Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]2[C:8]=1[CH:11]=[CH:12][CH:14]=[N:7]2
Reactant: Cc1ccc(Br)cc1N
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(Br)c2cccnc12
Temperature: 0 °C
Yield: 67.6 %

Procedure:
A solution of 5-Bromo-2-methylaniline (7.44 g), glycerol (7.4 g), nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at 150° C. for 3 hrs. The solution was cooled to 0° C. then carefully neutralized with aqueous sodium hydroxide. The reaction mixture became a dark gum and was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, then dried with sodium sulphate and the solvent removed in vacuo. The crude product was purified by column chromatography (dichloromethane) to afford the title compound as a solid (6 g). 1H-NMR (CDCl3, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[C:6]1[S:7][C:8]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[C:9]=2[N:10]=1.[Cl-].[NH4+]>C(OCC)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:11]1[C:9]2[N:10]=[C:6]([CH2:1][CH3:2])[S:7][C:8]=2[CH:14]=[C:13]([F:15])[CH:12]=1
Reactant: Fc1cc(Cl)c2nc(Cl)sc2c1
Reactant: CC[Mg]Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1nc2c(Cl)cc(F)cc2s1
Reaction time: 2 h

Procedure:
A solution of 0.2 mol of ethyl magnesium bromide in diethyl ether was added to a solution of 22.0 g (0.1 mol) of 2,4-dichloro-6-fluorobenzothiazole and 3.3 g (5 mmol) of dichlorobis(triphenylphosphine)nickel in 0.5 1 of diethyl ether. Stirring was carried out for 2 hours, after which the mixture was poured onto saturated aqueous ammonium chloride solution. The product was extracted with diethyl ether. The combined organic phases were washed with water, dried over magnesium sulfate and finally evaporated down. Purification of the crude product was effected by means of silica gel chromatography (eluent: 8:2 cyclohexane/methyl tert-butyl ether). Yield: 10.3 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[C:4](=[O:12])[CH:3]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:7]=[CH:6][N:5]([CH:8]4[CH2:11][O:10][CH2:9]4)[C:4](=[O:12])[CH:3]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: O=c1cc(Br)ccn1C1COC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccn(C3COC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pd(PPh3)4 (10 mg) was added to a solution of 4-bromo-1-(oxetan-3-yl)pyridin-2(1H)-one (14 mg) in 1,2-dimethoxyethane (6 mL) under nitrogen. The formed mixture was stirred at room temperature for 1 h prior to the addition of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (24 mg) in ethanol (2 mL) followed by saturated aqueous NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate (3×). The combined organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound. Yield: 14 mg (55% of theory); LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=445 [M-Me2CO+H]+; 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.12 (s, 3H), 1.45 (d, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.72 (m, 1H), 4.70 (m, 2H), 5.09 (m, 2H), 5.63 (m, 1H), 5.71 (m, 1H), 6.43 (m, 1H), 6.61 (m, 1H), 6.98 (d, 2H), 7.28 (m, 7H), 7.61 (d, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH2:20][CH:19]=[CH2:18])=[O:7]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1cccc(CCl)c1

Procedure:
A solution of 3-(chloromethyl)-benzoic acid (50.0 g, 0.293 mol), potassium carbonate (48.61 g, 0.352 mol) and allyl bromide (50.7 mL, 0.586 mol) in acetone (500 mL) is refluxed for 2 hours, after which time the solution was cooled to room temp. and filtered through celite. The filtrate is evaporated and the residue chromatographed (silica, 5% EtOAc/hexane) to yield allyl 3-(chloromethyl)-benzoate as a clear oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[OH:23])=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
To a solution of {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (227 mg, 0.589 mmol) in chloroform (10 mL) was added manganese dioxide (454 mg, 5.22 mmol). The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated to provide {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanone (200 mg, 89%) as a white solid. Rf 0.30 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.58 (d, 1H), 8.40 (d, 1H), 8.16 (d, 1H), 8.00 (d, 2H), 7.61 (t, 1H), 7.55–7.38 (m, 3H), 7.01 (t, 1H), 6.75 (d, 1H), 5.02 (d, 1H), 4.18 (m, 1H), 1.96 (m, 2H), 1.70–1.41 (m, 6H); MS m/z 384 (M+1).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:37])[C:21]([CH3:36])=[C:22]([C:24]3[CH:35]=[CH:34][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:37])[C:21]([CH3:36])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:34][CH:35]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-propyl-nicotinamide (Intermediate 31, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-propyl-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=1.[Na+]>CN(C)C=O>[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:3])(=[O:16])=[O:14])=[CH:9][CH:8]=1
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 3 °C
Reaction time: 2 h

