Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:10]([NH:12][CH2:13][C:14](O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[C:60]([NH:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][NH2:74])([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>C1COCC1>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][NH:67][C:60]([O:62][C:63]([CH3:64])([CH3:65])[CH3:66])=[O:61])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of Fmoc-Phe-Gly-OH (0.66 g) in anhydrous THF (20 mL) at 0° C. under N2 was added N,N′-dicyclohexylcarbodiimide (0.307 g) and 1-hydroxybenzotriazole hydrate (0.201 g). After stirring for 15 min, N-Boc-1,6-diaminohexane (0.322 g) was added. The reaction mixture was allowed to warm to RT and stirred overnight. Solids were filtered off and they were washed with EtOAc. The filtrate and washings were then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0 to 10% MeOH in CH2Cl2) to afford Fmoc-Phe-Gly-NH—(CH2)6NH-Boc as a white solid (0.9 g).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][Mg]I>>[CH3:12][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]=1
Reactant: C[Mg]I
Reactant: O=C1CCCc2ccccc21
Product: CC1=CCCc2ccccc21
Yield: 68 %

Procedure:
α-Tetralone was reacted with methylmagnesium iodide as described in J. Org. Chem., 26, 4165 (1961), without isolation of the intermediate 1-methyl-1-tetralol, to give the desired product, after distillation, in 68% yield as a colorless oil, boiling point 55-57° C. at 0.8 mm Hg.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14]Br)[CH2:5]3)[CH2:2]1)[CH2:9]2.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([C:12](=[O:16])[CH2:13][CH2:14][N:28]4[CH2:29][CH2:30][N:25]([C:20]5[N:19]=[CH:24][CH:23]=[CH:22][N:21]=5)[CH2:26][CH2:27]4)[CH2:5]3)[CH2:2]1)[CH2:9]2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(CCBr)N1CC2CC3CC(C2)CC1C3
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCN(c2ncccn2)CC1)N1CC2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 31 %

Procedure:
A solution of 1-(4-azatricyclo[4.3.1.1(3,8)]undec-4-yl)-3-bromo-1-propanone (2.00 g, 6.99 mmol), 1-(2-pyrimidinyl)piperazine dihydrochloride (1.66 g, 7.00 mmol), diisopropylethylamine (3.6 mL, 21 mmol) in anhydrous dimethylformamide (100 mL) was heated at 60° C. for 23 hours. The reaction mixture was poured into water (700 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried, preadsorbed into silica gel, and purified by flash chromatography (8 cm diameter, elution with 2.5% methanol in dichloromethane). The resulting solid was stirred over hexane for 2 hours and filtered to yield a beige solid (800 mg, 31%, m.p. 117°-119° C.).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][CH2:22][CH:23]1[CH2:27]O[C:25](=[O:28])[O:24]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:20][O:21][CH2:22][CH:23]1[O:24][C:25](=[O:28])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]3)=[CH:9][CH:10]=2)[CH2:27]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COCC1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Temperature: 160 °C
Yield: 8.6 %

