Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.Br[CH2:27][C:28](=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:27][C:28](=[O:30])[CH3:29])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CC(=O)CBr
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCC(C)=O
Yield: 63 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 10 ml of methyl ethyl ketone, and 0.15 g (1.10 mmol) of bromoacetone as a reaction reagent (XII) and 0.30 g (2.20 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=1:2) to give 0.29 g (yield 63%) of 4-methoxy-5-methyl-6-(5-acetylmethyloxy-1-ethylpyrazol-4-yl) carbonylthiochroman-1, 1-dioxide (Compound No. 59) as an end compound which comes under the general formula (XI). Table 20 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m, 4H), 7.65 (m, 2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z 454.0 (M++1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (5 g, 29 mmol), piperidine (2.9 mL, 29 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 120° C. for 4 h. The reaction mixture was cooled to room temperature and poured into ice cold water (100 mL). The crude solid product was collected by filtration, air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with CHCl3) to yield the product as orange crystals (1.4 g, 22%). See, Aust. J. Chem., 47:247–262 (1994).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[CH3:22])=[O:11])=[CH:4][C:3]=1[CH3:23].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH3:22][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][C:12]=1[C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:3]([CH3:23])[CH:4]=1
Reactant: C1=COCCC1
Reactant: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(O)c(C)c2)c(C)c1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(OC3CCCCO3)c(C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of (E)-N-(4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3-methylphenyl)acetamide (100 mg, 0.32 mmol) in DCM was added 300 mg of H2SO4/SiO2 (cat. amount), and 3,4-dihydro-2H-pyran (500 mg, 5.9 mmol). The reaction mixture was stirred for 1 h at room temperature. The resulting slurry was filtered, concentrated under reduced pressure, and the product was purified by column chromatography (EtOAc/Hex, 10% to 50% gradient), resulting in 80 mg (78%) of the title compound. MS (EI) for C24H27NO4: 394 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[C:14]([O:18][C:19]([NH:21][CH2:22][C@H:23]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:24]([O:26][CH3:27])=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>ClCCl>[C:14]([O:18][C:19]([NH:21][CH2:22][C@H:23]([N:28]1[CH2:29][CH2:30][N:31]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH2:32][CH2:33]1)[C:24]([O:26][CH3:27])=[O:25])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)C(C)C)CC1
Temperature: 0 °C
Yield: 81.1 %

Procedure:
1.2 ml (8.3 mmol) of triethylamine and then 0.8 ml (7.6 mmol) of isobutyryl chloride are added to a solution of 2.0 g (6.9 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate in 20 ml of dichloromethane, cooled beforehand to 0° C. After stirring at ambient temperature for 1 h 30, water is added. The reaction medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude residue obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 2.0 g (81%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(C[NH:16][CH2:17][CH2:18][CH2:19][NH2:20])CN.O>C(Cl)Cl>[C:4]([O:3][C:1]([NH:20][CH:19]([CH2:19][CH2:18][CH2:17][NH2:16])[CH2:18][CH2:17][NH2:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NCCCNCCCN
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCN)CCCN
Yield: 44.7 %

Procedure:
A solution of 33 g of tert-butyl dicarbonate in 200 ml of methylene chloride was added at 5° C. to a solution of 39.3 g of 3,3'-diaminodipropylamine in 300 ml of methylene chloride and after stirringf or 16 hours at 20° C., water was added, followed by decanting and evaporation to dryness. The residue was chromatographed on silica (eluant; methanol-ammonia (98-2)) to obtain 15.5 g of the expected product which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CN(C=O)C.C(OCC)(=O)C>[CH2:16]([O:8][C:7]1[C:2]([F:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1)[CH3:17]
Reactant: CCI
Reactant: Cc1ccc(O)c(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C)nc1F

Procedure:
2-Fluoro-3-hydroxy-6-picoline (500 mg) was initially introduced in absolute DMF (20 ml) and potassium carbonate (1 g) was added. After this, ethyl iodide (0.6 ml) was added dropwise with stirring and the mixture was stirred for 1 h. Subsequently, water and ethyl acetate were added to the reaction mixture. After separating off the organic phase, the mixture was additionally extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product obtained (477 mg) was reacted directly in the next stage.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(=O)(OCC)OCC>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(=O)OCC
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To a mixture consisting of 69.9 g (0.460 mol) of 2,3,5-trimethylhydroquinone, 52.5 g (0.386 mol) of zinc chloride, 150 ml of diethyl carbonate and 7.5 g of concentrated hydrochloric acid, 138.3 g (0.459 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 30°-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 30 ml of water, the solvent was distilled off. Toluene (300 ml ) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 201.2 g of the title compound were obtained as a brown oil (yield: 99.2%, GLC purity: 97.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][NH:33][C:34]([NH:36][OH:37])=[NH:35].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:32][NH:33][C:34](=[NH:35])[NH:36][OH:37])[CH2:10]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1cccc(Cl)c1Cl)C2
Temperature: 85 °C
Reaction time: 2 h
Yield: 188.2 %

