Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:11][S:12]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[N:11]([CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[C:35]([C:42]([F:45])([F:43])[F:44])[CH:36]=1)[S:12]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: O=S(=O)(Nc1nc2ccccn2c1Cl)c1ccc(N2CCOCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N(Cc1ccc(F)c(C(F)(F)F)c1)c1nc2ccccn2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of compound 11-E (0.030 g, 0.049 mmol) in DMF (1 mL) was added Na2CO3 (0.015 g, 0.15 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 90 as a yellow solid (0.008 g, 29%); MS m/z (M+H+) 570.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:26]=3)=[N:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:45]=CC=C[CH:41]=1.C(O)(C)C>ClCCl>[CH:40]([O:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]4)[CH:26]=3)=[N:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:45])[CH3:41]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)N1CCN(c2cc(-c3ncc(-c4cccc(O)c4)[nH]3)ccn2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1cccc(-c2cnc(-c3ccnc(N4CCN(C(C)C)CC4)c3)[nH]2)c1
Yield: 33 %

Procedure:
Diethyl azodicarboxylate (0.22 mL) was added via syringe to a solution of 1-{4-[5-(3-Hydroxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (304 mg) and triphenylphosphine (0.371 g) in a 1:1 mixture of isopropanol and dichloromethane (13 mL). The resultant solution was stirred at ambient temperature for 3 days and then washed with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (5% methanol in dichloromethane) to provide 1-{4-[5-(3-Isopropoxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (0.112 g). MS m/z 420 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>N1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:25]([C:22]3[S:21][C:20]4[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=4[C:23]=3[CH3:24])(=[O:27])=[O:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc3[nH]cc(CCN(C)C)c3c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a solution of 3.05 g (15 mMol) of 5-amino-3-(2-dimethylaminoethyl)-1H-indol in 100 ml of pyridine is added dropwise at ambient temperature a solution of 4.21 g (15 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonyl chloride in 20 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours. It is then evaporated to dryness, slightly alkalinised with diluted ammonia and dissolved in ethyl acetate. The organic phase is washed with water and a saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulphate. The organic solution is evaporated to dryness and the resulting solid is repeatedly washed with ethyl ether, to yield 5.5 g (82%) of N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide as a solid with m.p.=226-227° C.
Reaction SMILES: O[C:2]1([CH:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:9]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCCCC2)c2ncc[nH]2)cc1
Reaction time: 18 h
Yield: 21.6 %

Procedure:
At 0°, 10 g of crude 4-[1-hydroxycyclohept-1-yl-1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of dichloromethane and stirred with 10 ml of thionyl chloride for 4 hours. Then the mixture is concentrated to dryness under an oil pump vacuum, taken up in 100 ml of dichloromethane, and stirred with 40 ml of triethylamine for 18 hours at 25°. For working up purposes, the mixture is combined with water, extracted twice with dichloromethane, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 2.03 g of 4-[1-cycloheptylidene-1(imidazolyl)methyl]benzonitrile as the oily, free base.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([CH3:33])[CH:32]=1)[NH2:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:29][C:28]1[CH:30]=[C:31]([CH3:33])[CH:32]=[C:26]([CH3:25])[CH:27]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Reactant: Cc1cc(C)cc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)ccc2C#N)c1
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (150 mg, 0.380 mmol), 3,5-dimethylaniline (95 uL, 0.761 mmol), BINAP (40 mg, 0.064 mmol), Pd(OAc)2 (25 mg, 0.11 mmol) and K2CO3 (150 mg, 1.08 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 100 C for 4 h. EtOAc and water were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1S,2R)-2-(4-cyano-3-(3,5-dimethylphenylamino)phenylamino)cyclohexylcarbamate as a crude residue.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1.Cl>N1C=CC=CC=1>[C:8]([C:12]1[CH:19]=[CH:18][C:15](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48051.9 %

