Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5](C(OCC)=O)[C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1.Cl.[OH-].[Na+]>>[CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1
Reactant: CCOC(=O)C1C(=O)C(C)OC12CCN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1OC2(CCN(C)CC2)CC1=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4,5]decane-4-carboxylate (3.08 g) was dissolved in 50 ml of 1N--HCl, and the solution was heated under reflux for eight hours. The reaction mixture was allowed to cool to room temperature, then cooled in an ice-water bath, and basified by addition of 20% aqueous solution of caustic soda. This alkaline solution was extracted thrice with about 80 ml of chloroform, and the combined extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure from the dried solution left 2 g of yellow residue, which was purified by silica gel column chromatography by using, as eluent, a mixed solvent of chloroform/methanol (20:1 by volume), giving 1.8 g of 2,8-dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one as oil. It was dissolved in ether, and ethanolic hydrogen chloride was added, thus giving its hydrochloride as crystals.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)[CH:12]=2)[NH:7][C:6]1=[O:19])C.Cl.[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:4]=[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]4[O:18][CH:17]=[N:16][CH:15]=4)[CH:12]=3)[NH:7][C:6]2=[O:19])=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Product: CNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield from ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and N-methyl4-aminophenylmethanesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-d6): δ 10.72 (d,1H), 10.67 (s, 1H), 8.71 (d, 1H), 8.37 (s, 1H), 7.43-7.34 (m, 7H), 6.89 (m, 2H), 4.28 (s, 2H), 2.54 (d, 3H); APCI−MS m/z 409 (MH)−.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([Cl:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 111.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(3-chloro-4-methylphenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g), KOH (0.400 g), water (5 mL) and THF (10.0 mL) to afford 0.350 g of the desired product.
Reaction SMILES: [CH3:1][C@:2]([OH:7])([CH2:5]Cl)[CH2:3][OH:4].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:11]=1[CH3:21].[H-].[Na+].O>O1CCOCC1>[CH3:1][C@:2]([OH:7])([CH2:5][CH2:17][C:14]1[C:15]([CH3:16])=[C:10]([O:9][CH3:8])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]=1[O:18][CH3:19])[CH2:3][OH:4]
Reactant: COc1c(C)c(C)c(OC)c(C)c1C
Reactant: C[C@@](O)(CO)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
2.4 g (19.6 mmol) of (2R)-2-methyl-3-chloropropane-1,2-diol and 4.28 g (22 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene were dissolved in 20 ml of dioxane and heated to reflux temperature within 1 hour with 1.27 g (66 mmol) of sodium hydride (80% in mineral oil) and 0.1 ml of polyethylene glycol 400 (as the phase transfer catalyst) and stirred at this temperature for 16 hours. The mixture was then treated with 50 ml of water, filtered and washed with water. The residue was recrystallized from ether/hexane and there were obtained 4.91 g of (2S)-2-methyl-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1,2-butanediol in the form of white crystals with a melting point of 82°-84° C. and [α]D20 =+2.86° (c=1.5% in CHCl3).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Yield: 96.6 %

Procedure:
Method C. Reaction of benzoate 3 (1.96 g, 5.1 mmol) and 6 M HCl (50 mL) gave acid 4 (1.83 g, 97%) as a white solid: mp (H2O) 242-245° C.; 1H NMR δ 13.16 (br s, 1 H, CO2H), 8.05 (ddd, J=8.6, 1.9, 1.5 Hz, 2 H, H-2, H-6), 7.92 (ddd, J=8.6, 1.9, 1.5 Hz, 2 H, H-3, H-5), 7.67 (br d, J=8.3Hz, 2 H, H-2′, H-6′), 7.42 (br d, J=8.3Hz, 2 H, H-3′, H-5′), 4.63 (s, 2 H, CH2SO2), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); MS m/z 372.8 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.67; H, 4.57; N, 3.79%.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][I:22])[C:16](=[O:23])[C@@H:15]([CH2:24][C:25](OCC)=O)[O:14][C@H:13]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:40]=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][I:22])[C:16](=[O:23])[C@@H:15]([CH2:24][C:25]#[N:6])[O:14][C@H:13]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:40]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
Trimethylaluminium (2M in toluene, 15.0 ml, 30.1 mmol) was added dropwise to a suspension of ammonium chloride (1.6 g, 30.1 mmol) in toluene (25 ml) at ice bath temperature under a nitrogen atmosphere. The resulting solution was stirred for 1 hour. Ethyl trans-7-chloro-5-(1-naphthyl)-1-(4-iodobutyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (5.1 g, 8.6 mmol) was added as a solid and the solution heated at 85° C. for 18 hours. The solution was cooled and acidified with 2 N hydrochloric acid cautiously. Ethyl acetate (100 ml) was added and the layers were separated. The organic layer was washed with 2 N hydrochloric acid. The combined acidic layers were re-extracted once with ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide solution (2×), dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:4→2:3) to give a solid which was recrystallized from ethyl acetate/hexane to afford the title compound (1.58 g, 34%) as a pink solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH3:34][C:35]1[CH:39]=[C:38]([CH3:40])[N:37]([CH2:41][CH2:42][C:43](=[N:45]O)[NH2:44])[N:36]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:44]=[C:43]([CH2:42][CH2:41][N:37]3[C:38]([CH3:40])=[CH:39][C:35]([CH3:34])=[N:36]3)[N:45]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(C)n(CCC(N)=NO)n1