Procedure:
A mixture of 6.0 g of ethyl 4-(4-oxo-piperidin-1-yl)-phenylcarbamate, 5.0 g of 4-methoxymethyl-1,3-dioxolan-2-one and 0.6 g of potassium carbonate was heated to 160° C. under argon for 3 h. The reaction mixture was cooled, treated with methylene chloride and water and the phases were separated. The organic phase was dried with magnesium sulfate and concentrated. The residue (7.8 g) was chromatographed over silica gel 60 using ethyl acetate as the eluent. There was obtained 0.6 g of (RS)-5-methoxymethyl-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 7.46 (d, 2H), 6.98 (d, 2H), 4.76 (m, 1H), 3.99 (t, 1H), 3.88 (t, 1H), 3.64 (d, 2H), 3.57 (t, 4H), 3.44 (s, 3H), 2.56 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH3:16])[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][CH:25]([O:34][CH3:35])[CH2:26][C:27]1[N:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1.N1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:13]([NH:33][C:30]2[CH:29]=[N:28][C:27]([CH2:26][CH:25]([O:24][CH3:23])[O:34][CH3:35])=[CH:32][N:31]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C[C@@H](C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: COC(Cc1cnc(N)cn1)OC
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1)OC
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-propionic acid (prepared as in Example 1, 136 mg, 0.41 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (2 drops) was cooled to 5° C. and then treated with oxalyl chloride (75 μL, 0.86 mmol). The mixture was stirred at 5° C. for 5 min, the cooling bath was removed, and the mixture stirred an additional 10 min. The solvent was concentrated in vacuo. The residue was dissolved in benzene (10 mL), and the solvent again concentrated in vacuo. The resulting acid chloride was dissolved in methylene chloride (5 mL), cooled to 0° C., and then treated with a solution of 5-(2,2-dimethoxy-ethyl)-pyrazin-2-ylamine (75 mg, 0.41 mmol) and pyridine (85 μL, 1.05 mmol) methylene chloride (5 mL). The reaction mixture was stirred at 0° C. for 5 min, the cooling bath was removed, and the stirring was continued for 18 h. The mixture was diluted with methylene chloride (25 mL), and the solution was washed consecutively with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution, and a saturated aqueous sodium chloride solution (25 mL). Each aqueous wash was back-extracted with another small portion of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, eluted with 1/3 to 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,2-dimethoxy-ethyl)-pyrazin-2-yl]-propionamide (120 mg, 59%): (ES)+-HRMS m/e calcd for C23H30ClN3O5S (M+H)+ 496.1668, found 496.1672.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28](CCOC3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N([CH2:70][CH2:71][CH2:72][S:73]([NH2:76])(=[O:75])=[O:74])=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:70][CH2:71][CH2:72][S:73]([NH2:76])(=[O:75])=[O:74])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: [N-]=[N+]=NCCCS(N)(=O)=O
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: Cc1ccc(-c2cn(CCCS(N)(=O)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (1.37 mmol) and compound 412 (2.79 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 65:35 to 85:15 as the eluent to afford the title compound as almost white solid. 13C NMR (DMSO-d6) δ 194.9, 158.8 (dd), 155.7 (dd), 149.4, 145.5, 139.9, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.4 (dd), 124.9, 124.1 (dd), 121.6, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 51.4, 47.9, 24.6, 19.4
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:38])=[CH:14][C:15]2[N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C@H:20]3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[O:17][C:16]=2[CH:37]=1>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:13]1[C:12]([N:11]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:37][C:16]2[O:17][C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(N(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 40 °C
Reaction time: 4 h
Yield: 105.5 %

Procedure:
N-acylation of an amine of Structure 25 to an amide of Structure 26 Benzenesulfonyl chloride (5 μL, 0.04 mmol) was added under N2 to trans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2,-trifluoroacetamide (5.0 mg, 0.01 mmol) in a mixture of 1 mL of CH2Cl2 and 25 μL of triethylamine. The resulting mixture was stirred at 40° C. for 4 h. After cooling the mixture was evaporated and the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 1:0→0:1 (gradient) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (7.3 mg, 83%). Data: (m/z)=692 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:18])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.[NH2:28][C:29]([CH3:48])=[CH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[CH:45]=[CH:44][N:43]=[CH:42][C:41]=2[N:40]=[C:39]1[CH3:47])=[O:32]>C(O)C>[OH2:11].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]1[C:9]([C:8](=[O:18])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:28][C:29]([CH3:48])=[C:30]1[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[CH:45]=[CH:44][N:43]=[CH:42][C:41]=2[N:40]=[C:39]1[CH3:47])=[O:32].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]1[C:9]([C:8](=[O:18])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:28][C:29]([CH3:48])=[C:30]1[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[CH:45]=[CH:44][N:43]=[CH:42][C:41]=2[N:40]=[C:39]1[CH3:47])=[O:32]
Reactant: O=Cc1ccccc1Cl
Reactant: O=C(CC(=O)c1ccccc1)Nc1ccccn1
Reactant: CC(N)=CC(=O)OCCCCn1c(C)nc2cnccc21
Solvent: CCO
Product: CC1=C(C(=O)OCCCCn2c(C)nc3cnccc32)C(c2ccccc2Cl)C(C(=O)Nc2ccccn2)=C(c2ccccc2)N1
Product: O

