Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:24])=[C:14]([CH2:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:15]=1[CH3:16])=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[C:21]([O:20][CH2:19][CH2:18][CH2:17][C:14]1[C:15]([CH3:16])=[C:11]([C:9]([OH:10])=[O:8])[NH:12][C:13]=1[CH3:24])(=[O:23])[CH3:22]
Reactant: CC(=O)OCCCc1c(C)[nH]c(C(=O)OCc2ccccc2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OCCCc1c(C)[nH]c(C(=O)O)c1C
Reaction time: 8 h

Procedure:
4-(3-Acetoxypropyl)-3,5-dimethylpyrrole-2-carboxylic acid benzyl ester, the compound of formula (5) (18.6 g, 56.6 mmol), was dissolved in dry THF (440 mL), and 10% palladium on carbon (1.3 g) was added to the solution under a nitrogen stream. The reaction flask was evacuated until the solvent began to boil, and it was then backfilled with nitrogen (3×). The reaction flask was again evacuated until the solvent began to boil and was backfilled with hydrogen gas (5×). The reaction was then allowed to stir under hydrogen gas overnight. The resulting suspension was filtered to remove the palladium/carbon, and THF was added to redissolve the solids. Most of the THF was evaporated off, after which hexanes were added dropwise, with stirring, to the solution, causing a white solid to precipitate out. The solids were filtered, rinsed with hexanes, and dried overnight under vacuum to give 4-(3-acetoxypropyl)-3,5-dimethylpyrrole-2-carboxylic acid, the compound of formula (6) as a white crystalline powder (12.8 g, 94.2% yield). This compound (12.1 g, 50.2 mmol) was slurried in triethylorthoformate (60 mL), and the slurry cooled to 0° C. in an ice/brine bath. Trifluoroacetic acid (60 mL) was added while maintaining the temperature under 5° C. The resulting solution was stirred for 1 hr, after which water (100 mL) and methylene chloride (100 mL) were added. The mixture was separated, and the organic layer was washed twice with 100 mL water, three times with 100 mL of saturated sodium bicarbonate, and once more with 100 mL of water to neutralize the mixture. The organic layer was then separated and dried, filtered and the solvent was removed from the filtrate under reduced pressure to give an oil. The oil was dried under vacuum overnight, to give crude 4-(3-acetoxypropyl)-3,5-dimethyl)-2-formylpyrrole, the compound of formula (7) as a solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>>[S:8]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCO
Product: Cc1ccc(S(=O)(=O)OCCCCCO)cc1

Procedure:
By following a procedure of Reference Example 1, 6.2 g (60 mmole) of 1,5-pentanediol and 5.7 g (30 mmole) of tosyl chloride were treated to give 1,5-pentanediol monotosylate as a colorless oily material Yield 4.1 g (yield: 53%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].[N+:19]([O-])([OH:21])=[O:20]>>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:19]([O-:21])=[O:20])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C
Product: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Yield: 85 %

Procedure:
220 gm of 4,4-dimethyl-7-acetamino-2H,4H-isoquinoline-1,3-dione were added in portions to 800 ml of fuming nitric acid at -20° C. while stirring. The mixture was stirred for one hour at this temperature. Then, the reaction mixture was poured over ice, the precipitate was suction-filtered off, washed neutral with water, dried in the air, and boiled with isopropanol. After cooling, the crystals were suction-filtered off and washed with ether, yielding 222 gm (85% of theory) of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione, m.p. 249° C. (decomp.).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[O:5][CH2:16][CH3:17]
Reactant: NC(=O)c1ccccc1I
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1ccccc1I

Procedure:
starting from o-iodobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl o-iodobenzimidate as an oil; 1H-NMR(CDCl3): 1.42 (t, CH3), 4.38 (q, CH2), 6.8-7.6 (3 aromatic H+NH), 7.8-8.05 (1 aromatic H);
Reaction SMILES: [C:1]1([SnH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[CH2:29])=[CH2:21].N(C(C)(C)C#N)=N[C:32](C)(C)[C:33]#N>>[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[CH2:29])=[CH2:21].[CH:32]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Sn:7]([CH2:21][CH2:20][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:33]
Reactant: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=Cc1ccccc1C=C
Product: C=Cc1ccccc1[Sn](CCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 30 h

