Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[CH3:18][C:19]1[N:20]=[C:21]([CH2:25][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=323.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[CH:8][CH:7]=1)=O)C.O.[NH2:27][NH2:28]>>[NH:27]([C:4]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[CH:8][CH:7]=1)=[O:3])[NH2:28]
Reactant: NN
Reactant: CCOC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Solvent: O
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)NN)cc2)on1
Temperature: 0 °C

Procedure:
A mixture of 3.0 g (0.086 mole) of 5-[7-(4-ethoxycarbonylphenoxy)heptyl]-3-methylisoxazole (Example 22) and 10 ml of hydrazine hydrate was heated at reflux for six hours. The reaction mixture was cooled to 0° C. whereupon the solid product separated. The latter was collected, washed and dried in vacuo to give 2.6 g of 5-[7-(4-hydrazinocarbonylphenoxy)heptyl]-3-methylisoxazole, m.p. 121°-122° C., MIC vs. rhinovirus Type 2 in vitro=0.64 μg/ml.
Reaction SMILES: O.[NH2:2][NH2:3].[IH:4].CS[C:7]1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]=1.CCOCC>CCO>[IH:4].[NH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[N:2][NH2:3]
Reactant: CSC1=NCCCCN1
Reactant: NN
Agent: I
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NN=C1NCCCCN1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
Hydrazine hydrate (0.44 ml, 7.23 mmol) was added to a solution of 2-(methylthio)-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide (1.79 d, 6.58 mmol) in EtOH (12 ml). The reaction mixture was refluxed for 5 h and cooled to r.t. Et2O was added and the product was collected by filtration, washed with Et2O and dried under vacuum to give 1.46 g (100%) crude title compound which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:17])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[O:5][C:4](=[O:18])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21].CCN(C(C)C)C(C)C.[CH3:32]/[C:33](/[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34]\[CH:35]=O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21]/[C:20](=[CH:35]\[CH:34]=[C:33]([CH3:32])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])/[C:19]([C:3]1[C:4](=[O:18])[O:5][C:6]([CH:8]([CH3:17])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:2]=1[OH:1])=[O:22]
Reactant: CCCCC/C(C)=C/C=O
Reactant: CCC(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCC(C)=C/C=C(\C)C(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Reaction time: 0.33 h

Procedure:
To (E)-methyl 6-(4-hydroxy-2-oxo-3-propionyl-2-H-pyran-6-yl)hept-2-enoate (VII; 0.63 g, 2.05 mmol) in 30 ml anhydrous CH2Cl2 at −72° C., was added titanium tetrachloride (0.88 ml; 8 mmol; Aldrich) under argon, and the reaction mixture was stirred for 20 min. DIPEA (1.64 ml; 9.43 mmol; Aldrich) was added, and the reaction mixture was stirred for 90 min. (E)-3-methyl-octenal (XXI; 1 g; 7.25 mmol) in 5 ml anhydrous CH2Cl2 was added in two portions over 10 min, and the reaction mixture was stirred at −72° C. for 48 h and at 0° C. for 1 hour. The reaction was quenched with 40 ml ice water and extracted with 2×40 ml CH2Cl2. The CH2Cl2 extracts were pooled, washed with saturated NH4Cl, washed twice with saturated NaHCO3, and dried with anhydrous Na2SO4. The product was purified by silica flash chromatography (EtOAc gradient in hexanes).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-5-methylphenyl)boronic acid gave 238. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.52 (s, 1H), 8.22 (dd, J=7.3, 2.2 Hz, 1H), 7.84 (s, 1H), 7.43-7.29 (m, 2H), 4.89 (dd, J=10.1, 3.9 Hz, 1H), 4.57-4.37 (m, 1H), 4.35-4.20 (m, 1H), 4.17-3.94 (m, 1H), 3.79 (s, 3H), 3.29-3.17 (m, 1H), 2.40 (s, 3H), 2.19-2.07 (m, 1H), 1.92-1.77 (m, 1H), 1.76-1.66 (m, 4H). LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH:19]1[C:24]([CH:25]=O)=[CH:23][C:22]2[O:27][CH2:28][O:29][C:21]=2[CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:28]1[O:29][C:21]2[CH:20]=[CH:19][C:24]([CH:25]=[CH:10][CH:9]=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:23][C:22]=2[O:27]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1ccc2c(c1)OCO2