Procedure:
A solution of N-(pyrid-2-yl)-3-phenyl-3-oxopropionamide (0.84 g, 3.5 mM--see Preparation 15), 2-chlorobenzaldehyde (0.49 g, 3.5 mM) and 4-(2-methylimidazo[4,5-c]pyrid-1-yl)butyl 3-aminobut-2-enoate (1.01 g, 3.5 mM--see Preparation 13) in absolute ethanol (20 cm3) was heated at reflux, under nitrogen, for 16 hours. The cooled solution was evaporated to dryness and the residue purified by column chromatography on silica (Merck "Kieselgel 60"--Trade Mark) (2 passes) eluting primarily with ethyl acetate:diethylamine 97:3 and, secondly, dichloromethane: methanol 97:3. The product-containing fractions were evaporated to dryness, the residue re-dissolved in 2 cm3 dichloromethane, and the required solid precipitated by the addition of 25 cm3 ether, yield 0.35 g (16%), m.p. 124°-127°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[NH2:15]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NN)c2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-2-methylquinoline (5.01 g, 28.2 mmol) and 80% hydrazine hydrate (8 ml) solution was refluxed in ethanol (30 mL) for 8 h. The resulting solution was cooled to room temperature and the solid formed was collected by filtration, washed with ethanol, and dried to yield known 4-hydrazino-2-methylquinoline,53,54 4.712 g (79.70%); mp 195-197° C.; 1H NMR (DMSO-d6) δ 2.64 (3H, s, Me), 5.15 (2H, brs, exchangeable, NH2), 6.99 (1H, s, ArH), 7.58 (1H, t, J=7.6 Hz, ArH), 7.86 (1H, t, J=7.6 Hz, ArH), 7.85 (1H, d, J=8.4 Hz, ArH), 8.42 (1H, d, J=8.2 Hz, ArH), 10.64 (1H, s, exchangeable, NH), Anal. Calcd. for (C10H12N3.HCl): C, 57.28; H, 5.77; N, 20.04. Found: C, 57.28; H, 5.77; N, 20.04.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([S:19][C:20]4[CH:36]=[CH:35][C:23]5[N:24]=[C:25]([NH:27]C(=O)OC(C)(C)C)[S:26][C:22]=5[CH:21]=4)=[N:17][N:18]=3)[N:15]=2)=[CH:6][CH:5]=1.[CH3:37][O:38][CH2:39][CH2:40]Cl.C1(C)C=CC=CC=1>CN(C)C=O.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([S:19][C:20]4[CH:36]=[CH:35][C:23]5[N:24]=[C:25]([NH:27][CH2:40][CH2:39][O:38][CH3:37])[S:26][C:22]=5[CH:21]=4)=[N:17][N:18]=3)[N:15]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCNc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
45 mg of sodium hydride at 60% in oil are added to a mixture of 263 mg of 1,1-dimethylethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate and 0.10 cm3 of 2-chloroethyl methyl ether in 3 cm3 of N,N-dimethylformamide at 20° C. The suspension is heated in a bath at 90° C. overnight. The cooled reaction mixture is coevaporated to dryness several times with toluene. The residue obtained is taken up in methanol. After paste formation for 15 min, the brownish-yellow suspension is spin-filter-dried. The insoluble material is washed several times with methanol. This solid is treated with 0.4 cm3 of trifluoroacetic acid in 3 cm3 of dichloromethane at 20° C. for 2 h. The resulting reaction mixture is concentrated to dryness under vacuum, to give 116 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-N-(2-methoxyethyl)-1,3-benzothiazol-2-amine in the form of a yellowy-beige powder, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[OH-:27].[K+]>CCO>[O:27]1[CH:18]=[CH:17][CH:16]=[C:25]1[CH:24]=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)[CH:17]=2)[C:22]1=[O:26]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Solvent: CCO
Product: O=C1C(=Cc2ccco2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 76 %

Procedure:
According to the method of Example 32, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.270 g, 0.75 mmol) was reacted with 2-furylaldehyde (0.095 mL, 1.14 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.190 g (76%) of the title compound as a foam which solidified on standing to give a dark red powder, mp 57-60° C.: CI-MS m/e 335 (M++1).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:15][C:16]=2[CH3:17])[CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:27].[Na+].C(OC)(C)(C)C>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:14]2[O:15][C:16]([CH3:17])=[C:12]([CH2:11][O:10][C@@H:6]3[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:27])[CH2:5]3)[N:13]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
750 mg of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methoxyphenyl)-5-methyloxazole are dissolved in 20 ml of diethyl ether, and 1.4 g of sodium periodate, dissolved in 20 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 hours, 100 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 740 mg of {cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyl}acetaldehyde as a yellow-brown oil. C20H25NO4 (343.43), MS(ESI): 344 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.10.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][C:8](=O)[CH2:9][CH3:10].[NH2:13][NH2:14]>CC#N.O>[CH2:9]([C:8]1[CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[N:13]=1)[CH3:10]
Reactant: NN
Reactant: CCC(=O)CC(=O)CCCCCl
Solvent: CC#N
Solvent: O
Product: CCc1cc2n(n1)CCCC2