Procedure:
To a 250 ml round bottomed flask equipped with a magnetic stir bar is added 28.0 grams of triphenyltin hydride, 33.0 grams of 91% divinylbenzene, and 0.26 gram of 2,2'-azo-bis-isobutyronitrile. The mixture is placed under a nitrogen blanket and heated to a temperature of from 40° to 45° C. Samples of the reaction mixture are periodically taken and subjected to infrared analysis. The reaction is terminated when the tin-hydrogen absorption at 1850 cm-1 in the infrared spectrum disappears. This occurs after approximately 30 hours of heating the reaction mixture. The product is then stored at 0° C. until used for the preparation of the polymer.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH2:9]([Mg]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C1COCC1.[Cu]Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCCCCl
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Cu]
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCCCCl)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.67 h

Procedure:
10 g of 5-chlorovaleroyl chloride in 50 ml of anhydrous THF is loaded into a 250 ml three-necked flask, under a nitrogen atmosphere. The reaction medium is cooled down to -20° C. and 1.06 g of copper (I) chloride is added. Agitation is carried out for 40 minutes, then 36 ml of a 2 M solution of benzylmagnesium chloride in THF is added over 1.5 hour. Agitation is carried out for 1 hour at -20° C., then the temperature is allowed to return to 20° C. over 1.5 hour. The reaction medium is cooled down to -10° C. and 90 ml of 0.4 M hydrochloric acid is added. Agitation is carried out for 20 minutes, then the aqueous phase is extracted twice with 100 ml of MTBE. The organic phase is washed twice with 50 ml of water, dried over magnesium sulphate, filtered and concentrated. In this way, 13.5 g of sought product is obtained.
Reaction SMILES: Br[C:2]1[C:11](Br)=[C:10]([N+:13]([O-])=O)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[NH2:13][C:10]1[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]([C:16]([OH:18])=[O:17])=[CH:2][CH:11]=1
Reactant: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)O)c2c1OCCO2
Reaction time: 8 h
Yield: 259.3 %

Procedure:
An autoclave container was charged water (4.0 mL), 6,7-dibromo-8-nitro-1,4-benzodio-xane-5-carboxylic acid (1.9 g, 0.5 mmol), saturated sodium carbonate (1.0 mL), and Pd/C (500 mg). The mixture was hydrogenated at 40 kg/cm2 at 50° C. for overnight. It was then filtered and the filtrate was treated with hydrochloric acid (3.0 mL). The suspension was filtered and the solid was washed with water to afford the title compound (253 mg, 26%). LCMS: ESI (3 minute run), m/z=196 [M+1]+; Retention time: 0.30 minute.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:14][C:15]1[C:16](=[O:22])[NH:17][N:18]=[CH:19][C:20]=1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[N:14]=[C:15]2[C:16](=[O:22])[NH:17][NH:18][CH:19]=[C:20]2[N:21]=1
Reactant: Nc1cn[nH]c(=O)c1N
Reactant: COc1cc(SC)ccc1C(=O)O
Product: COc1cc(SC)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Temperature: 50 °C

Procedure:
Two grams of 2-methoxy-4-methylmercapto-benzoic acid are suspended in 20 ml of polyphosphoric acid, and 1.2 gm of 4,5-diamino-2H-pyridazin-3-one are added thereto with stirring at 50° C. The mixture is heated for 90 minutes to 100°-110° C. and then poured onto ice water, and the product which is precipitated on stirring is subjected to suction filtration. The mother liquor is extracted with ethyl acetate, after which the aqueous phase is made ammoniacal and extracted again with ethyl acetate. The last ethyl acetate phase is evaporated. The residue is combined with the above solid product and purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:0 to 100:3)].
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C1
Yield: 75.4 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.77 mmol), TBSCl (6.35 mmol, 956 mg) in DCM (11.5 mL), was stirred for 72 hrs at room temperature. The solvent was removed under reduced pressure, EtOAc was added to the residue, and the solid material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography with gradient elution with EtOAc/hexane (9:1) to EtOAc/hexane (1:1), to afford title compound 295 (1.25 g, 75% yield) as a syrup. MS (m/z): 310.1 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].S(Cl)(O[CH2:26][Cl:27])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH2:26][Cl:27])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Temperature: 25 °C
Yield: 111.4 %

