Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([OH:43])=O.C(N(C(C)C)CC)(C)C.[NH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[N:58][CH:59]=1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([NH:53][C:54]1[CH:59]=[N:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=1)=[O:43]
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 92.9 %

Procedure:
HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92 mmol) in DMF stirred at room temperature under argon. After stirring 5 min, the solution was added with 5-amino-2-trifluoromethylpyridine (CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by silica gel column chromatography (100% hexanes→7:93 EtOAc:hexanes) to afford 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) as a white solid (1.17 g, 2.50 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 10.93 (s, 1H), 9.23 (d, J=1.9 Hz, 1H), 8.60 (dd, J=6.8, 1.4 Hz, 1H), 8.38 (d, J=4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J=7.1, 1.5 Hz, 1H),), 6.04 (dd, J=8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m, 2H); ESIMS found for C19H16BrF3N4O2 m/z 470.0 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:37][C:27]1[CH:28]=[C:29]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:31]([F:32])[C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([OH:10])[C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cn1cc(C(O)Cc2cccc(Br)n2)cn1
Product: Cn1cc(C(O)Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)cn1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using (2-(6-bromopyridin-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethanol (0.090 g, 0.32 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccc(Cl)cc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and 4-chlorophenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-chlorophenoxycarbonyloxy)-2-(1H)-pyrimidinone as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1.Br.C(O)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COc1ccc(Oc2cccc(F)c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Oc2cccc(F)c2)cc1

Procedure:
m-fluorophenol and 4-bromoanisole yield p-(m-fluorophenoxy)anisole of b.p. 130°-131° C./0.2 Torr and reaction with hydrobromic acid/acetic acid yields p-(m-fluorophenoxy)phenol; m.p. 53°-55° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:22](Br)[C:23]#[CH:24]>>[CH2:24]([O:11][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: CC(CCOc1ccc(C(=O)O)cc1)CCC(C)C(C)C
Product: C#CCOC(=O)c1ccc(OCCC(C)CCC(C)C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(3,6,7-trimethyloctyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(3,6,7-trimethyloctyl)oxy]benzoic acid propargyl ester; B.P. 153°-154° C/0.05 mmHg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=O)[CH:15]=2)[N:10]=1.C[N:23](C=O)C>ClCCl>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([NH2:23])=[O:21])[CH:15]=2)[N:10]=1
Reactant: COc1ccc2cc(C(=O)O)ccc2n1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2cc(C(N)=O)ccc2n1
Temperature: 25 °C

Procedure:
Oxalyl chloride (10.3 cm3) was added dropwise to a stirred solution of 2-methoxyquinoline-6-carboxylic acid (12.0 g) in dichloromethane (100 cm3) and DMF (0.1 g) at 0°. The mixture was warmed to room temperature and after 2 hours volatile material was removed in vacuo. The residue was taken into dichloromethane (100 cm3), cooled to 0° and treated cautiously with aqueous ammonia solution (30 cm3 of S.G. 0.880). After 2 hours the mixture was concentrated in vacuo and the solid residue was recrystallised from isopropanol to afford 2-methoxyquinoline-6-carboxylic acid amide, m.p. 212°-214°, (7.9 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccco3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3ccco3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Tert-butyl[4-butoxy-6-(2-furyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.28 g, 0.6 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diisopropyl ether to give 3-(aminomethyl)-4-butoxy-6-(2-furyl)-2-isobutyl-1(2H)-isoquinolinone hydrochloride (0.22 g, 91.7%) as crystals.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7](Cl)([CH3:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCCCC.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC>[C:1]([N:5]=[N:6][C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)c1ccccc1
Yield: 66 %