Procedure:
To a solution of 1.85 g (46.3 mmol) of a mineral oil containing 60% sodium hydride in dry tetrahydrofuran (100 ml) was added in an argon atmosphere 10.6 ml (47.8 mmol) of triethyl 4-phosphonocrotonate. The mixture was reacted at 0° C. for 1 hour, followed by addition of 4.86 g (32.3 mmol) of piperonal. The mixture was reacted at room temperature for 1.5 hours. Saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and subjected to silica gel column chromatography. There was obtained 7.23 g (29.6 mmol) of ethyl 5-(3,4-methylenedioxyphenyl)-2,4-pentadienoate. Spectrophotometric data of the product support the structure shown below. ##STR73##
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)[CH:46]([OH:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:70][CH:71]=[CH2:72].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH:52]=3)[CH:46]([O:61][CH2:72][CH:71]=[CH2:70])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 33% methylene chloride/cyclohexane is added 1.5 equivalents of allyl trichloroacetimidate, and the reagents are allowed to mix for 5 minutes. A catalytic amount of trifluoromethanesulfonic acid is then added slowly via syringe and the mixture is stirred at room temperature. After 3 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:27][C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[NH2:20])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(S)c1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Sc2cccc(N)c2)c2c(Cl)ncnc21
Yield: 25.6 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 0.98 mmol) was treated with 3-aminobenzenethiol (120 mg, 0.96 mmol), copper(I) iodide (300 mg, 1.58 mmol), potassium carbonate (300 mg, 2.17 mmol) and 8 ml N,N-dimethylformamide as solvent according to Preparation 86. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 100 mg (25% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:9]2[C:8]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=3[S:6][C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:10]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin in 80 ml. of chloroform are heated together with 38.4 g. of 1-carbethoxy-piperazine under reflux conditions for 20 hours. The reaction mixture is poured over ice water and extracted with chloroform. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained oily 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo [b,f]thiepin-10-yl)-piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]([C@H:26]1[NH:30][CH2:29][C@H:28]([OH:31])[CH2:27]1)=[O:25].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH:18]=[CH2:19])[C:10]([N:30]1[CH2:29][C@H:28]([OH:31])[CH2:27][C@H:26]1[C:24]([O:23][CH3:22])=[O:25])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a slurry of (3R)-2-((tert-butoxycarbonyl)amino)-3,7-dimethylnon-8-enoic acid (6.5 g, 21.7 mmol), L-4-hydroxyproline methyl ester hydrochloride (3.9 g, 21.7 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.36 g, 21.7 mmol) in DCM (50 mL) at 0° C., N,N-diisopropylethylamine (11.5 mL, 66.6 mmol) was added dropwise. The resulting light yellow mixture was stirred at rt overnight, washed with 1M HCl (35 ml) and brine, dried over Na2SO4, filtered, concentrated in vacuo. The residual oil (12 g) was purified by conventional column chromatography (60-120 g silica gel column), eluted with 4%˜8% IPA-Hexane to afford the desired product (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (9a, 4.3 g, 46% yield) as a white foam and the undesired diastereomer (2S,4R)-methyl 1-((2R,3R)-2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (9b, 1.9 g, 20% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3): δ ppm 5.73-5.64 (m, 1H), 5.19-5.17 (m, 1H), 4.97-4.88 (m, 2H), 4.70-4.66 (t, J=8.4 Hz, 1H), 4.53 (bs, 1H), 4.29-4.25 (m, 1H), 3.99-3.96 (d, J=10.8 Hz, 3H), 3.72 (s, 3H), 3.70-3.66 (m, 1H), 2.34-2.11 (m, 1H), 2.10-2.00 (m, 2H), 1.85-1.81 (m, 1H), 1.49-1.41 (m, 9H), 1.39-1.14 (m, 3H), 0.98-0.86 (m, 7H) MS: MS m/z 427.2 (M++1).