Procedure:
A flask containing 300 ml dry dimethyl formamide was cooled in an ice/salt bath to 3° C. Thionyl chloride (250 ml) was added dropwise with stirring over a period of 2 hrs. Sodium styrene p-sulphonate (200 g}was added in aliquots over a further 1 hour. The reaction mixture was allowed to stand for 24 hours at room temperature. The solution was poured onto ice and extracted with toluene (1000 ml). The extract was neutralised with sodium carbonate, washed with water, dried over magnesium sulphate and the solvent removed by evaporation under vacuum at 30° C. Finally the purified styrene p-sulphonyl chloride was filtered and stored at 5° C. in the dark.
Reaction SMILES: [SH:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH2:10]([C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:11]O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:30][C:13]([F:31])([C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][O:4][C:3](=[O:5])[CH:2]([SH:1])[CH2:6][C:7]([O:9][CH2:11][CH2:10][C:13]([F:30])([F:31])[C:14]([F:28])([F:29])[C:15]([F:26])([F:27])[C:16]([F:24])([F:25])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[O:8]
Reactant: O=C(O)CC(S)C(=O)O
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CC(S)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 94.7 %

Procedure:
Mercaptosuccinic acid (Aldrich) (12.5 g, 0.083 mole) and 1H,1H,2H,2H-perfluorooctan-1-ol (Fluorochem Ltd.) (60.6 g, 0.166 mole) were suspended in toluene (400 ml). p-Toluene sulfonic acid hydrate (Aldrich) (0.36 g) was added and the mixture refluxed under argon atmosphere for 72 hours in a flask equipped with a Dean & Stark reflux condenser. The solution was allowed to cool and the toluene was removed by evaporation under reduced pressure. The resulting oil was redissolved in ethyl acetate (1000 ml) and washed with saturated aqueous sodium hydrogen carbonate (800 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2-mercaptosuccinic acid bis-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) ester as a pale yellow oil (66.2 g, 100% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].ClCCCl.[S:13](=O)(=[O:16])([OH:15])[OH:14].C(C(CCCC)C([O-])=O)C.[K+:28]>C(OCC)(=O)C>[K+:28].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:13]([O-:16])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 87.6 %

Procedure:
Hydroquinone (10 g, 0.09 mol) and 1,2-dichloroethane (30 mL) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 40° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 18 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: C([C:3]1[C:4](Cl)=[N:5][C:6]([Cl:9])=[N:7][CH:8]=1)C.[CH3:11][S-:12].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[C:4]([S:12][CH3:11])[CH:3]=[CH:8][N:7]=1
Reactant: CCc1cnc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.6 %

Procedure:
To a solution of ethyl 2,4-dichloropyrimidine (20.0 g, 0.13 mol) in 150 mL of anhydrous tetrahydrofurane was added sodium thiomethoxide (49.30 mL, 0.15 mol) at −10° C. The reaction mixture was allowed to warm up to room temperature and then stirred for 5 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (×2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was slurrified with diethyl ether and then collected by filtration to afford the desired intermediate 10 as a white solid (11.2 g, 52%)
Reaction SMILES: [CH:1](OC(=O)C)=[O:2].[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:9]=1[CH2:10][OH:11]>C1C=CC=CC=1.CCCCCC>[CH:1]([NH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:9]=1[CH2:10][OH:11])=[O:2]
Reactant: CC(=O)OC=O
Reactant: Cc1cccc(N)c1CO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: Cc1cccc(NC=O)c1CO
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Acetic formic anhydride (1.85 g) was added to a solution of 2-amino-6-methylbenzyl alcohol (2.74 g) in benzene (55 ml) at room temperature. After being stirred for 2 hours, the mixture was diluted with n-hexane (10 ml) and the precipitates were collected by filtration to give 2-formamido-6-methylbenzyl alcohol (2.8 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:40][S:41](O)(=[O:43])=[O:42]>O1CCCC1>[CH3:40][S:41]([O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:8]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:13]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3cc(OS(C)(=O)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 60 °C

