Procedure:
1-amino-5-chlorindoline was reacted with benzoyl isothiocyanate in boiling tetrahydrofuran. Saponification of the resulting product with dilute aqueous sodium hydroxide under reflux for 15 minutes gave 1-(5-chloroindolin-1-yl)-thiourea (M.Pt. 199° - 200° from ethyl acetate/petroleum ether). This thiourea was heated in boiling methanol in the presence of methyliodide for 1 hour to give 1-(5-chloroindolin-1-yl)-2-methylisothiourea hydroiodide. The base was liberated with aqueous sodium hydroxide. Reaction of the base with 2N ethanolic hydrogen chloride yielded 1-(5-chlorindolin-1-yl)-2-methylisothiourea hydrochloride (M.Pt. 178° - 179° from ethanol/ether).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH2:9](O)[CH2:10][OH:11].C(OCC)(OCC)OCC.C(OCC)(=O)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:2][C:1]1([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[O:11][CH2:10][CH2:9][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2ccco2)OCCO1
Yield: 46.4 %

Procedure:
A mixture of 4 mL (139.6 mmol) 2-acetylfuran, 8.7 mL (156 mmol) of ethylene glycol, 198 mg (1 mmol) of p-toluenesulfonic acid monohydrate, and 22 mL (132.3 mmol) of triethyl orthoformate was reacted at room temperature under N2 for 3 days. The reaction mixture was poured into a mixture of ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layer was washed with water (100 mL), sodium bicarbonate solution (150 mL), and brine (100 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and the residue was distilled under reduced pressure (1.5 torr) to afford 9.98 g (50%) of 2-(2-methyl-1,3-dioxolan-2-yl)-furan, as a clear oil, b.p. 24° C./1.5 mm.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 38 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 38% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([SH:28])[CH:26]=[CH2:27].F[C:30]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1>C(#N)C>[CH2:25]([S:28][C:30]1[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH2:27]
Reactant: C=CCS
Reactant: NS(=O)(=O)c1ncccc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCSc1cccnc1S(N)(=O)=O

Procedure:
33.2 g (0.24 tool) of potassium carbonate as well as 1.32 g (0.005 tool) of 18-crown-6 and 15.8 g (0.17 tool) of 80 % allylmercaptan in 50 ml of acetonitrile are added to a solution, cooled to +5° C., of 17.62 g (0.1 mol) of 3-fluoropyridin-2-ylsulfonamide in 400 ml of acetonitrile.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[NH4+:24].[NH4+].CCOC(C)=O>CN(C=O)C>[N+:17]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][C:2]=1[NH2:24])([O-:19])=[O:18]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C

Procedure:
The nitro compound obtained as above (1.5 mmol) is dissolved in DMF (4 mL) and added with ammonium carbonate (500 mg). The reaction mixture is then heated at 80° C. for 48 h. EtOAc (2×10 mL). The combined organic layers are then washed with water and brine and dried over Na2SO4. Removal of the solvent in vacuo yielded the 2-nitro-5-(3-diethylamino-1-propoxy)aniline (300 mg) which is used for further transformation without any purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:20]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[C:19]([I:20])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: II
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2)cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(I)c3c2)cc1OC
Temperature: -40 °C

Procedure:
5-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 82, (0.270 g, 0.00106 mol) was dissolved in Tetrahydrofuran (8.5 mL, 0.10 mol) under an atmosphere of Nitrogen. The solution was stirred at −40° C. and Iodine (0.269 g, 0.00106 mol) dissolved in 2.5 mL of Tetrahydrofuran was added. The chilled reaction mixture was stirred for 2 h and was then quenched with the addition of Sodium thiosulfate, pentahydrate (0.13 g, 0.00053 mol) in water (1M). The reaction mixture was partitioned between water (20 mL and ethyl acetate (30 mL). The two layers were seperated, and the aquous layer was extracted with ethyl acetate. The organic layers were washed with water and brine, dried with sodium sulfate, then concentrated under reduced pressure. The dark colored crude residue was carried onto the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:21](CC3C=CC(OC)=CC=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]3[N:13]([C:15]([C:18]#[C:19][CH3:20])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N1CCCC(NC2C=C(N(CC3C=CC(OC)=CC=3)C3C=CC=CC=3)C3N(C(C#N)=CN=3)N=2)C1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:12]3[N:13]([C:15]([C:18]#[C:19][CH3:20])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1
Reactant: CC#Cc1cnc2c(N(Cc3ccc(OC)cc3)c3ccccc3)cc(N[C@H]3CC[C@H](N)CC3)nn12
Agent: COc1ccc(CN(c2ccccc2)c2cc(NC3CCCN(Cc4ccccc4)C3)nn3c(C#N)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#Cc1cnc2c(Nc3ccccc3)cc(N[C@H]3CC[C@H](N)CC3)nn12
Reaction time: 2 h

