Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1,1-dimethylethyl (4RS,5RS)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (3.7 g, 8.42 mmol) in methanol (20 ml) was gradually added a solution of sodium hydroxide (0.40 g, 10.10 mmol) in methanol (20 ml) under ice-cooling. The reaction solution was stirred for 1 hr, diluted with 1N hydrochloric acid (15 ml) and water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (2.24 g, 64%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=2)[N:43]=1
Reactant: COc1nc(Cl)ccc1C#N
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1C#N

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-2-methoxypyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3-carbonitrile in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]([OH:27])[CH2:25][CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)[C@H](CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)[C@H](CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)acetic acid (0.038 g, 0.077 mmol; Example 158, Step B) in a mixture of THF and methanol (4:1, 5 mL) was added sodium borohydride (9 mg, 0.24 mmol) at 0° C. Then the reaction was allowed to warm to room temperature. After being stirred at room temperature for 1.5 h, another 2 eq. of sodium borohydride were added and stirred for another 0.5 h. The reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (MgSO4), and concentrated under reduced pressure. The crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound as the first eluting fraction as a white solid after lyophilization.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:45])[C:19]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30](=[O:44])[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:25][CH2:24]2)=[O:20])=[O:14])=[CH:8][CH:7]=1.Cl.O>C(#N)C>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:45])[C:19]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([O:29][C:30](=[O:44])[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:27][CH2:28]2)=[O:20])=[O:14])=[CH:8][CH:7]=1)=[O:1]
Reactant: CN(CCCC(=O)Nc1ccc(C2OCCO2)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CN(CCCC(=O)Nc1ccc(C=O)cc1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-(1,3-dioxolan-2-yl)phenylcarbamoyl)propyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (98 mg, 0.16 mmol) in acetonitrile (2 mL) was added aqueous hydrochloric acid (3 M, 1.07 mL). The resulting dark orange solution was stirred at room temperature. Water was added and the resulting mixture was extracted with DCM (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[C:15](=[O:14])[CH:16]=1
Reactant: Cc1ccc(C)c(CNN)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(C)c(Cn2[nH]c(N)cc2=O)c1
Reaction time: 8 h

Procedure:
26.6 g of 2,5-dimethylbenzylhydrazine were added dropwise to a solution of 28.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 130 ml of ethanol, in the course of which the temperature rose from 25 to 35°C. After stirring overnight, the compound identified above separated out, and was filtered off and recrystallised from ethanol. Melting point: 124°, 20 g (52%).
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH:11](C)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC1(/C=C/C(C)OCc2ccc3ccccc3c2)CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1(CCCOCc2ccc3ccccc3c2)CCOCC1
Yield: 66.7 %

Procedure:
4-methoxy-4-[3-methyl-3-((napth-2yl)methoxy)-trans-prop-1-enyl]tetrahydropyran (320 mg, 1.02 mmol), prepared as in Example 3, was hydrogenated over palladium on calcium carbonate, poisoned with lead, with hydrogen (1 atm) in ethyl acetate at ambient temperature for 18 hours. After flushing the reaction solution with nitrogen, the solution was filtered through a pad of celite. The filter cake was thoroughly rinsed with ethyl acetate. The combined flltrates were concentrated in vacuo and chromatographed on silica gel (14 g, 15% ethyl acetate:hexanes) to provide the title compound (214 mg, 66%) as a colorless oil. 1H NMR (300 MHz, CDCl3); 7.75-7.87 (4H, m), 7.43-7.53 (3H, m), 4.67 (2H, s), 3.68 (4H, d,d, J=8,3 Hz), 3.52 (2H, t, J=6 Hz), 3.17 (3H, s), 1.49-1.78 MS (M+H)+ =315, (M+NH4 )+ =332. Analysis calc'd for C20H26O3 : C, 76.40; H, 8.33; Found: C, 76.30; H, 8.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]3[CH:14]([CH3:16])[CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(C)C1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC(C)C1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Isopropyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([C:28](=O)[CH3:29])[CH:27]=1>CO.C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](/[C:28](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([S:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])[CH:12]=2)/[CH3:29])[CH:27]=1
Reactant: CC1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 13.6 %

