Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9](OS(C)(=O)=O)=[CH:8][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH3:36]N(C)C=O>>[C:32]([O:31][C:29]([N:23]1[CH2:28][CH2:27][N:26]([C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[CH3:36])[CH2:25][CH2:24]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)Cn1nc(-c2ccccc2)cc(OS(C)(=O)=O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C=O
Product: Cc1c(-c2ccccc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.5 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxy-6-phenyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted in N,N-dimethylformamide as a solvent to yield the title compound as a yellow oil (yield: 83.5%).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21](OCC)=[O:22])[CH2:4]1)[CH3:2].O/[N:27]=[C:28](\[NH2:32])/[CH2:29][O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21]2[O:22][N:32]=[C:28]([CH2:29][O:30][CH3:31])[N:27]=2)[CH2:4]1)[CH3:2]
Reactant: COC/C(N)=N/O
Reactant: CCOC(=O)C[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H]1C[C@H](Cc2nc(COC)no2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 130 °C
Yield: 55.5 %

Procedure:
To a solution of ethyl 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate (0.100 g, 0.293 mmol) in toluene (0.20 mL) and MeOH (0.20 mL) was added (Z)-N′-hydroxy-2-methoxyacetimidamide (0.300 g, 2.89 mmol, Tyger) and K2CO3 (0.100 g, 0.726 mmol). The solution was heated in a CEM microwave at about 130° C. for about 1 h (250 psi maximum pressure, 1 min ramp, 300 max watts). The solvent was removed under reduced pressure. The residue was diluted with DCM (3 mL) and a small amount of MeOH. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM. The residue was dissolved in EtOAc and heptane was added. The solvent was concd. The solid was dried in a heated vacuum oven (about 70° C.) for about 20 h to afford 5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole (0.062 g, 56%) as a white solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 382 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5](=[O:18])[N:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:7]([CH3:10])[C:8]=2[CH3:9])[CH2:3][CH2:2]1.[Br:19]Br>O1CCOCC1.O.CCOC(C)=O>[Br:19][CH2:9][C:8]1[N:7]([CH3:10])[N:6]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:5](=[O:18])[C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)c(=O)n(-c2ccc(F)cc2)n1C
Reactant: BrBr
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(CBr)c(C2CC2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 4-cyclopropyl-2-(4-fluoro-phenyl)-1,5-dimethyl-1,2-dihydro-pyrazol-3-one (0.32 g) in a round bottom flask under argon in dioxane (5 mL) was added bromine (0.20 g). The reaction was stirred at ambient temperature for 2 days. The reaction was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted with more EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified via ISCO combiflash chromatography (EtOAc/heptane) to afford the desired 5-bromomethyl-4-cyclopropyl-2-(4-fluoro-phenyl)-1-methyl-1,2-dihydro-pyrazol-3-one as a light brown solid. MS (ESI+): 327.1 ([M+H]+).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([O:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:16])=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Oc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 93.5 %

Procedure:
4-Hydroxy-benzoic acid phenyl ester (5 g, 23.3 mmol), benzyl bromide (5.54 mL, 46.7 mmol), K2CO3 (9.6 g, 70.0 mmol), and anhydrous acetone (200 mL) were mixed and reflux overnight. All acetone was removed. To the mixture was added water (300 mL). The solid was filtered, washed with methanol (50 mL×3), and dried to give the desired compound (6.63 g, 93%). MS (DCI) m/z 305 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 5.17 (s, 2H) 7.30-7.09 (m, 2H) 7.17-7.23 (m, 2H) 7.27 (m, 1H) 7.34-7.48 (m, 7H) 8.13-8.19 (m, 2H)
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@:4]1([NH:18]C(=O)OC(C)(C)C)[C:6](=[O:17])[NH:7][S:8]([C:11]1([C:14]([CH3:16])=[CH2:15])[CH2:13][CH2:12]1)(=[O:10])=[O:9])=[CH2:2].[ClH:26]>O1CCOCC1>[ClH:26].[NH2:18][C@:4]1([C:6]([NH:7][S:8]([C:11]2([C:14]([CH3:16])=[CH2:15])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[O:17])[CH2:5][C@H:3]1[CH:1]=[CH2:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C(=C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C(=C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of step 1 (136 mg) was dissolved in a solution of HCl in dioxane (1.5 mL). The mixture was stirred for 3 hours at room temperature. The solvent was removed in vacuo and the crude product was used in the next step. 1H NMR (400 MHz, CDCl3): δ (ppm) 5.69-5.62 (m, 1H), 5.41 (d, 1H), 5.26 (d, 1H), 5.23 (s, 1H), 5.21 (s, 1H), 2.77-2.72 (m, 1H), 2.02-1.98 (m, 1H), 1.95 (s, 3H), 1.93-1.84 (m, 2H), 1.74-1.69 (m, 1H), 1.17-1.06 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[CH:33]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2/[CH:33]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 100 °C
Yield: 116.1 %