Product: CON=C1C[C@@H](c2nc(CCn3nc(C)cc3C)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-N′-hydroxy-propanimidamide, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=485.3.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(OC(C)(C)C)=O.O1CCCCC1[O:20][NH:21][C:22](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([C:36]2[CH:47]=[CH:46][C:39](COS(C)(=O)=O)=[CH:38][CH:37]=2)=[O:35])=[CH:28][CH:27]=1)=[O:23]>CN(C=O)C.C(Cl)Cl.O>[OH:20][NH:21][C:22](=[O:23])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](=[O:35])[C:36]2[CH:47]=[CH:46][C:39]([CH2:1][N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:38][CH:37]=2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCNCC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
N-Boc-piperazine (46 mg, 0.246 mmol) was added to a stirred mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester (prepared as described in Preparation 5, 100 mg, 0.206 mmol) and TEA (0.057 ml, 0.412 mmol) in DMF (1 ml) and DCM (1 ml). The resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 99:1:0.2). The resulting product was dissolved in DCM and treated with HCl/Et2O for 4 h. The precipitate was filtered off and rinsed with DCM to give 42.6 mg of (E)-N-hydroxy-3-{4-[(E)-3-oxo-3-(4-piperazin-1-ylmethyl-phenyl)-propenyl]-phenyl}-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:41][NH2:42].N1C=CN=C1>ClCCl.C(OCC)(=O)C.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1
Reactant: C[Si](C)(C)ON
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1)NO
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(4-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 106) (380 mg, 0.96 mmol) in dichloromethane (10 ml) was treated with 1,1′-carbonyldiimidazole (156 mg, 0.96 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (388 μl, 2.89 mmol) was added and the mixture was stirred for 3.5 hours. The mixture was then treated with methanol (5 ml) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 95:5 (dichloromethane:methanol) to afford a white solid. Analysis suggests that 10% imidazole remains. The solid was dissolved in ethyl acetate and washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a white solid (128 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:25]=[C:22]([C:23]#[N:24])[C:21]([NH2:26])=[CH:20][CH:19]=1)([O-:17])=[O:16].CN(C)C=O.CC(N(C)C)=O>CS(C)=O>[C:23]([C:22]1[CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:10])#[N:24]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Equimolar quantities of 4-nitrophthalic anhydride and 5-nitroanthranilonitrile (Aldrich Chemical Co.) can be heated in a solvent such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide to give N-(2'-cyano-4'-nitrophenyl)-4-nitrophthalimide, which can be isolated and purified by recrystallization. An alternative method of synthesis for this intermediate is the reaction of 2-chloro-5-nitrobenzonitrile with the potassium salt of 4-nitrophthalimide, using one of the solvents listed above.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].ClCC1C=C(NC(N2C3C(=CC(OC4C5CCN(C(OC(C)(C)C)=O)CC=5N=CN=4)=CC=3)C=C2)=O)C=C(C(F)(F)F)C=1>C(Cl)Cl.CCOC(C)=O>[CH3:52][S:53]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CO)cc(C(F)(F)F)c3)c2)C1
Agent: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CCl)cc(C(F)(F)F)c3)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.211 g, 0.361 mmol) in 6 mL of DCM with DIEA (0.19 mL, 1.08 mmol) at 0° C., methanesulfonyl chloride (0.037 mL, 0.469 mmol) is added and the reaction stirred for 3 h. At that point the reaction is diluted with EtOAc, washed with saturated sodium bicarbonate, brine and the organic layer is dried over sodium sulfate. Concentration provides a mixture of the title compound and tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (3:7), which is carried on to next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:11][CH2:10]1.C(O[Na])(C)(C)C.O>CS(C)=O>[CH:9]1([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Fc1ccc(S)cc1
Reactant: BrC1CC1
