Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=12.[C:15]([O-])(=[O:17])C.[Na+].C=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[OH:17][CH2:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2=[N:1][CH:2]=1
Reactant: CCOC(=O)c1cccn2ccnc12
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cccn2c(CO)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
A mixture of ethyl imidazo[1,2-a]pyridine-8-carboxylate (1 g, 5.26 mmol), sodium acetate (1.725 g, 21.03 mmol), formaldehyde (36.5% wt. in water, 2.5 mL, 33.1 mmol) and acetic acid (1.145 mL, 20 mmol) was stirred at room temperature for 3 hours. The reaction mixture was then heated at reflux for a further 4 hours and then cooled and diluted with water (50 mL). The pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution (ca. 10 mL) and the solution was extracted successively with ethyl acetate (3×50 mL) and 3:1 chloroform:isopropanol (100 mL). The organic extracts were combined, washed successively with saturated sodium bicarbonate (50 mL) and brine (50 mL) and dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane and purified on a silica cartridge (100 g) using a 0-30% methanol (+1% Et3N)-DCM gradient over 60 mins. The product containing fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (1.007 g)
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:37])[C:35]#[CH:36])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.ClCCl.CO.N>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:37])[C:35]#[C:36][C:2]3[CH:19]=[CH:18][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccc(CN2CCC(N3CCCC3)CC2)cc1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CN2CCC(N3CCCC3)CC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-pyrrolidin-1-ylpiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 15 mg (7% of theory); melting point: 191° C.-192° C.; C31H32ClN3O (M=498.07); calc.: molecular ion peak (M+H)+: 498/500; found: molecular ion peak (M+H)+: 498/500; Rf value: 0.45 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.CN(C)[CH:30]=[O:31].Cl>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([CH:30]=[O:31])=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C=O)sc2-c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M) in hexane (36 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (8.0 g) in tetrahydrofuran (80 ml) at -60° C. The mixture was stirred for 30 minutes, and N,N-dimethylformamide (3.7 ml) was added dropwise over ten minutes to the mixture. The mixture was stirred at -70° to -20° C. for 2 hours. 1N Hydrochloric acid (70 ml) was added dropwise, and the solution was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residual syrup was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (9:1). The obtained crystals (4.5 g) were recrystallized from ethyl acetate to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbaldehyde (3.7 g).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10].[N:18]([C:21]1[S:22][C:23]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:24]([CH3:26])[N:25]=1)=[N+:19]=[N-:20]>>[CH2:30]([NH:29][C:27]([C:23]1[S:22][C:21]([N:18]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:20]=[N:19]2)=[N:25][C:24]=1[CH3:26])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 8 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 1-ethynyl-4-fluorobenzene to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 8% yield: mp 203-205° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.77-8.75 (m, 1H), 8.36-8.31 (m, 1H), 7.41-7.16 (m, 8H), 6.10 (br s, 1H), 4.64 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.13, 153.3, 142.3, 137.4, 130.3, 130.2, 129.0, 128.9, 128.2, 128.1, 127.9, 127.9, 124.8, 124.7, 119.8, 119.7, 116.1, 115.8, 44.4, 17.5; MS (ES+) m/z 394.3 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O-:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Na+].C(O)C.S(O[CH:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CC(=O)[O-])cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccc(CC(=O)OC(C)C(=O)OCC)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-(allylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-(allylamino)phenylacetate as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:39][CH:38]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:40]4[CH:39]=[CH:38][N:37]=[CH:42][CH:41]=4)[CH2:45][CH2:46]3)=[O:23])[CH:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(Cc4ccncc4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 1-(pyridin-4-ylmethyl)piperazine (53 mg, 0.30 mmol) in DCE (4.5 mL).
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:15][CH3:16])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>>[CH3:16][O:15][C:10](=[O:14])[CH2:11][CH:12]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])[CH3:13]
Reactant: C/C=C/C(=O)OC
Reactant: CNCc1ccccc1
Product: COC(=O)CC(C)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 110.4 %