Procedure:
To a mixture of 6-chlorooxindole (4.58 g, 20 mmol) and 4-(4-bromo-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (10 g, 26 mmol) in methanol (50 mL) was added piperidine (2.56 mL, 26 mmol) dropwise. The mixture was then heated at 100° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (12.4 g, 90%).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[N:16]([O-])=O.[Na+].[OH-].[Na+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[OH:28][C:22]1[CH:27]=[CH:26][C:25]([N:16]=[N:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:14][CH:13]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: O=N[O-]
Reactant: CCCCCCCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
32.9 g (0.17 M) of 4-heptylaniline was cooled to 0° C. or below, 85 g of 10% aqueous hydrochloric acid solution was added, and then a solution of 12.1 g of sodium nitrite in 70 ml of water was added. During the addition, the mixture was cooled so as not to exceed 0° C. After the addition, the mixture was allowed to react for 30 minutes, transferred into a dropping funnel and added dropwise into 300 ml of an 8% NaOH aqueous solution containing 16 g of phenol held at 5° C. or below. After the addition, the mixture was stirred for 1 hour, and then 10% hydrochloric acid aqueous solution was added thereto until a pH of 5-6 to precipitate the reaction product. The precipitate was separated by filtration, washed with water and dried overnight under reduced pressure. After the drying, the product was washed with 500 ml of petroleum ether and further dried under reduced pressure to obtain 34.7 g (0.12 M) of 4-hydroxy-4'-heptylazobenzene. The yield was 71%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]([NH2:20])[CH:11]=[C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:13]=1.C(O)(=O)C.[CH:25](N)=[NH:26]>CC(O)CC.[OH-].[Na+]>[CH3:8][C:9]1[N:10]([NH:20][CH:25]=[NH:26])[CH:11]=[C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:13]=1
Reactant: Cc1nc(-c2cnn(C)c2)cn1N
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCC(C)O
Product: Cc1nc(-c2cnn(C)c2)cn1NC=N
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-amine, trifluoroacetate salt (103.0 g, 353.7 mmol) and formamidine acetate (98%, 131 g, 1.23 mol) were combined in 2-butanol (350 mL). The reaction was heated to 100° C. for 3 hours, at which time it was allowed to cool to room temperature and diluted with a 2:1 mixture of 10 N sodium hydroxide solution/saturated aqueous sodium chloride solution (300 mL). After vigorous stirring, the layers were separated, and the aqueous layer was extracted with 2-butanol (4×250 mL). The combined organic layers were concentrated in vacuo, and the resulting solid was slurried with acetonitrile (550 mL), stirred for 2 hours at room temperature and filtered. The collected solids were washed with dry acetonitrile (3×100 mL), then dried in vacuo at 40° C. for 2 hours to provide the product as an off-white solid. Yield: 61.5 g, 301 mmol, 85%. The mother liquor was concentrated to dryness, then dissolved in acetonitrile (200 mL) and allowed to stand for 18 hours. The resulting solid was isolated by filtration to provide additional product as an off-white solid. Combined yield: 64.8 g, 317 mmol, 90%. 1H NMR (500 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.25 and 2.29 (2 s, 3H), 3.88 and 3.88 (2 s, 3H), 7.03 and 7.19 (2 s, 1H), 7.39 and 7.94 (2 s, 1H), 7.69 and 7.67 (2 s, 1H), 7.77 and 7.75 (2 s, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([N:4](C(OC(C)(C)C)=O)[CH:5]([CH3:45])[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH:19]([CH3:30])[N:20]([CH2:28][CH3:29])C(OC(C)(C)C)=O)[CH3:3]>CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH2:28]([NH:20][CH:19]([CH3:30])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[CH3:45])[CH3:29]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)CCN(CCCCCCCN(CCC(C)N(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNC(C)CCNCCCCCCCNCCC(C)NCC
Reaction time: 8 h

Procedure:
Add 1N HCl in methanol (50 ml) to 1,17-diethyl-2,16-dimethyl-1,5,13,17-tetra(t-butoxycarbonyl)-1,5,13,17-tetraazaheptadecane (3.9 g, 0.0054 mol) and stir overnight. Remove the solvent in vacuo and recrystallize the residue two times from methanol/acetonitrile (40/60, v/v) to yield 0.90 g of the title compound as a white solid (mp 249°-50 ° C.). Rf is 0.56 for TLC on silica gel developed with 40% conc. ammonia in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(Cl)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: COc1cc(Cl)cc(C=O)c1
Reaction time: 1.25 h
Yield: 77.1 %