Procedure:
3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.235 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (40.2 mg, 0.235 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (15 mg, 0.032 mmol, 13.60% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.11 (m, 2H), 7.81 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.19 (m, 1H), 6.89 (m, 1H), 3.69 (m, 2H), 2.41 (m, 2H), 2.24 (m, 2H), 1.63 (m, 2H), 1.24 (m, 4H), 0.87 (d, 3H, J=4.4 Hz). Mass [M+H]+: 450.2
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]2CCC[N:12](C(=O)C(F)(F)F)[CH2:11]2)[CH:5]=[CH:6][C:7]=1OC.CCC([O:26]CC)=S.ClOC(C)(C)C.Cl>C(N(CC)CC)C.C(Cl)Cl>[N:12]1[C:11](=[O:26])[CH:10]=[C:4]2[C:5]=1[CH:6]=[CH:7][CH:2]=[CH:3]2
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N
Reactant: CCOC(=S)CC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=c2ccccc2=N1
Temperature: -65 °C

Procedure:
604 mg of 3-(3-amino-4-methoxyphenyl)-1-trifluoroacetyl piperidine were added with stirring under an inert atmosphere to 20 ml of methylene chloride and 0.26 ml of ethyl methylthioacetate cooled to -65° C., and then 0.24 ml of tert-butyl hypochlorite were added over 5 minutes. After stirring for an hour, 0.29 ml of triethylamine were added dropwise and the temperature was allowed to return to ambient. 5 ml of aqueous 2 N hydrochloric acid were added and the mixture was stirred for an hour. The decanted organic phases were washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica (eluent benzene-ethyl acetate 7-3) to obtain 580 mg of 1,3-dihydro-7-methoxy-3-methylthio-4-[1-trifluoroacetyl)-3-piperidinyl]-2H-indol-2-one which after crystallization from ethanol melted at ≃189° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:17](Br)[CH:18]=[CH2:19].C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.C(OC(=O)C)C>[CH2:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:11][CH:12]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A 500 ml round bottom flask, equipped with a reflux condenser and an oil bath with a magnetic stirrer was charged with 13.94 g of the above 4-(2-benzoxazolyl)-phenol, 9.7 g of allyl bromide and 17.5 g of anhydrous Na2CO3 in 300 ml of 1-methyl-2-pyrrolidone. A trace of KJ was added. After 5 h hour at 110° C. no starting material could be observed on tlc. The reaction mixture was diluted with ethylacetate and washed with 1n NaOH, water and NaCl solution, dried with Na2SO4, concentrated and recrystallised from hexene to yield 14.3 g (86%) of 2-(4-prop-2-enyloxy-phenyl)-benzoxazole. M.p. 95-96° C., UV (ethanol) 308 nm (26′184).
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([O:47][CH3:48])[C:45]#[CH:46].C(NCC)C>CN(C=O)C.[Cu](I)I>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:46]#[C:45][CH2:44][O:47][CH3:48])=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CCOC
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COCC#Cc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a mixture of 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (450 mg), 52 mg bistriphenylphosphinpalladium dichloride, 14 mg copperiodide, 146 mg triphenylphosphine and methyl propargyl ether (0.12 mL) in 10 mL DMF is added diethylamine (1.9 L). The mixture is heated in the microwave oven for 40 min at 120° C. The reaction mixture was cooled to room temperature and partitioned between 1 N hydrochloric acid and ethyl acetate. The organic phase was purified by gradient chromatography on silica gel with heptane:ethyl acetate to yield 0.13 g of the title compound as a light yellow solid, MS (ISP) 399.1 (M+H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[S:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=2>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15][CH:19]=2)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: c1ccc2sccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)c2csc3ccccc23)ccc1Cl
Reaction time: 0.25 h