Agent: CC(C)(C)O[Na]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(SC2CC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To a stirred solution of 4-fluorobenzenethiol (134 g, 1.05 mol) in DMSO (3 L) under nitrogen atmosphere were added cyclopropyl bromide (140 g, 1.15 mol) and t-BuONa (138.7 g, 1.44 mol). Then the reaction mixture was heated to 80° C. and stirred for 2 days. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (2 L), extracted with diethyl ether (1.5 L×3). The combined organic phases were washed with water (1 L), then brine (1 L), dried over Na2SO4 and concentrated in vacuum to give cyclopropyl(4-fluorophenyl)sulfane (129 g, 73.1%) as a colorless oil. To a mixture of cyclopropyl(4-fluorophenyl)sulfane (129 g, 0.77 mol) and acetic acid (1.9 L) was added 30% H2O2 (1.2 L), and the mixture was heated to reflux and stirred overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (1 L), then Na2S2O3 (200 g) was added to consume excess H2O2, then Na2CO3 was added to adjust pH =7. The mixture was extracted with ethyl acetate (1.5 L×2). The combined organic layers were washed with water (1 L), dried over Na2SO4 and concentrated in vacuum to give 69 g of crude product, which was purified by column chromatography (25% ethyl acetate in petroleum ether) to give the title compound (42 g, 27.3%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])#[N:2].[N+]([O-])(O)=[O:26].[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].O>C(O)C>[C:19]([OH:20])(=[O:26])[CH3:18].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][NH:29][NH:30][C:31]([NH2:33])=[NH:32])(=[O:11])=[O:10])#[N:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Reactant: N=C(N)NN
Solvent: O
Solvent: CCO
Product: CC(=O)O
Product: Cc1cc(OCCCNNC(=N)N)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 151 %

Procedure:
[2-[3-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]ethyl-1-methylene]ydrazinecarboximidamide hydrochloride: A solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propionaldehyde (240 mg, 0.7 mmol), as prepared in the preceding step, and aminoguanidine nitrate (200 mg, 1.5 mmol) in ethanol (8 mL) was stirred at ambient temperature overnight. Water (20 mL) was added to the reaction mixture. The precipitates were collected, washed with water (2×15 mL) and diethyl ether (2×20 mL), and dried under high vacuum. The solid was suspended in water (40 mL), treated with 2N sodium hydroxide (1.0 mL), and extracted into dichloromethane (3×50 mL). The organic phase was dried over K2CO3. After removing the solvent, the residue was dissolved in dichloromethane (1 mL), and the dichloromethane solution was added to the solution of 1.5 mL of 0.6M HCl methanol in diethyl ether (50 mL) to give the title compound as a colorless solid (245 mg, 80%). 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (m, 1H), 8.09 (m, 1H), 7.97-8.04 (m, 2H), 7.55 (br s, 5 H), 6.80 (s, 1H), 6.50 (s, 2H), 4.15 (t, J=6.3 Hz, 2H), 2.68 (m, 2H), 2.22 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H19N5O4S: 402.1 (M+H), 424.1 (M+Na), 440.1 (M+K). Found: 402.1, 424.1, 440.1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CO>O1CCOCC1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:35]4[N:34]=[CH:33][N:32]=[C:31]([NH2:30])[CH:36]=4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)ncn1
Yield: 59.8 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-pyrimidine (48.5 mg, 0.37 mmol). The vial was capped and microwaved at 200° C. for 5 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (76.6 mg).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](C3C4C(=C(C)C=CC=4)NC=3)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:27][N:28]([CH:30]=O)[CH3:29].[H-].[Na+].CI>CCOC(C)=O>[CH3:27][N:28]1[C:29]2[C:1](=[CH:3][CH:6]=[CH:11][C:10]=2[CH3:12])[CH:2]=[C:30]1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c[nH]c4c(C)cccc34)c(C)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCC(CC)c1cc(C)nn2c(-c3cc4cccc(C)c4n3C)c(C)nc12
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(7-methyl-1H-indol-3-yl)-imidazo[1,2-b]pyridazine (0.037 g, 0.11 mmol) and DMF (2 mL) is added 60% NaH (0.005 g, 0.13 mmol). The solution is stirred for 30 minutes and MeI (0.008 mL, 0.13 mmol) is added. The solution is stirred for 1 h, diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (30%-50% EtOAc gradient) to furnish the title compound (0.025 g, 0.069 mmol, 66%). 1H NMR (CDCl3), δ 0.91 (t, J=7.5 Hz, 6H), 1.77-1.95 (m, 4H), 2.48 (s, 3H), 2.53 (s, 3H), 2.83 (s, 3H), 3.35-3.44 (m, 1H), 4.17 (s, 3H), 6.62 (s, 1H), 6.94-7.01 (m, 2H), 7.25 (s, 1H), 7.30 (dd, J=7.6, 1.3 Hz, 1H). LC/MS (m/z): calcd. for C23H28N4 (M+H)+: 361.6. found: 361.2.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])=[CH2:2].C(O)(=[O:13])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]1[CH2:2][O:13]1
Reactant: CC(=O)O
Reactant: C=Cc1ccccc1OC
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 2-vinyl anisole (5.0 g, 0.037 mol) and acetic acid (2.1 mL, 37 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (7.30 g, 40.1 mmol) in three portions. The reaction was allowed to warm to R.T. and after 1 hour, 2M NaOH (50 ml) was added. The reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 7.56 g slightly tinted oil. This was dissolved in dioxane, 2N NaOH was added and the reaction was stirred at RT overnight. Repeated aqueous work-up gave 5.60 g of the title compound as a nearly colorless oil.