Procedure:
A mixture of 7-(2,3-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (306 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (320 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (6 ml) was stirred at 85° C. (bath temperature) for 2 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (25 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. The residue was recrystallized form ethanol and dried to give 7-(2,3-dichlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 95) (390 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5]=[CH:6][C:7]1[S:8][C:9]([Br:12])=[CH:10][CH:11]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[S:8][C:9]([Br:12])=[CH:10][CH:11]=2)[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[N:24]=1)=[O:14]
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)s1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
4-(5-Bromo-thiophen-2-yl)-2-oxo-3-butenoic acid methyl ester (19.9 mg, 72.2 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (14.2 g, 79.4 mmol) were added to acetic acid (250.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 18.9 g of the titled compound as a pale yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH:16]O>C(O)(=O)C>[C:11]([C:7]1[C:6](=[O:15])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9](=[O:16])[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: OO
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Temperature: 55 °C

Procedure:
A mixture of 2,6-di-t-butylphenol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 3 h. The catalyst was recovered by simple filtration and 2,6-di-tert-butyl-1,4-benzoquinone formed (65%) was separated by chromatographic purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]([NH:17][C@@H:18]([CH:39]([CH3:41])[CH3:40])[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([NH:28][CH:29]([CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[CH:30]([CH3:32])[CH3:31])=[O:27])=[O:20])=[O:16].ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O.C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]([NH:17][C@@H:18]([CH:39]([CH3:41])[CH3:40])[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]([NH:28][CH:29]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:30]([CH3:32])[CH3:31])=[O:27])=[O:20])=[O:16]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(C)C)C(O)C(F)(F)F)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(=O)C(F)(F)F)C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.84 g) was added to a solution of (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide (0.41 g) dissolved in dimethylsulphoxide (DMSO; 5 ml) and toluene (5 ml), followed by dropwise addition of dichloroacetic acid (0.32 ml). The resulting solution was allowed to stir at 20° C. for 2 hours. The solution was then poured into ethyl acetate (200 ml) and washed successively with 1M hydrochloric acid, water and brine. The organic solution was dried (MgSO4) and concentrated under vacuum. The residue was purified by flash chromatography (gradient elution; methanol:methylene chloride, 3:97 to 5:95) to give (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoroacetyl)propyl]pyrrolidine-2-carboxamide (0.27 g) as a white foam (as a mixture of ketone and hydrated forms); TLC, Rf =0.4 (methanol:dichloromethane, 2.5:97.5); 1H NMR (DMSO/D2O): 4.44 (m, 1H), 4.00 (m, 2H), 3.72 (m, 1H), 3.51 (m, 4H), 202-1.75 (m, 6H), 0.95-0.78 (m, 12H); Analysis for C18H28F3N3O5 0.3H2O: Calculated: C, 50.42; H, 6.72; N, 9.80; Found: C, 50.31; H, 6.28; N, 9.56.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7]1.Cl.[NH2:25][C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/[C:32](O)=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[NH2:25][C:26]1[CH:27]=[CH:28][C:29](/[CH:30]=[CH:31]/[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=3)[CH2:7]2)=[O:33])=[CH:35][CH:36]=1
Reactant: NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(/C=C/C(=O)NCCCCN2CCc3ccc(OS(=O)(=O)C(F)(F)F)cc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A mixture of 2-(4-aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (440 mg, 1.25 mmol), trans-4-aminocinnamic acid hydrochloride (250 mg, 1.25 mmol), triethylamine (0.174 ml, 1.25 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.25 mmol) and 1-hydroxybenzotriazole (100 mg, 0.74 mmol) in dichloromethane (50 ml) was stirred at room temperature for 18 h. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 10-100% ethyl acetate-hexane gradient elution to afford the title compound (280 mg, 45%).
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[C:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH2:4][CH3:5].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Pd]>[NH2:1][C:2](=[O:44])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH2:4][CH3:5]
Reactant: CCC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reaction time: 16 h
Yield: 244.9 %

Procedure:
A suspension of 10% Pd/C (100 mg), tert-butyl 4-(4-((4-((2-(1-amino-1-oxobutan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A1) (167 mg, 0.275 mmol) and Et3N (1.0 mL) in DMF (10 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL), filtered through Celite then the solvent removed under reduced pressure to give the title compound A2 as a yellow oil (412 mg, 98%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.49-7.42 (m, 1H), 7.31 (s, 1H), 7.22-7.14 (m, 5H), 6.87 (s, 1H), 4.06 (d, J=10.5 Hz, 2H), 3.61 (dd, J=8.8, 6.1 Hz, 1H), 3.29-2.94 (m, 4H), 2.88-2.74 (m, obscured by solvent), 2.70-2.59 (m, 1H), 2.04-1.92 (m, 1H), 1.74 (d, J=12.6 Hz, 2H), 1.61-1.43 (m, 3H), 1.41 (s, 9H), 0.83 (t, J=7.3 Hz, 3H). LCMS-A: rt 6.722 min; m/z 612 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([CH2:12][C@@H:13]2[CH2:16][C@H:15]([OH:17])[CH2:14]2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:17][C@H:15]1[CH2:16][C@@H:13]([CH2:12][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1C[C@@H](CN2CCOCC2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1C[C@@H](CN2CCOCC2)C1
Reaction time: 1 h