Procedure:
Benzyl-methyl-amine (20 g, 165 mmol, 1.0 equiv) was added neat to methyl crotonate (19.8 g, 198 mmol, 1.2 equiv). The resulting solution was stirred at room temperature for 72 h. The excess crotonic ester was removed in vacuo to yield the desired product (40.3 g, ˜100%) which was used without further purification; MS, m/z 222=M+1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH2:7][CH2:6]2.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2cc(OC)ccc2C1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
To a solution of 3,4-dihydro-6-methoxy-1(2H)-isoquinolinone (852 mg, 4.81 mmol, prepared according to J. Chem. Soc., 1969, p 183) in THF (45 mL) at −78° C. was added 0.5M potassium hexamethyldisilazide (10.6 mL, 5.28 mmol) dropwise and the reaction mixture stirred at −78° C. for 5 minutes. The reaction mixture was warmed to 0° C. in a ice/water bath and ethyl bromoacetate (1.20 g, 7.21 mmol) was added dropwise and the mixture stirred at that temperature for 1 hour, and then at room temperature for 2 hours. The reaction mixture was quenched by addition of sat. NaHCO3, diluted with ethyl acetate, and the organic layer was washed with saturated NaHCO3 and then brine. It was dried (MgSO4) and concentrated in vacuo to afford the title compound (1.1 g, 86%) as a yellow solid. Molecular weight (MS): 263.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)C1C=CC=C(N(CC)CC)C=1)C.C(OC(=O)C)(=O)C>CO>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][O:9]1)=[O:8]
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2ccccc21
Temperature: 52 °C
Yield: 247.1 %

Procedure:
A mixture of 2-(4-dimethylamino)benzoyl)benzoic acid (8.07 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (7.26 g.) and acetic anhydride (5 ml.) was heated (at 52° C.) during one and one-half hours. Addition of methanol (10 ml., then 15 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-dimethylamino)phenyl)phthalide (I: X = (CH3CH2)2N, Y2 = Z4 = Z5 = Z6 = Z7 = H, Y4 = (CH3)2N) (10.92 g., m.p. 117°-119° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:23]([OH:26])[CH2:24][CH3:25].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(O)c1cccc(F)c1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)c1cccc(F)c1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 1 %

Procedure:
1-{2-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluorophenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml). Sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (2 mg, yield 1%).
Reaction SMILES: [C:1](NC(=C)C(O)=O)(=O)C.[C:10]([NH:13][C:14](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])(=[O:12])[CH3:11].[Si](C=[N+]=[N-])(C)(C)C>>[C:10]([NH:13][C:14](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:1])=[O:16])(=[O:12])[CH3:11]
Reactant: C=C(NC(C)=O)C(=O)O
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)C(=Cc1ccccc1)NC(C)=O

Procedure:
2-Acetamidoacrylic acid and acetamidocinnamic acid were hydrogenated using the same general procedure, derivatised using TMS-diazomethane and analysed using the same method described for the corresponding methyl esters.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:16]([CH3:17])=[N:19][N:20]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2c(ccc(Br)c2C2CC2)N1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)c(C3CC3)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-5-cyclopropyl-3,4-dihydroquinoline-2(1H)-thione (147-7; 0.6 g, 0.00212 mol) in n-butanol (10 mL) was added acetic hydrazide (0.3 g, 0.005 mol). Reaction mass was warmed at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 305.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[O:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3)CC2)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (0.15 g, 1.063 mmol) and 4-phenoxypiperidine hydrochloride (0.250 g, 1.169 mmol) in dimethylformamide (2.126 ml) was treated with potassium carbonate (0.367 g, 2.66 mmol). The suspension was stirred at ambient temperature 2 hours, at 55° C. for 4 hours and at ambient temperature for 16 hours. The reaction was poured into water and the suspension was filtered and vacuum dried to provide the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C-]#N.[Na+].[CH3:27][NH:28]CCNC>C1(C)C=CC=CC=1.[Cu]I>[C:27]([C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)#[N:28]
Reactant: CNCCNC
Reactant: CC(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(C#N)n2n1
Yield: 24.3 %

Procedure:
A solution of (S)-iso-propyl 2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate (300 mg, 0.79 mmol), NaCN (46 mg, 0.94 mmol), CuI (15 mg, 0.08 mmol), KI (27 mg, 0.16 mmol) and N1,N2-dimethylethane-1,2-diamine (0.085 mL, 0.79 mmol) in toluene (0.8 mL) was stirred at 110° C. for 12 h. The reaction was cooled, concentrated, taken up with EtOAc and water, extracted and dried organic layer with MgSO4. The organic layer was concentrated and purified by ISCO (0-5% MeOH/DCM), then following PREP HPLC (neutral) to give (S)-isopropyl 2-(((3-cyanoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate (63 mg, 25% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.00 (s, 1H), 7.72 (d, J=9.85 Hz, 1H), 6.91 (d, J=9.85 Hz, 1H), 4.20 (m, 1H), 3.38-3.61 (m, 4H), 1.97-2.05 (m, 4H), 1.16-1.25 (m, 6H); LRMS (ESI) m/e 329.2 [(M+H)+, calcd for C16H21N6O2 329.4].
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]=[C:19]=[O:20].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH3:17][NH:18][C:19]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:20]
Reactant: CN=C=O
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
11.1 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 2.9 parts of methyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 80 parts of dry benzene were heated at reflux for 48 hours, cooled and filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethanol, and dried in vacuo to give 9 parts of 14-methylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one, having a melting point of 98° to 100°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[N:8]=[C:9](OS(C(F)(F)F)(=O)=O)[C:10]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=3[N:24]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36].C1COCC1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([NH:36][CH3:35])[C:10]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=3[N:24]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccc(F)cc3)nc(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CNc1nc(Cc2ccc(F)cc2)nc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 48 h