Procedure:
To a solution of 1-chloro-5,7-nonanedione (14.74 g, from Step 1) in a mixture of CH3CN (100 mL) and H2O (33 mL) was added 4.87 mL of hydrazine. After refluxing for 18 h, the reaction mixture was partitioned between EtOAc and aqueous NaHCO3 (saturated). Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. After concentration, the residue was purified by flash chromatography with 20% EtOAc in hexanes followed by 50% EtOAc in hexanes to give the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.24 (t, 3H, J=7.5 Hz), 1.79-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.62 (q, 2H, J=7.8 Hz), 2.75 (t, 2H, J=6.4Hz), 4.08 (t, 2H, J=6.1 Hz), 5.78 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1

Procedure:
2-(4-ethylphenoxy)-5-nitropyridine (7.33 g, 30 mmol) was dissolved in carbon tetrachloride (100 mL), and to the resulting solution were added N-bromosuccimide (5.34 g, 30 mmol) and benzoyl peroxide (0.73 g, 3 mmol). This solution was refluxed overnight under a nitrogen atmosphere. The reaction solution was allowed to cool, after which insoluble matter was removed by filtration. The resulting filtrate was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 1.34 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[N:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[N:15]=[N:16][NH:17][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nn[nH]n1
Yield: 52.2 %

Procedure:
The title compound of Example 11 (8.34 g, 42.5 mmol), sodium azide (3.04 g, 46.8 mmol), and ammonium chloride (2.50 g, 46.8 mmol) were stirred in DMF (30 mL) at 100° C. for 12 h. The reaction was concentrate and partitioned with DCM and 3 M HCl. The organic extracts were dried over sodium sulphate, filtered and concentrated. The resulting solid was triturated with ether and filtered to afford the title product (5.31 g, 52%) as a white solid.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[C:17](Cl)=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[O:15])=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[CH:9][N:8]=1.CN(C=O)C.C1COCC1>O>[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[C:17]([S:4][CH2:2][CH3:3])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[O:15])=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[CH:9][N:8]=1
Reactant: CCS
Reactant: CNc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(C(F)(F)F)nc1Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCSc1nc(C(F)(F)F)ccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
256 mg of ethyl mercaptan sodium salt (80%) was added to a mixture of 810 mg of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 4 ml of DMF and 1 ml of THF under ice cooling, then the mixture was heated to room temperature, and stirred for 3 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 705 mg of 2-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 2-Ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH2:7]([Br:11])[CH2:8][CH2:9][CH3:10]>>[Br-:11].[NH2:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH3:10])[N:3]=1
Reactant: CCCCBr
Reactant: Nn1ccnn1
Product: CCCCn1cc[n+](N)n1
Product: [Br-]

Procedure:
Using the same method as previously mentioned, 1-amino-1,2,3-triazole (2) 2.00 g (23.8 mmoles) was reacted with n-butyl bromide (16.01 g., 116.8 mmoles) at 60° C. Upon work-up, 4.12 g (78%) of 1-amino-3-butyl-1,2,3-triazolium bromide (2e) was recovered, mp 131-132° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)=[CH:12][N:11]=1)[CH2:2]2.[OH:25]O>>[NH:20]1[C:21]2[C:17](=[C:16]([C:13]3[CH:12]=[N:11][C:10]([O:9][C@@H:3]4[CH:4]5[CH2:5][CH2:6][N+:1]([O-:25])([CH2:8][CH2:7]5)[CH2:2]4)=[N:15][CH:14]=3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: OO
Reactant: c1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)c2cc[nH]c2c1
Product: [O-][N+]12CCC(CC1)[C@@H](Oc1ncc(-c3cccc4[nH]ccc34)cn1)C2

Procedure:
The product of Example 12A (10 mg, 0.03 mol) was oxidized with H2O2 (Aldrich, aq., 30%) according to the procedure of Example 23. The title compound was purified by chromatography [SiO2, CH2Cl2:MeOH (v. 5% NH3.H2O), 90:10]. 1H NMR (300 MHz, CD3OD) δ 2.01-2.32 (m, 3H), 2.42-2.64 (m, 2H), 3.41-3.70 (m, 5H), 3.91-4.24 (m, 1H), 5.39-5.59 (m, 1H), 6.55 (d, J=4.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 8.96 (s, 2H) ppm.