Procedure:
To a vigorously stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (4 g, 18.41 mmol), tetrabutylammonium hydrogen sulfate (1.25 g, 3.68 mmol), and Na2CO3 (9.76 g, 92 mmol) in DCM 80 (mL) and water (80 mL), cooled in an ice/water bath, was slowly added chloromethyl chlorosulfate (3.8 mL, 36.8 mmol) over 4 min. After stirring in the ice/water bath for 30 min, the cold bath was removed and the reaction mixture was allowed to stir at room temperature. After stirring 16 h at room temperature, the reaction mixture was diluted with water and extracted with DCM. The aqueous layer was back extracted with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated to afford Intermediate 38A (5.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Br[CH2:30][CH2:31][C:32]#[N:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:30][CH2:31][C:32]#[N:33])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 65 °C
Yield: 56.4 %

Procedure:
A mixture of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (500 mg, 1.24 mmol), 3-bromopropanenitrile (412 mg, 3.08 mmol), Cs2CO3 (1.21 g, 3.70 mol) in N,N-dimethylformamide (15 mL) was purged with a gentle flow of nitrogen gas. The resulting mixture was stirred in a sealed tube at 65° C. for 16 then poured into water (200 mL). The crude product was collected by filtration and then purified by flash chromatography on silica eluting with ethyl acetate/petroleum ether (1:2). Appropriate fractions were collected and evaporated to afford N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-cyanoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid (320 mg, 57%). LCMS (Method 17) [M+H]+=458.1, RT=1.67 min.
Reaction SMILES: Cl.C(OC1C=CC(C(N)=N)=CC=1)CCCCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:37]([C:39]1[C:40](O)=[N:41][C:42]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:47][CH:46]=2)=[N:43][CH:44]=1)#[N:38].P(Cl)(Cl)([Cl:62])=O>C(O)C>[Cl:62][C:40]1[C:39]([C:37]#[N:38])=[CH:44][N:43]=[C:42]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:47][CH:46]=2)[N:41]=1
Reactant: CCCCCCCOc1ccc(-c2ncc(C#N)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCCCCCOc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-heptyloxybenzamidine hydrochloride with α -ethoxymethylene-α -cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-heptyloxyphenyl)-pyrimidine (melting point 180.8° C; smectic up to 231.5° C. (clearing point) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-heptyloxyphenyl)-pyrimidine having a melting point of 133.3°-134.6° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C@@H:13]([OH:31])[C@H:12]2[OH:32])=[C:4]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>ClCCl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[NH2:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:33][CH2:34][CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:12]([OH:32])[C@@H:13]1[OH:31]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S,3R,5S)-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(di-Boc-amino)-cyclopentane-1,2-diol (10.3 g, 15.50 mmol) is dissolved in dichloromethane (50 ml). TFA (25 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo to give the title compound. 1H nmr (MeOD, 400 MHz); 7.90(s, 1H), 7.30-7.10(m, 10H), 4.65(m, 1H), 4.50 (m, 1H), 4.40(m, 1H), 4.20(m, 1H), 4.10(m, 2H), 3.50(m, 1H), 2.75(m, 1H), 2.15(m, 1H), MS (ES+) m/e 465 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=O)=[CH:13][C:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[N:34]1([NH:33][C:15]([C:14]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])=[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH:13]=2)=[O:17])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1
Reactant: NN1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCCCC1)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(benzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid (30 mg, 0.062 mmol) from Step A in methylene chloride (1 mL) was added 1-aminopiperidine (9.3 mg, 0.093 mmol), DIPEA (0.016 mL, 0.093 mmol) and PyBOP (17.4 mg, 0.093 mmol). The reaction was stirred at rt for 20 h and was then diluted with aq. saturated sodium carbonate and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluted with 50% ethyl acetate in hexanes to yield N-(piperidin-1-yl)-2-(benzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxamide as the slower eluting band. HPLC/MS: 566 (M+1), 568 (M+3); Rt=4.56 min; 1HNMR (CDCl3): δ 1.2-1.9 (4 m, 6H), 2.7-3.1 (2 m, 4H), 7.07 (m, 2H), 7.20-7.38 (m, 10H), 7.668 and 8.074 (2 s, 1H).