Procedure:
To a solution of the triflate from Step C (90.0 mg, 0.18 mmol) in DMA (2 mL) was added methylamine solution in THF (0.45 mL, 2.0M, 0.89 mmol) and the reaction was stirred for 48 h. The reaction mixture was concentrated in vacuo and the material was used without further purification. A quantitative yield was assumed. LRMS ES+ and AP+ m/z 387 [MH]+.
Reaction SMILES: [C:1]([O:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9]Cl)(=[O:3])[CH3:2].[I-:22].[Na+]>CC(C)=O>[C:1]([O:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9][I:22])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Oc1ccc(CCl)cc1C(OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(CI)cc1C(OC(C)=O)OC(C)=O
Yield: 91.1 %

Procedure:
3-(Diacetoxymethyl)-4-acetoxybenzyl chloride (987 g., 3.14 mole) and sodium iodide (494 g., 3.20 moles) in 3.5 liters acetone are refluxed for 6 hours. The reaction mixture is filtered, the filtrate is evaporated to dryness, triturated in ether and filtered to yield 1,162 g (91%) of 3-(diacetoxymethyl)-4-acetoxybenzyl iodide, m.p. 117°-120° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:10])[CH3:9].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6]/[C:5](=[N:12]\[OH:13])/[CH2:4][C:3]1([CH3:10])[CH3:9]
Reactant: NO
Reactant: CC1(C)CC(=O)CCC1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(C)C/C(=N/O)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
The mixture of 4-hydroxy-3,3-dimethylcyclohexanone (1.0 equiv.), hydroxylamine hydrochloride (2.0 equiv.) and sodium bicarbonate (2.5 equiv.) in MeOH (0.7 M) was stirred at room temperature overnight. The solvent were removed and the residue was passed through a short silica gel column (50% ethyl acetate in petroleum ether) to afford the crude (E)-4-hydroxy-3,3-dimethylcyclohexanone oxime (96% yield) as a colorless oil.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:21]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:21](/[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)\[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCC/C(=N\Nc1ccc(Br)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
A mixture of 1.91 g (8.55.10−3 mol) of 4-bromophenylhydrazine hydrochloride and 0.73 g (8.9.10−3 mol) of sodium acetate in 17 ml of water is prepared and 2.05 ml (35.8.10−3 mol) of acetic acid are added. This mixture is subsequently heated to 70° C., with stirring, and a suspension of 2.0 g (8.54.10−3 mol) of ethyl ε-oxobenzenehexanoate in 27 ml of water is then added slowly. The reaction mixture is stirred at 70-80° C. for 45 min and then at room temperature for 12 hours, after which it is extracted with 2 times 50 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3.38 g of the expected compound, which is used directly in the next step.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[S:10][C:6]([CH2:5][O:4][CH3:3])=[CH:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1ccc(CO)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1ccc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(methoxymethyl)thiophen-2-yl)methanol (900 mg, 5.69 mmol) in dry CH2Cl2 (20.0 mL) was treated at 0° C. with Et3N (1.19 mL, 8.53 mmol) followed by DMAP (70 mg, 0.57 mmol) and Ms-Cl (0.57 mL, 7.39 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 1.38 of crude (5-(methoxymethyl)thiophen-2-yl)methyl methanesulfonate as an orange oil. LC-MS-conditions 07: tR=0.51 min. A solution of this crude material in DMF (10.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (7.05 g of a 9.6% solution in DMF, 5.93 mmol) in DMF (15.0 mL) pre-treated for 30 min with DIPEA (1.96 mL, 11.9 mmol) and the reaction mixture was stirred overnight at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (2×15 mL) and the combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 95:5 hept-EA to 80:20 hept-EA) gave the title compound as a yellow oil. TLC: rf (8:2 hept-EA)=0.36. LC-MS-conditions 07: tR=0.80 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]([OH:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]([O:18][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(C(=O)OCC)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl 6-((2,4-dichlorobenzyl)oxy)-3-hydroxy-1-benzothiophene-2-carboxylate (200 mg) in DMF (dry) (5.0 mL) were added K2CO3 (104 mg) and ethyl 2-bromoacetate (0.084 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (152.7 mg).