Procedure:
A mixture of 3-chloro-5-methoxybenzyl alcohol (5.0 g, 28.9 mmol) and pyridinium chlorochromate (20% on alumina, 40 g, 37.8 mmol) was allowed to stir for 1.25 hr. Diethyl ether (200 ml) was then added followed by filtration of precipitate. The filtrate was concentrated under reduced pressure and the resulting residue was purified via silica gel chromatography using 40% dichloromethane, 60% petroleum ether as eluant, to give 3.8 g of 3-chloro-5-methoxybenzaldehyde. 1H-NMR (CDCl3): 3.84 (s, 3H) 7.13 (s, 1H), 7.28 (s, 1H), 7.41 (s, 1H), 9.89 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)C=Cc1cccc(N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-(3-nitro-phenyl)-acrylic acid methyl ester (22) (10.0 g, 48 mmol) and SnCl2.2H2O (54 g, 240 mmol) in anhydrous ethanol (200 ml) was heated at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, then the solvent was partially evaporated by vacuum rotary evaporator (up to ca. ½ volume). The residue was poured in ice water, neutralised (pH˜7) with saturated Na2CO3 and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with saturated NaCl and dried (Na2SO4). The extract was filtrated through a small amount of silicagel and evaporated to give pure title compound in a form of white crystals (8.5 g, 99%). 1H NMR (CDCl3, HMDSO), δ: 3.69 (2H, br s); 3.79 (3H, s); 6.39 (1H, d, J=16.0 Hz); 6.61-7.03 (3H, m); 7.18 (1H, t, J=7.6 Hz); 7.62 (1H, d, J=16.0 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44])[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:40][C:39]1=[O:44])[CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCN1CCNCC1=O
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1=O
Yield: 35 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-butylpiperazin-2-one as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[NH:21](/[C:25](/[CH3:31])=[CH:26]\[C:27](OC)=[O:28])[C:22]([CH3:24])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:27](=[O:28])[CH:26]=[C:25]([CH3:31])[N:21]=[C:22]2[CH3:24])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][S:12][CH2:13][CH2:14]1
Reactant: Nc1ccc(N2CCSCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCSCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50.4 %

Procedure:
To a solution of 3-fluoro-4-thiomorpholinoaniline (1.20 g, 5.65 mmol) in anhydrous CH2Cl2 (60 mL) was added trimethylaluminium (28.5 mL, 28.5 mmol, 1 M in heptane) carefully dropwise under the protection of N2. Upon the end of addition the mixture was stirred at rt for 40 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (2.66 g, 16.92 mmol) in anhydrous CH2Cl2 (20 mL). Upon the end of addition the reaction mixture was stirred at rt for another 6 h, then quenched with water and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as pale yellow solid (0.91 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH3:14])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.Br[C:16]1[S:17][CH:18]=CC=1.Cl.C(O[CH2:25][CH3:26])C>[Ni]>[CH2:12]([C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([C:16]3[S:17][CH:18]=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)=[CH:11][CH:10]=1)[CH2:13][CH3:14]
Reactant: Brc1cccs1
Reactant: CCOCC
Reactant: CCCc1ccc(-c2ccc(Br)s2)s1
Agent: [Ni]
Agent: Cl
Product: CCCc1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 0 °C