Procedure:
5.1 g of powdered 4-chloro-3-sulfamoylbenzoyl chloride are introduced into a solution of 3 g benzo[b]thiophene in 50 ml anhydrous toluene, and subsequently, 12 g titanium tetrachloride are added with agitation. Agitation is continued for 15 minutes at room temperature, the mixture is heated to boiling for about 15 minutes, cooled and poured onto a water/ice suspension. Extraction is carried out then with 70 acetic ester, the organic phase is separated and stirred for 5 hours with an aqueous sodium bicarbonate solution having a pH of 8.5. After separation of the organic phase and drying thereof over magnesium sulfate, the solvent is distilled off and the residue crystallized from toluene. M.p. 154°-156° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(OCC)(=O)C>CN1CCCC1=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: S=C=NCCC1=CCCCC1
Reactant: Nc1ccccn1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: S=C(NCCC1=CCCCC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 50.1 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-aminopyridine (941 mg, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100° C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4×) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 1.31 g of the titled product (50%) as a white crystalline solid: mp 153°-155° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:18][C:15]1[N:16]=[N:17][C:12]2[CH:11]=[C:10]([C:3]3[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=3[Cl:1])[CH:20]=[C:19]([CH3:21])[C:13]=2[N:14]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(N)nc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 72.8 %

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.158 g, 0.527 mmol, 1 equiv) was diluted with 10 mL DCM and chilled to 0° C. using an ice bath. A 1.0 M solution of BBr3 in DCM (3.16 mL, 3.16 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 3.5 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 3-5 minutes. Additional DCM was added and this mixture was washed with sodium bicarbonate followed by brine. The organic phase was separated, dried over sodium sulfate (Na2SO4), filtered and evaporated to dryness. Solids were then diluted with minimum amount of ethyl acetate and precipitated out with hexanes. Product was filtered off and dried to yield a yellow solid (0.110 g, 73% yield). MS (ESI+): m/z=287.1, LC retention time: 2.46 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[S:5][CH:6]=1.[Cl:14][C:15]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:35])[Cl:34])[CH:27]=[C:26]([Cl:36])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:15]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:35])[Cl:34])[CH:27]=[C:26]([Cl:36])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Cc1csc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)n1

Procedure:
96 mg of 4-(4-methyl-thiazol-2-yl)-phenol, 212 mg of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester and 207 mg of potassium carbonate are stirred for 24 hours at 50° C. in 3 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.23).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:21]O)[CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH:9]=1)[CH3:2].S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:21][C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1
Reactant: CCOc1cc(CO)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(CCl)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-Ethoxy-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methanol from Step 2 (350 mg, 1.12 mmol), in dichloromethane (3 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (0.122 mL, 1.68 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. The mixture was evaporated in vacuo to afford the desired product as an oil.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>C(O)C>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24][NH:33][CH:30]3[CH2:32][CH2:31]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
A solution of 20.5 g (50 mmol) of 4-[3-(acetylamino)cyclopentyl]-α-(ethoxymethylene)-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester, in 100 ml of absolute ethanol was cooled to 10° and 3.4 g (60 mmole) of cyclopropylamine was added dropwise maintaining the temperature below 15° with an ice bath. After the addition was complete, the reaction was stirred at 5°-10° for 1.5 hours and then at room temperature for 1 hour. The resulting suspension was chilled to 5° and the solid removed by filtration and washed with ethanol and then hexane. The combined filtrate and washings were evaporated in vacuo and the residue was recrystallized from pentane to give 16.1 g of the title compound.
Reaction SMILES: N([O-])=O.[Na+].[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([NH-])=[O:12].[OH2:21]>S(=O)(=O)(O)O>[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([OH:21])=[O:12]
Reactant: O
Reactant: [NH-]C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Temperature: 25 °C

Procedure:
30 ml of an aqueous solution containing 6.60 g (0.096 moles) of sodium nitrite were slowly added dropwise, whilst stirring and ice-cooling, to a suspension of 15.53 g (0.064 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoyl amide [(XXVI), X=X'=F, R16 =NH2 ] [prepared as described in step (b) above] in 20 ml of concentrated aqueous sulfuric acid, and the mixture was heated under reflux for 30 minutes. At the end of this time, it was cooled to room temperature, and then 50 ml of water were added it. The reaction mixture was then extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 15.59 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br:13]Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:13][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[NH2:7]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxy-2-nitroaniline (35 g) in dichloromethane (350 mL) was subsequently added dropwise bromine (12.9 mL) at −20° C. After stirring for 30 minutes at the same temperature, this was poured into ice water, adjusted to pH 7 to 8 with saturated sodium bicarbonate aqueous solution and then extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). After concentration of the desired fraction, the resulting residue was crystallized from hexane and ethyl acetate and then collected by filtration to obtain the title compound as reddish orange crystals (29.6 g).