Procedure:
MsCl (0.27 mL, 3.5 mmol) was added dropwise to a solution of intermediate 40, cis-3-(Morpholin-4-ylmethyl)cyclobutanol (0.5 g, 2.9 mmol) and triethylamine (1 mL, 7.0 mmol) in CH2Cl2 (5 mL) in argon under stirring on an ice bath. The mixture was brought to room temperature for 1 h, water (10 mL) was added, and the layers were separated. The organic layer was washed with water. The water layer was washed with the saturated NaCl solution, dried over Na2SO4, and evaporated to give the title compound as a yellow oil in 99% (718 mg, 2.88 mmol) yield. This material was used without additional purification. 1H-NMR (400 MHz)-data (dmso-d6): 4.83 (dddd, 1H, J=7.5 Hz, CHOMs), 3.51-3.58 (m, 4H, CH2OCH2), 3.12 (s, 1H, Ms), 2.46-2.55 (m, 2H, cyclobutylCHH), 2.28-2.40 (m, 6H, (CH2)3N), 2.00-2.12 (m, 1H, CHCH2N), 1.80-1.89 (m, 2H, cyclobutylCHH).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[F:7][C:8]([F:12])([F:11])[CH:9]=[CH2:10]>N(C(C)(C)C#N)=NC(C)(C)C#N.C(C1C=CC=CC=1)(=O)CCCCCCC.C1(C)C=CC=CC=1>[F:7][C:8]([F:12])([F:11])[CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: C=CC(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 60 °C
Reaction time: 27 h
Yield: 82.5 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with azobisisobutyronitrile (AIBN, 0.231 g, 1.41 mmol), toluene (45 mL), 3-mercaptopropionic acid (3.40 g, 32.0 mmol), and octanophenone (526.2 mg) as an internal standard, and was purged and pressure checked with nitrogen (N2). The reactor was cooled with dry ice and the 3,3,3-trifluoropropene (3.1 g, 32.3 mmol) was condensed into the reactor. The ice bath was removed and the reactor heated to 60° C. and stirred for 27 hours. The internal yield of the reaction was determined to be 80% by use of the octanophenone internal standard. The pressure was released and the crude mixture removed from the reactor. The mixture was concentrated by rotary evaporation and 50 mL of 10% sodium hydroxide was added. The solution was washed with methyl tert-butylether (50 mL) then acidified to pH ˜1 with 6 N hydrochloric acid. The product was extracted with 100 mL methyl tert-butylether, dried over magnesium sulfate (MgSO4), filtered, and concentrated to give the crude titled compound as an oil (5.34 g, 26.4 mmol, 83%): 1H NMR (400 MHz, CDCl3) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.76-2.64 (m, 4H), 2.47-2.30 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 177.68, 125.91 (q, J=277.1 Hz), 34.58 (q, J=28.8 Hz), 34.39, 26.63, 24.09 (q, J=3.3 Hz); 19F NMR (376 MHz, CDCl3) δ −66.49.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:22][CH2:23][O:24][C:25]([CH2:27][CH:28]1[C:33](=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:29]3[CH:28]([CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])[CH2:33][CH2:32][CH2:31][C:30]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-trifluoromethylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:20](=O)[C:19]4[C:14](=[CH:15][C:16]([OH:24])=[C:17]([CH2:22][CH3:23])[CH:18]=4)[O:13][C:12]=3[CH3:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O.[NH2:27][NH2:28]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:20]([C:19]4[CH:18]=[C:17]([CH2:22][CH3:23])[C:16]([OH:24])=[CH:15][C:14]=4[OH:13])=[N:27][NH:28][C:12]=3[CH3:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: CCc1cc2c(=O)c(-c3ccc4c(c3)OCCO4)c(C)oc2cc1O
Solvent: O
Product: CCc1cc(-c2n[nH]c(C)c2-c2ccc3c(c2)OCCO3)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-6-ethyl-7-hydroxy-2-methyl-chromen-4-one (0.6 g, 1.77 mmol), hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-methyl-1H-pyrazol-3-yl]-6-ethyl-benzene-1,3-diol as a clear oil which solidified over a period of 1 month (0.38 g, 60.9%); Rf 0.4 cf SM 0.6 Hexane/Ethyl acetate/MeOH (8/4/1).