Procedure:
Place 6-(5-methylthiophen-2-yl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ol (105.7 mg, 0.23 mmol) in a vial. Add ethyl acetate (2 mL) and methanesulfonic acid (18 μL). Warm the resulting mixture to ˜60° C. with stirring. Add tetrahydrofuran (1 mL) to the resulting burnt orange solution with some dark brown gum on the bottom of the vial. Sonicate the resulting solution for 15 minutes. Carefully decant the suspension from gum that forms on the flask. Carefully collect the resulting solids by vacuum filtration and wash the resulting cake with pentane (2×2 mL). Dry the resulting solids in a 40° C. vacuum oven overnight to obtain the title compound. MP (DSC)=161.90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (0.690 g, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.1 g, 0.016 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.20 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 27%) as a yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@@H:7]([CH:30]([CH3:32])[CH3:31])[C:8]([N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)=[O:9].CCN(C(C)C)C(C)C>ClCCl>[CH2:26]([N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[C:8](=[O:9])[C@@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:30]([CH3:31])[CH3:32])[CH2:27][CH2:28][CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)[C@@H](N)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)[C@@H](NS(C)(=O)=O)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.75 g (6.5 mmol) of methanesulfonic acid chloride in 5 ml of dichloromethane is added dropwise, with stirring, to a solution of 1.8 g (5 mmol) of 2-(S)-amino-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-3-methyl-butanoic acid amide and 1.4 ml (8 mmol) of Hunig base in 10 ml of dichloromethane. The reaction mixture is stirred at room temperature for a further 5 hours, diluted with 50 ml of dichloromethane and extracted with 20 ml of 4N hydrochloric acid. The dichloromethane phase is separated, washed in succession with water, 10 ml of bicarbonate solution and brine, dried and concentrated by evaporation to yield crude N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-2-(S)-methanesulfonylamino-3-methylbutanoic acid amide in the form of a yellowish oil of Rf value 0.56 [toluene/isopropanol/glacial acetic acid (170:30:2)]that can be used in the next step without being further purified.
Reaction SMILES: [CH3:1][C:2](OC(OC(OC(C)(C)C)=O)=O)(C)C.[CH2:16]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29](=[O:50])[CH2:30][C@@H:31]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH2:32][N+:33]([O-])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Br)=C>[CH2:16]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29](=[O:50])[CH2:30][C@@H:31]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)[C:32]1[CH:2]=[CH:1][O:34][N:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(C[C@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C=CBr
Agent: CN(C)c1ccncc1
Product: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.3 %

Procedure:
(Boc)2O (6.9 g, 31.65 mmol) was added at room temperature to a solution of 7.3 (10 g, 21.1 mmol), vinyl bromide (230 mL, 1.0 M solution in THF), DMAP (256 mg, 2.1 mmol), and TEA (3.5 mL, 25.3 mmol). The mixture was stirred at room temperature for 2.5 days. During the reaction, more (Boc)2O (2 g twice) was added. After HPLC indicated that all 7.3 was consumed, the reaction mixture was taken into EtOAc (500 mL), and saturated sodium bicarbonate (400 mL) was added. The organic layer was separated, washed with brine, dried, and concentrated under vacuum. The crude product was taken into hot MeOH (70 mL). The mixture was stirred vigorously at 75° C. for 5 hours. The mixture was then cooled to room temperature and allowed to stand for 3 hours. The solid product was collected by filtration and washed with MeOH to give 7.4 (9.5 g). MS ESI (pos.) m/e: 483 (M+H). 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.30 (m, 12H), 6.95 (d, 2H), 6.15 (d, 1H), 5.05 (s, 2H), 4.76 (dd, 1H), 4.64 (m, 1H), 4.15 (d, 2H), 4.05 (dd, 1H), 3.56 (dd, 1H), 3.23 (dd, 1H), 2.78 (dd, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60% in oil, 55 mg, 1.22 mM) in dry THF (10 ml) stirring at 0° C. was added a solution of methyl indazole-3-carboxylate (von Auwers et al, Ber., 52, pg 1345 (1919), 210 mg, 1.22 mM) in dry THF (10 ml). After 10 min benzyl bromide (0.15 ml, 1.22 mM) was added and the solution left stirring at room temperature overnight. Water (2 ml) was added and the solvent removed in vacuo. The residue was partitioned between water and ethyl acetate and the combined organic dried over magnesium sulfate and evaporated. Column chromatography (ethyl acetate/cyclohexane 1:4) provided methyl 1 benzyl-indazole-3-carboxylate as a yellow powder (250 mg, 77%). M.pt. 181° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[OH-].[K+].[C:28](=S)=[S:29]>CCO.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][O:5][C:4]3[CH:22]=[CH:23][C:24]4=[N:25][C:28](=[S:29])[N:1]=[C:2]4[CH:3]=3)[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(OCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: S=C1N=c2ccc(OCCN3CCC(Cc4ccc(Cl)cc4)CC3)cc2=N1
Yield: 87.2 %

Procedure:
From a mixture of 1-[2-(3,4-diaminophenoxy)ethyl]-4-(4-chlorobenzyl)piperidine (1.30 g, 3.67 mmol), KOH (240 mg, 4.28 mmol) and CS2 (250 μL, 4.16 mmol) in EtOH (5 mL) and water (0.8 mL) was obtained 1.28 g (88%) of the title compound as a foam solid. 1H NMR (CDCl3): 1.38-1.68 (m, 5H), 2.09-2.17 (m, 2H), 2.481 (d, 2H, J=6.5), 2.851 (t, 2H, J=4.5), 3.18-3.21 (m, 2H), 4.142 (t, 2H, J=4.5), 6.561 (bs, 1H), 6.596 (d, 1H, J=8.5), 6.936 (d, 1H, J=8.5), 7.036 (d, 2H, J=8), 7.029 (d, 2H, J=8). 1H NMR (DMSO-d6): 12.360 (s, 1H), 12.402 (s, 1H). The hydrochloride, mp. 291-3° C. Analysis, Calcd. for C21H25ClN3OS: C 57.53, H 5.75, N 9.58; Found: C 57.82, H 5.65, N 9.44.