Procedure:
To a clean, dry, 500 ml, 4-neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser with drying tube and under a nitrogen atmosphere was added a solution of 70 grams (0.253 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in Example XX) in 200 ml. of pentane and the solution cooled to 5° C. With rapid stirring 86.6 ml. (0.26 moles) of a 3 molar solution of phenylmagnesium bromide in ether was added from a dropping funnel over 1/2 hour holding the reaction temperature at 10°-15° C with an ice bath. After the addition was complete, the reaction was stirred for an additional 45 minutes at 15° C. Ice chips were then added to the stirred reaction until the excess phenylmagnesium bromide was destroyed. The reaction mixture was then stirred into 200 ml. of 5% HCl until the magnesium salts dissolved. The pentane layer was separated, washed with 5% HCl, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 53 grams (66% yield) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:22])=[CH:18][CH:19]=1)#[N:13]
Reactant: Nc1ccc2ncccc2c1
Reactant: N#Cc1ccc(N=C=O)cc1
Product: N#Cc1ccc(NC(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Prepared from 6-aminoquinoline and 4-cyanophenyl isocyanate. m/z (ES+) 289 (M+H)+.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Br[C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[NH2:30].[OH:35][C@@H:36]([CH2:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1)[C:37]([O:39][CH3:40])=[O:38].[F-].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.O>[NH2:30][C:29]1[CH:28]=[C:27]([C:45]2[CH:44]=[N:43][N:42]([CH2:41][C@H:36]([OH:35])[C:37]([O:39][CH3:40])=[O:38])[CH:46]=2)[CH:33]=[C:32]([CH3:34])[CH:31]=1
Reactant: COC(=O)[C@@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(N)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](O)Cn1cc(-c2cc(C)cc(N)c2)cn1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
Butyl di-1-adamantylphosphine (1.07 g, 2.98 mmol), Pd(OAc)2 (0.33 mg, 1.49 mmol), dioxane (12 mL) and water (2.4 mL) were added to an oven-dried flask and stirred for 10 minutes. 3-bromo-5-methylaniline (1.58 g, 8.51 mmol), methyl (2S)-2-hydroxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate (3.5 g, 10.64 mmol), and potassium fluoride (1.24 g, 21.3 mmol) were added followed by additional dioxane (12 mL). The mixture was heated to 95° C. overnight then cooled to room temperature, filtered and diluted with water. The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford methyl (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate. MS ESI calcd. for C14H18N3O3 [M+H]+ 276. found 276. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.67 (s, 1H), 6.51 (s, 2H), 6.21 (s, 1H), 5.90 (d, J=6.1 Hz, 1H), 4.93 (s, 2H), 4.43 (tt, J=4.6 Hz, 9.2 Hz, 1H), 4.36 (d, J=4.2 Hz, 1H), 4.27-4.21 (m, 1H), 3.63 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([S:6]/[C:7](=[C:11](\[OH:15])/[C:12]([OH:14])=[O:13])/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(Cl)=[S:25]>C1COCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([S:6]/[C:7](=[C:11](\[OH:15])/[C:12]([OH:14])=[O:13])/[C:8]([OH:10])=[O:9])=[CH:16][CH:17]=1)=[C:24]=[S:25]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(S/C(C(=O)O)=C(\O)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)/C(O)=C(/Sc1ccc(N=C=S)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 2-[4'-(amino)thiophenoxy]-3-hydroxymaleic acid (0.370 g, 1.438 mmol) and freshly powdered, freshly dried K2CO3 (1.217 g, 8.806 mmol in THF (30 mL) under nitrogen was added thiophosgene (0.33 mL, 0.498 g, 4.33 mmol). The reaction mixture was stirred vigorously at room temperature for 1 hour, then at reflux for 30 minutes. Upon cooling to room temperature, the reaction mixture was filtered and the solvent evaporated off to afford crude 2-[4'-(isothiocyanato)-thiophenoxy]-3-hydroxymaleic acid as an orange oil; (This material was used directly in the next step but could be crystallized from CHCl3) MP 156°-158° C. with decomposition; 1H NMR (acetone-d6, d) 10.2 (2H, br), 7.58 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.8 Hz), 4.99 (1H, br s), 4.79 (1H, d, J=4.8 Hz), 4.26 (1H, d, J=4.8 Hz); 13C NMR (acetone-d6, d) 172.7, 171.0, 135.7, 133.7, 130.9, 127.1, 127.0, 71.7, 55.7; IR (Nujol mull, cm-1) 3390 (br, m), 2040 (s), 1730 (s), 1695 (s); mass spectrum, m/e 299, 263, 191, 166, 108, 57 (base).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:19]=[N:18][CH:17]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:20]3[CH:19]=[N:18][CH:17]=[N:16][CH:21]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrimidin- 5-yl-benzaldehyde, of Preparation 26, using the method described in Example 1, Step A except the mine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.92 (s, 2H), 7.55 (m, 4H), 7.25 (m, 3H), 7.11 (d, 1H), 3.87 (s, 2H), 3.81 (s, 2H), 3.66 (s, 3H), 2.95 (t, 2H), 2.63 (t, 2H); MS 362 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([CH3:14])[CH3:13].C(O)C.[H][H]>[Pd].O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: CC(C)=C1C(=O)Nc2ccc(O)cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C1C(=O)Nc2ccc(O)cc21
Yield: 81 %

Procedure:
23 g. 5-Hydroxy-3-isopropylideneindolinone are dissolved in 100 ml. ethanol and 150 ml. tetrahydrofuran and hydrogenated in the presence of 1 g. 10% palladium-charcoal at ambient temperature and 1 bar hydrogen pressure. After filtering off the catalyst with suction, the filtrate is distilled off in a vacuum and the residue is triturated with diethyl ether and filtered off with suction. There are obtained 19 g. of the title compound; yield 81% of theory; m.p. 175° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([C:20]([O:22][CH3:23])=[O:21])=[C:5]([C:10]2[CH:11]=[C:12]([F:19])[C:13]([C@H:16]([NH3+:18])[CH3:17])=[N:14][CH:15]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[F:24][C:25]([F:36])([F:35])[C:26]([NH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1)=[O:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([C:10]2[CH:15]=[N:14][C:13]([C@H:16]([NH:18][C:32]([C:29]3([NH:28][C:26](=[O:27])[C:25]([F:24])([F:35])[F:36])[CH2:30][CH2:31]3)=[O:33])[CH3:17])=[C:12]([F:19])[CH:11]=2)[C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1-c1cnc([C@@H](C)[NH3+])c(F)c1
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Cl)cc(Cl)cc1-c1cnc([C@@H](C)NC(=O)C2(NC(=O)C(F)(F)F)CC2)c(F)c1