Procedure:
19.20 g (0.185 mol) of malonic acid were dissolved in pyridine (33 ml) and stirred for 15 minutes at RT. 25.00 g (0.154 mmol) of para-tert.-butylbenzaldehyde and 1.50 ml (0.020 mol) of piperidine were then added. The reaction mixture was heated for 8 hours at 100° C., with stirring. After pouring the reaction solution into a mixture of concentrated hydrochloric acid and ice, stirring was continued for a further two hours at room temperature. The resulting precipitate was filtered out with suction. Recrystallisation of the precipitate from methanol yielded 15.20 g (0.074 mol, 48% of theory) of para-tert.-butyl-trans-cinnamic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH2:13][CH:14]2[CH:18]=[CH:17][CH2:16][NH:15]2)[C:5](Br)=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][CH:14]3[CH:18]=[CH:17][CH2:16][N:15]3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1OCC1C=CCN1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: COC(=O)c1c(N)ccc2c1OCC1C=CCN21
Temperature: 90 °C
Yield: 30 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-(2,5-dihydro-1H-pyrrol-2-ylmethoxy)-benzoate (Intermediate 18, 1.64 g), copper (I) iodide (0.095 g), L-proline (0.115 g) and potassium phosphate tribasic (2.13 g) in anhydrous DMSO (10 mL) was evacuated and purged with nitrogen then heated to 90° C., under an atmosphere of nitrogen overnight. The resultant mixture was cooled and partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with more ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-30% to give methyl 7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.370 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19]CC3C=CC(OC)=CC=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Reactant: FC(F)(F)c1cccc(CCl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Temperature: 45 °C
Yield: 29 %

Procedure:
To a solution of Intermediate 3 (250 mg, 0.81 mmol) in N,N-dimethylformamide (3 mL) was added 2-(chloromethyl)-6-(trifluoromethyl)pyridine (158 mg, 0.81 mmol), potassium carbonate (224 mg, 1.62 mmol) and 18-crown-6 (40 mg). The slurry was heated at 45° C. for eighteen hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a colorless oil. (110 mg, 29% yield). MS (M+H): 468
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](C(NN)=O)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:19]([O-])=O.[Na+].C1(C2C=CN=C(C(N=[N+]=[N-])=S)C=2)C=CC=CC=1.[N-]=[N+]=[N-]>C(O)(=O)C.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:19])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)c1cc(Sc2ccccc2)ccn1
Reactant: O=N[O-]
Agent: Cl
Agent: [N-]=[N+]=NC(=S)c1cc(-c2ccccc2)ccn1
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Sc2ccccc2)ccn1
Reaction time: 0.33 h

Procedure:
A solution of 4-phenylthiopicolinic acid hydrazide 2.3 g. (0.050 mole) in 4.3 ml. of concentrated hydrochloric acid and 25 ml. of water is cooled to 75° C and a solution of 3.55 g. of sodium nitrite in 6 ml. of water is added. The solution is stirred at 0°-5° for 20 minutes after the addition is complete. The resultant suspension is extracted with methylene chloride and the combined extracts are dried over sodium sulfate and evaporated in vacuo to yield 12.7 gm. of crude 4-phenylthio picolinic acid azide. The azide is heated in 60 ml. of 50% aqueous acetic acid at steam bath temperature for 40 minutes. The suspension is filtered and the filtrate is made basic with 50% sodium hydroxide. The solids are collected by filtration, washed with water, dried and chromatographed on silica gel. Elution with ethyl acetate yields 4-phenylthio 2-amino pyridine, the structure of which is characterized analytically.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23].O>CN(C=O)C>[CH2:22]([NH:24][C:25](=[S:26])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CCN=C=S
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)OCCOc1ccc(SC(C)CC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above alcohol (2.16 g, 10.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 10 ml of DMF is cooled to 5° and ethyl isothiocyanate (1.10 ml, 12.0 mmol) in 10 ml of DMF is added dropwise. After addition is complete, the mixture is allowed to warm to RT and is stirred at RT overnight. Water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, the solvent removed and the residue is purified by column chromatography to give O-2-[4-(1-methylpropylthio)phenoxy]ethyl N-ethylthiocarbamate (compound 38, Table A).
Reaction SMILES: [O-]CC.[Na+].[I:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].C(O)C.[C:19](OCC)(=[O:25])[C:20]([O:22]CC)=[O:21]>O>[I:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][C:19](=[O:25])[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c(I)cccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)Cc1c(I)cccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Sodium ethoxide solution (35 ml, 44 mmol) in an ice-water bath was added dropwise with a solution of 1-iodo-2-methyl-3-nitro-benzene 74b in ethanol (35 ml, 40 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred until substantial brown precipitates were formed, and added with diethyl oxalate (6 ml, 44 mmol) in one portion. The reaction mixture was refluxed at 100° C. in an oil bath for 0.5 hour, added with water (70 ml) and refluxed for another 1 hour. The reaction mixture was concentrated under reduced pressure to evaporate ethanol, washed with ethyl acetate (50 ml) under base condition, adjusted to pH 3 with hydrochloric acid (1M), and extracted with ethyl acetate (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 3-(2-iodo-6-nitro-phenyl)-2-oxo-propionic acid 74c (2.94 g) as a brown oil to be used directly in the next step.
Reaction SMILES: [C:1]([C:3]([O:6][N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])([CH3:5])[CH3:4])#[N:2].N(C(C)(C)C#N)=N[C:21](C)([CH3:24])[C:22]#N>>[C:1]([C:3]([O:6][N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH2:12][CH2:22][CH2:21][CH3:24])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CNC(=O)C(C)(C)N(OC(C)(C)C#N)C(C)(C)C
Product: CCCCNC(=O)C(C)(C)N(OC(C)(C)C#N)C(C)(C)C
Yield: 48 %