Reaction SMILES: C(N(CC)CC)C.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([OH:38])=O.[NH2:39][C:40]1[N:45]=[C:44]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=2[F:54])[N:43]=[C:42]([C:55](=[N:57]O)[NH2:56])[N:41]=1>CN(C=O)C>[Cl:53][C:49]1[C:48]([F:54])=[C:47]([NH:46][C:44]2[N:45]=[C:40]([NH2:39])[N:41]=[C:42]([C:55]3[N:56]=[C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)[O:38][N:57]=3)[N:43]=2)[CH:52]=[CH:51][CH:50]=1
Reactant: O=C(O)c1ccccn1
Reactant: NC(=NO)c1nc(N)nc(Nc2cccc(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(Nc2cccc(Cl)c2F)nc(-c2noc(-c3ccccn3)n2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
Triethylamine (1.10 mL, 7.58 mmol) and 1H-benzotriazol-1-ol (0.77 g, 5.05 mmol) were added to a solution of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.97 g, 5.05 mmol) in DMF (10 mL) and the mixture was stirred for 20 min at room temperature. Picolinic acid (0.62 g, 5.05 mmol) was added and the mixture was stirred for 30 min at room temperature. 4-Amino-6-[(3-chloro-2-fluorophenyl)amino]-N′-hydroxy-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 73, 1.50 g, 5.05 mmol) was added and the mixture was stirred at room temperature overnight before being heated to 85 C for approximately 24 h. The crude compound was purified over Ambersep resin but the impurities remained. The residue was then successively washed with EtOAc, acetone and MeOH and finally hot MeOH to afford the title compound (330 mg, 17%).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=[N:11]C=2C=1.[N:15]1([CH2:21][C:22]([OH:24])=O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CN(C=O)C>[N:15]1([CH2:21][C:22]([NH2:11])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C(O)CN1CCOCC1
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
To a solution of [5-(3-amino-ethoxy)-1,3-dihydro-isoindol-2-yl]-(2,4-dihydroxy-5-isopropyl-phenyl)-methanone hydrochloride (100 mg, 0.255 mmoles) in DMF (10 ml) was added EDC (59 mg, 0.306 mmoles), HOBt (41 mg, 0.306 mmoles), morpholin-4-yl-acetic acid (37 mg, 0.255 mmoles) and triethylamine (43 μl, 0.306 mmoles) and stirred at ambient temperature for one hour. To the reaction mixture was added further EDC (20 mg, 0.104 mmoles), HOBt (14 mg, 0.104 mmoles), morpholin-4-yl-acetic acid (12 mg, 0.083 mmoles) and triethylamine (14 μl, 0.100 mmoles) and stirred at ambient temperature for a further 2 hours. Solvent removed in vacuo. The residue was purified by flash chromatography [Biotage SP4: 25S, flow rate 25 ml/min, gradient 20% DMAW 90 in DCM to 100% DMAW 90] and then by preparative HPLC to give N-{2-[2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindol-5-yloxy]-ethyl}-2-morpholin-4-yl-acetamide as a colourless viscous oil (40 mg, 33%). 1H NMR (Me-d3-OD) 7.20 (1H, br s); 7.18 (1H, s); 6.90 (2H, br m); 6.40 (1H, s); 4.10 (2H, t); 3.73 (4H, m); 3.63 (2H, t); 3.20 (1H, m); 3.18 (2H, s); 2.60 (4H, m); 1.25 (6H, d). MS [M+H]+ 484.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29]1>>[CH:28]1([CH2:31][C:32]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:33])[CH2:30][CH2:29]1
Reactant: O=C(O)CC1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (48 mg, 73%), MS (ISP) m/z=413.5 [(M+H)+], mp 197.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-cyclopropyl-acetic acid.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+].C(=O)([O-])[NH2:19].[NH4+].CN1CCCC1=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:19])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: NC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol), ammonium carbamate (7.78 g, 99.6 mmol) and dry N-methylpyrrolidinone (40 ml) are placed in a glass-lined, stainless steel reactor. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (80 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to give 0.52 g (56%) picramide (Table 2, entry 2).