Procedure:
To a 2 dram vial was added crude N6-((trans)-4-aminocyclohexyl)-N8-(4-methoxybenzyl)-N8-phenyl-3-(prop-1-ynyl)imidazo[1,2-b]pyridazine-6,8-diamine (0.065 g, 0.13 mmol) from (1b) and a 1:1 mixture of TFA and CH2Cl2 (2 ml). The reaction was stirred for 2 hours, concentrated, diluted with MeOH and purified by preparative HPLC to provide the titled compound (0.0025 g, 5%) as a TFA salt. 1H NMR (400 MHz, MeOD) δ ppm 7.44 (2H, dd, 8 Hz), 7.33 (2H, d, 8 Hz), 7.18-7.26 (1H, m), 7.18-7.25 (2H, m), 6.39 (1H, s), 3.68-3.82 (1H, m), 3.06-3.21 (1H, m), 2.23-2.35 (2H, m), 2.18 (3H, s), 1.46-1.62 (2H, m), 1.25-1.41 (2H, m). LC/MS, m/z 361 (M+1). HPLC Rt, 2.30 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: C.[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:5][N:4]=1.O.NN>CO>[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)cnc1N
Reaction time: 12 h
Yield: 63.9 %

Procedure:
0.051 g of ferric chloride and 0.085 g of activated charcoal are added to a suspension of 0.35 g of 2-amino-5-(3,4-dichlorphenyl)-3-nitropyridine (starting material G2) in 10 ml of methanol and the mixture is heated under reflux. 0.270 ml of hydrazine hydrate are added slowly and reflux is continued for 12 hours. After cooling the mixture is filtered and the filtrate is evaporated. The residue is partitioned between sodium-EDTA-solution (0.25M; pH 9–10) and dichloromethane. The organic phase is evaporated to give 0.20 g of the title compound as a yellowish solid of m.p. 202–204° C. The mass spectrum shows the molecular peak MH+ at 254.2 Da.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Si:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
tert-butyldimethylsilyl chloride (3.7 g, 1.5 eq) was added portionwise to a solution of 3-hydroxybenzaldehyde (2.0 g, 16 mmol), triethylamine (3.4 mL, 1.5 eq) and dimethylaminopyridine (50 mg, 0.025 eq) in DCM (100 mL). After stirring for 2 h at rt, water was added. The aqueous phase was extracted with DCM, the combined organic phases dried over sodium sulfate and concentrated in vacuo to afford 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (3.6 g, 16 mmol, 100%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]=[C:12]1[CH2:18][CH:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13]1.[CH2:36](Br)[CH:37]=[CH2:38].Cl>O1CCCC1.ClCCl.O>[CH2:38]([C:17]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13][C:12](=[CH2:11])[CH2:18]1)[CH:37]=[CH2:36]
Reactant: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)c2ccccc2)CC(=C)COc2ccc(C(=O)OC)cc21
Reaction time: 0.25 h
Yield: 67 %

Procedure:
0.023 ml (1.1 equivalents) of 1,3-dimethylpropyleneurea and then 0.189 ml (1.1 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 61 mg (0.17 mmol) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 1, in solution in 1.8 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After stirring for 15 minutes, 0.0165 ml (1.1 equivalents) of allyl bromide is added. After stirring for 5 minutes, water, 1N hydrochloric acid and dichloromethane are added. After separating the organic and aqueous phases, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 25/55) to give 51 mg (67%) of methyl 5-allyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of an oil; 1H NMR (300 MHz, CDCl3): 3.25 (m, 4H), 3.9 (s, 3H), 4.25 (d, J=14.3 Hz, 1H), 4.6 (d, J=14.3 Hz, 1H), 4.93 (s, 1H), 5.10 (s, 1H), 5.21 (m, 2H), 5.83 (m, 1H), 6.86 (d, J=8.5 Hz, 1H), 7.4 (m, 4H), 7.57 (m, 1H), 7.95 (dd, J=8.46 and 2 Hz, 1H), 8.21 (d, J=2.07 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][C:19]#[CH:20])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:20]#[C:19][CH2:18][NH:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:21])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: C#CCNC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)o1

Procedure:
The title compound of Step A was prepared from 5-bromo-furan-2-carboxylic acid methyl ester and prop-2-ynyl-carbamic acid tert-butyl ester as described in Step A of Preparation 2.