Procedure:
Next, 8 g (0.028 mol, 1 eq) of the obtained 5-bromo-5′-propyl-2,2′-bithiophene and 0.04 g (0.07 mmol, 0.0025 eq) of Ni (dppp) Cl2 were introduced into a three-necked flask, and this was flushed with Ar. To this, 100 ml of diethyl ether was added and stirred (reaction fluid α). 0.94 g (0.0385 mol, 1.38 eq) of Mg was introduced to another three-necked flask, and flushed with Ar. To this, 50 ml of diethyl ether was added and stirred. To this, a solution, of which 5.7 g (0.035 mol, 1.25 eq) of 2-bromothiophene was diluted with 50 ml of diethyl ether, was dropped. After dropping, this was refluxed for 2 hours, and was laid for cooling (reaction fluid β). The reaction fluid β was dropped to the reaction fluid α, which was cooled to 0° C. After dropping, this was stirred for 2 hours and was refluxed for 12 hours. This was cooled to 0° C., 30 ml of 2N—HCl was dropped. After dropping, the temperature was returned to the room temperature, and stirred for 2 hours. This was extracted with chloroform, water washed with Na2CO3 aqueous solution until pH is 7, and dehydrated with Na2SO4. After removing Na2SO4 by filtration, the solvent was removed. This was purified by silica gel chromatography, and specified substance of 5-propyl-2,2′:5′,2″-terthiophene (4 in the chemical reaction formula) was obtained. Yielding quantity was around 6 g, and yielding percentage was 75%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH2:15]([O:17][C:18]([CH:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([CH:20]1[CH2:21][N:22]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:23][CH2:24][N:25]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:19])[CH3:16]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1
Product: CCOC(=O)C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 31 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-naphthylsulphonyl chloride was reacted with 3-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine to give 2-ethoxycarbonyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 31% yield;
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccccn3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1ccc(CC[C@H]2CNCCN2)nc1
Reaction time: 0.67 h
Yield: 74.8 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-(2-pyridin-2-yl-ethyl)-piperazine (2.86 g, 7.69 mmol) in ethanol (50 mL). Add ammonium formate (2.43 g, 38.5 mmol) and palladium (430 mg, 5 wt. % on carbon) and heat to reflux. After 6 hours 40 minutes, filter the palladium on carbon and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (5%–15%) as the eluent to give the title compound (1.1 g, 75%): mp 83–87° C.; mass spectrum (ion spray): m/z=192 (M+1). Analysis calculated for C11H17N3: C, 69.07; H, 8.96; N, 21.97. Found: C, 68.84; H, 8.85; N, 21.65.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:11][C:10]=3[F:23])[N:7]=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=2)[CH2:3][CH2:2]1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([C:4]2[N:8]([C:9]3[C:10]([F:23])=[CH:11][C:12]([NH:16][C:17](=[O:22])[C:18](=[CH:30][N:31]([CH3:33])[CH3:32])[C:19](=[O:21])[CH3:20])=[CH:13][C:14]=3[F:15])[N:7]=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Product: CC(=O)C(=CN(C)C)C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Step-2: N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3,5-difluorophenyl)-3-oxobutanamide (1 g, 2.6 mmol) and N,N-Dimethylformamide dimethylacetal (1.7 g, 14.2 mmol) were mixed and stirred at rt for overnight. Workup (AcOEt/H2O) followed by purification on 60-120 mesh silicagel using AcOEt and Peteher (1:1) as eluent afforded N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (0.7 g).
Reaction SMILES: B([O-])O[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=CCCCCCC.B1C2CCCC1CCC2.[OH-].[Na+].[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44](Br)[CH:45]=2)[C:40]([CH2:48][OH:49])=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:45]=2)[C:40]([CH2:48][OH:49])=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCCCCCCCOB[O-]
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2ccc(Br)cc21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CCCCCCCCc1ccc2c(CO)cn(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An octyl boronate intermediate is generated by adding 1-octene (1.38 g, 14.1 mmol) to a solution of 9-BBN in THF (28.3 mL of a 0.5 M solution, 14.1 mmol). The reaction mixture is stirred at room temperature overnight. An aqueous solution of sodium hydroxide (5.0 mL of a 3.0 M solution) is added, followed by the addition of compound 25 (3.10 g, 10.0 mmol) and Pd[P(Ph)3]4 (0.310 g, 0.270 mmol). The reaction is brought to reflux and maintained for 12 hours under an inert atmosphere. The reaction is cooled, filtered, concentrated in vacuo and the residue purified using silica gel chromatography with hexane/ethyl acetate (75:25) as solvent.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[O:21][CH3:22])/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[O:21][CH3:22])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CO[C@@H]1CCCC[C@H]1O/N=C(\C(=O)O)c1csc(N)n1

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(trans-2-methoxycyclohexyloxyimino)acetate (1.79 g) was hydrolysed with IM sodium hydroxide (10.75 ml) in ethanol (20 ml) as described in Example 4e. After acidification of the aqueous phase to pH 2-3 the water was removed under reduced pressure. The residue was extracted with hot ethanol and concentrated to dryness to give a brown foam. Trituration with ethyl acetate gave the title compound as a buff coloured solid (0.904 g). νmax (KBr) 3302, 3207, 1628, 1534, and 1450 cm-1 ; δH ((CD3)2SO) inter alia 1.00-2.00 (8H, m), 3.00-3.33 (4H, m and s), 3.90-4.30 (1H, m), 6.87 (1H, s), and 7.28 (3H, br. s). [Mass spectrum: +ve ion (thioglycerol) MH+ (300), MNa+ (322)].