Procedure:
A solution of (1R)-1-{5-[3,5-dichloro-2-(methoxycarbonyl)phenyl]-3-fluoro-pyridin-2-yl}ethanaminium chloride (0.277 g, 0.73 mmol), 1-[(trifluoroacetyl)amino]cyclo-propanecarboxylic acid (0.160 g, 0.812 mmol), 1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.311 g, 1.62 mmol), 1-hydroxy-7-azabenzotriazole (0.010 g, 0.15 mmol), and triethylamine (0.45 mL, 3.25 mmol) in 5 mL CH2Cl2 was stirred at room temperature for 3 days. The solution was washed with aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 10–30% ethyl acetate in hexanes to provide methyl 2,4dichloro-6-(5-fluoro-6-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}pyridin-3-yl)benzoate that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 522.05 for M+H+.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1([Br:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].CC(O)(C)C>O>[Br:14][C:4]1([Br:3])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Br:1])[CH:11]=2)[NH:6][C:5]1=[O:13]
Reactant: BrBr
Reactant: O=C1Nc2ncccc2C1(Br)Br
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1Nc2ncc(Br)cc2C1(Br)Br
Temperature: 15 °C
Yield: 84.1 %

Procedure:
Bromine (13.4 mL, 0.262 mol) was added dropwise over a period of 30 min to a cooled (ice bath) and stirred suspension of 2 (37.86 g, 0.131 mol) in water:t-BuOH=1:1 (1500 mL). Cooling bath was removed and the mixture was stirred at r.t. overnight. Then the solution was cooled to 15° C. and saturated aqueous solution of NaHCO3 (278 mL) was added. A yellow suspension, which was formed, was concentrated in vacuum (bath temperature <32° C.) until about 1000 mL of condensate was collected. The solid was filtered off, washed with water (200 mL), and dried in vacuum to afford 3 (40.85 g, 85%) as tan powder.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][C:5]([CH3:9])([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH3:13])[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:18](Cl)Cl>>[CH3:18][O:11][C:10]([C:3]1([CH3:13])[CH2:4][C:5]2([CH3:9])[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2)=[O:12]
Reactant: ClCCl
Reactant: CC12CCC(C)(C1)C(C)(C(=O)O)C2
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)CC2(C)CCC1(C)C2
Reaction time: 1 h
Yield: 45 %

Procedure:
1,2,4-Trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid (obtained as detailed above) was dissolved in methylene chloride (50 mL), and added dropwise to thionyl chloride (100 mL) at 50° C. After 1 hour, excessive thionyl chloride was distilled out and methanol (100 mL) was added. The reaction mixture was stirred overnight and then poured into saturated aqueous sodium bicarbonate. The resulting mixture was extracted with toluene and the organic phase was distilled to provide 1,2,4-trimethyl-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (65 g, 45% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][O:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CO)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(COS(C)(=O)=O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 124.9 %

Procedure:
To a solution of {4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (971 mg, 2.72 mmol) in DCM (40 mL), DIPEA (526 mg, 4.07 mmol) and methanesulfonyl chloride (373 mg, 3.26 mmol) is added. The reaction mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM. The combined organic extracts are dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (1.48 g) as an orange solid containing {5-[3-(4-chloromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine; LC-MS: tR=0.58 min; [M+1]+=436.11. b) A solution of the above crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (248 mg, 0.569 mmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vial at 80° C. for 16 h. The solvent is removed in vacuo and the residue is dissolved in EA and washed with brine and water. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 5% of 7N NH3 in methanol to give the title compound (137 mg) as a pale yellow oil; LC-MS: tR=0.38 min; [M+1]+=357.30; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 3.98 (s, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.67 (s, 1H), 8.13 (d, J=7.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][OH:25])=[CH:16][CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C1COCC1>[CH3:37][S:38]([O:25][CH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:12]2[CH2:13][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:26]([F:28])([F:29])[F:27])[CH2:10][N:11]=2)=[CH:15][CH:16]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reaction time: 1 h

Procedure:
{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methanol (0.6 g) and triethylamine (0.35 g) were dissolved in THF (5 ml), and methanesulfonyl chloride (0.15 ml) was added gradually. The mixture was stirred for 1 hour, and then added water. The mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain the desired compound as crude product (0.7 g).