Reaction SMILES: S(O)(C)(=O)=O.[F:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[CH:9][C:8]=1[S:16][CH2:17][C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([O:13][CH3:14])=[C:7]([F:6])[C:8]=2[S:16][CH:17]=1
Reactant: COC(=O)CC(=O)CSc1cc(C)cc(OC)c1F
Agent: CS(=O)(=O)O
Product: COC(=O)Cc1csc2c(F)c(OC)cc(C)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
MsOH (3.0 mL) was added to methyl 4-((2-fluoro-3-methoxy-5-methylphenyl)sulfanyl)-3-oxobutanoate (330 mg) at 0° C. After stirring at 0° C. for 10 min, the mixture was poured into ice water at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (299 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([N:24]3[CH2:29][CH:28]([CH3:30])[O:27][CH:26]([CH3:31])[CH2:25]3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([N:24]3[CH2:25][CH:26]([CH3:31])[O:27][CH:28]([CH3:30])[CH2:29]3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N1CC(C)OC(C)C1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CC1CN(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)CC(C)O1
Temperature: 25 °C

Procedure:
A solution of crude 4-chloro-N-[5-chloro-2-(2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2 h. Upon cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to afford 28 mg of 4-chloro-N-[5-chloro-2-(2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS m/z: 512.0 (M+H).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:39])[CH3:38]>ClCCl>[CH:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1)([CH3:39])[CH3:38]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CC(C)N1CCNCC1
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 128.2 mg of 1-isopropylpiperazin in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]#[N:22])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.[Cl-].[NH4+].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1)[CH2:20][C:21]1[NH:27][N:26]=[N:25][N:22]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CC#N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Yield: 38.5 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenylacetonitrile (154 mg) in 6.3 ml of dimethyl formamide, ammonium chloride (297 mg, 5.21 mmol) and sodium azide (339 mg, 5.21 mmol) was added at reflux. After 4.5 hours the reaction mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 96:4:1 chloroform/methanol/acetic acid) to give 68 mg (37%) of the title compound.
Reaction SMILES: [C:1](OCC)(=[O:7])[C:2](OCC)=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1.CC[O-].[Na+].C(O)(=O)C>O>[OH:3][C:2]1[C:1]([OH:7])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Diethyl oxalate (83 ml, 0.61 mol) was added dropwise to a stirred solution of diethyl 2,2′4-(4-methoxyphenyl)azanediyl)diacetate (4) (180 g, 0.61 mol) in NaOEt (21% by wt in EtOH) (506 ml, 1.3 mol), the mixture was stirred at 100° C. for 1 h. The reaction was quenched with acetic acid (210 ml, 3.7 mol) and the resulting suspension was poured into iced water (1 L), the resulting off-white solid collected by vacuum filtration. The crude product was recrystallised from hot EtOH (3.5 L) to give diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-001) (152 g, 71%) as a white solid: m/z 350 (M+H)+ (ES+); 348 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 7.13-7.01 (m, 2H), 6.92-6.81 (m, 2H), 3.99 (q, J=7.1 Hz, 4H), 3.78 (s, 3H), 0.99 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a stirred solution containing 11.5 g (0.05 mole) of 3,5-ditrifluoromethylphenol, 3.3 g (0.05 mole) of 85% potassium hydroxide, 200 ml of N,N-dimethylformamide and 10 ml of water, 0.055 mole of ethyl bromoacetate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 46 hours. After cooling 25° C., 500 ml of water and 500 ml of ethyl ether were added; and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 mm of Hg. A product was obtained with ND25 of 1.4226 with a yield of 85%.
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10](O)=O)[NH:5][C:4]=2[C:3]=1[N:13]([CH3:22])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])=[O:15].Cl.C([S:43][CH2:44][CH2:45][NH2:46])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.O.CN(C)C=O.C(N(CC)CC)C>[S:43]1[CH2:44][CH2:45][N:46]=[C:10]1[C:6]1[NH:5][C:4]2[C:3]([N:13]([CH3:22])[S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])=[C:2]([CH3:1])[S:9][C:8]=2[CH:7]=1
Reactant: Cc1sc2cc(C(=O)O)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc2cc(C3=NCCS3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a mixture of 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.35 g), 2-(tritylthio)ethaneamine hydrochloride (0.43 g), 1H-1,2,3-benzotriazol-1-ol (0.19 g), triethylamine (0.2 mL) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a colorless oil. To a solution of triphenylphosphine oxide (0.83 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.25 mL) at 0° C., the mixture was stirred for 10 min. The colorless oil was added to the mixture and the mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-[5-(4,5-dihydro-1,3-thiazol-2-yl)-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl]-N-methylthiophene-2-sulfonamide (111 mg, yield 29%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:20→1:1, volume ratio). melting point 140° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([N:6]=[C:7]=[S:8])=[O:5].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:9])[CH3:1])=[S:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: CC(C)=CC(=O)N=C=S
Solvent: c1ccccc1
Product: CC(C)=CC(=O)NC(=S)N1CCCCC1
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To a solution of 3-methylbut-2-enoyl isothiocyanate (2 g, 14.2 mmol, Eq: 1.00) in benzene (40.0 ml) was added a solution of piperidine (1.21 g, 1.4 ml, 14.2 mmol, Eq: 1.00) in benzene (20.0 ml). The mixture was stirred for 2 hours. The mixture was evaporated affording 3-methyl-but-2-enoic acid (piperidine-1-carbothioyl)-amide (3.32 g, 104%) as a yellow oil. MS: m/z=227.2 (M+H+)