Procedure:
The compound is prepared in analogy to compound (201) from the nitroxide (103) and azobisisobutyronitrile in 48% yield as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH3:13][C:14]1([CH3:22])[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[NH:15]1.CCCCCC>C1(C)C(C)=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[N:3]=[C:2]([N:15]2[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH2:19][C:14]2([CH3:22])[CH3:13])[N:7]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CC(C)Oc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: CC(C)Oc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1

Procedure:
104.0 g of 2,4-dichloro-6-isopropyloxy-1,3,5-triazine and 148.3 g of 2,2,6,6-tetramethylpiperidine are reacted in 300 ml of xylene as described in Example 1 and worked up. 2-Chloro-4-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained by crystallization from hexane as colorless crystals having a melting point of 111°-112°.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[NH2:12][C:13]1[N:18]=[C:17]([S:19][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:16]=[C:15]([OH:20])[CH:14]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Nc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(O)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of 2-(bromomethyl)-1,3,4-trichlorobenzene (580 mg, 2.1 mmol), 6-amino-2-sulfanylpyrimidin-4-ol (290 mg, 1.8 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The solid product was suspended in water (50 mL). The solid material was recovered by filtration, washed with water (1×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (325 mg, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.64 (s, 2H), 5.03 (s, 1H), 6.57 (s (br), 2H), 7.54 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=8.8 Hz); M+ 337; HPLC purity: 95.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16](Cl)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]([C:17]([F:20])([F:19])[F:18])=[N:24][N:23]=[N:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
(4-Benzyloxy-phenyl)-(1-chloro-2,2,2-trifluoro-ethylidene)-amine (66 mmol) was added to a stirred flask of glacial acetic acid (250 ml) at 70° under nitrogen. After 4 min sodium azide (210 ml) was added and heating was continued for 3 h. After cooling the mixture was filtered, the filtrate poured into water (750 ml) then extracted with dichloromethane (500 ml×3). The combined organic extracts were dried (Na2 SO4) and evaporated in vacuo. Purification by FCC using hexane-ethyl acetate (19:1) gave the title compound as a white solid (14.5 g). T.l.c. (Cyclohexane/ethyl acetate (19:1) Rf 0.22
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc(-c2cc(C(Oc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(Oc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 4-{cyclohexyl[5-(4-methoxyphenyl)-2-methylfuran-3-yl]methoxy}benzoic acid (181 mg), ethyl 3-(methylamino)propanoate (66 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg), hydroxybenzotriazole monohydrate (77 mg) and triethylamine (70 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (211 mg, 97%).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:36])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][S:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:24][CH2:23]2)[CH:17]([CH:37]([OH:39])[CH3:38])[C:16]3=[O:40])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:45].O>[Pd].O1CCOCC1>[Na+:45].[F:35][C:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:27][CH:25]2[O:24][CH2:23][CH:22]([S:21][C:20]3[CH:19]([CH3:36])[CH:18]4[N:15]([C:16](=[O:40])[CH:17]4[CH:37]([OH:39])[CH3:38])[C:14]=3[C:12]([O-:13])=[O:11])[CH2:26]2)=[CH:30][CH:31]=1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CSc4ccc(F)cc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CSc4ccc(F)cc4)C3)C(C)C12
Yield: 33.4 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.230 g of product from Example 41, 0.118 g of 10% palladium/carbon, 0.038 g of sodium bicarbonate, 2.5 ml of water and 6.0 ml of dioxane to give 0.062 g of the desired product.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:42])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:39][CH2:40][CH3:41])([CH3:15])([CH3:14])[CH3:13]>CC#N.CCOC(C)=O.O>[C:12]([O:16][C:17](=[O:42])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:1][CH:2]=[CH:3][CH3:4])[S:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)(=[O:30])=[O:31])=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:39][CH2:40][CH3:41])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC=CCN(c1ccc2c(c1)nc(CCC)n2CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Crotyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.