Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)[CH:29]=1>>[ClH:26].[ClH:26].[ClH:26].[ClH:26].[CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:42]=[CH:43][C:34]=1[C:30]1[CH:29]=[C:28]([CH2:27][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)[CH:33]=[CH:32][N:31]=1.[ClH:26]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: ClCc1ccnc(-c2ccc3ccccc3c2)c1
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5ccc6ccccc6c5)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]-methyl]piperazine (69 mg) and 4-chloromethyl-2-(2-naphthyl)pyridine (56 mg) were reacted in the same manner as in Example 1 to obtain the title compound in the form of a hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7](=S)[NH:6][C:5]2=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1.O=P(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:18][C:7]1[O:8][C:4]2[C:5](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:6]=1
Reactant: COC(=O)c1cc(Cl)cc2oc(=S)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)cc2oc(Cl)nc12
Temperature: 125 °C
Yield: 99.1 %

Procedure:
A mixture of the product from Step A (2.00 g, 8.20 mmol), POCl3 (1.26 g, 8.21 mmol), and PCl5 (1.71 g, 8.21 mmol) was heated to 125° C. for 2.5 hours. The reaction mixture was dried under high vacuum for 24 hours to afford methyl 2,6-dichlorobenzoxazole-4-carboxylate (2.00 g, 99%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 4.04 (s, 3H); MS (ESI+) m/z 247 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23]([OH:25])=[O:24])[CH2:4][CH2:3]1.[CH3:32][Si](C=[N+]=[N-])(C)C.O>CO.C(Cl)Cl>[CH3:32][O:24][C:23]([C:13]1[N:14]2[C:10]([CH:9]([O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15]2)=[N:11][C:12]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(=O)O)CC1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid (example 256B) (50 mg, 0.120 mmole) in MeOH (2 mL) is added a 2M solution of trimethylsilyldiazomethane in CH2Cl2 (0.2 mL). After 2 hours, as the reaction is only partial, a 2M solution of trimethylsilyldiazomethane in CH2Cl2 (0.2 mL) is added and the reaction mixture is heated at 45° C. overnight. Water is added and the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) from (100:0) to (95:5) to give 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid methyl ester.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16].O>C(O)C>[O:12]=[C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CCOC(=O)CN1CCOCC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCOCC1=O
Temperature: 80 °C

Procedure:
Ethyl-2-(3-oxomorpholino)acetate (600 mg, 3.21 mmol) was dissolved in ethanol (3 mL) and hydrazine hydrate (160.46 mg, 3.21 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was transferred into 50 mL water and extracted with EtOAc (3×50 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product, which was used without further purification in the subsequent step (Crude yield: 54%). LCMS m/z 174.05 [M+H]+ tR 2.489 min.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:8](F)([C:27](F)(F)F)[C:9](F)(F)[C:10](F)(F)[C:11](F)(F)[C:12](F)(F)[C:13](F)(F)[C:14](Cl)=O.O>O1CCCC1>[CH2:27]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:2]=[CH:3][CH:4]=[CH2:5].[CH2:27]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: C=CC=C
Product: C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 10% hydroxylated SBS copolymer (3.5 g, 4.5 mmol reactive OH group) dissolved in anhydrous tetrahydrofuran (250 mL) was treated first with pyridine (0.72 g, 9.1 mmol) followed by pentadecafluorooctanoyl chloride (2.08 g, 4.81 mmol). The resulting solution was stirred under argon at room temperature for one hour and then heated to a mild reflux for an additional 24 hours. The reaction mixture was poured into water (500 mL), immediately giving a white precipitate. The crude product was redissolved into tetrahydrofuran (200 mL) and then reprecipitated into water. Two additional tetrahydrofuran—water dissolution-precipitation steps were used to obtain the desired product in purified form. The fluoroalkylated copolymer was then dried in vacuo at 40 degrees C. for 48 hours to give a white, elastomeric solid. The product was stored in the dark under an argon atmosphere. Analysis of the product by FTIR revealed the absence of a broad peak centered near 3329 cm−1 consistent with the esterification of the reactive hydroxyl groups within the copolymer's backbone. An additional signal near 1780 cm−1 (ester carbonyl stretch) was also observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][CH2:24][CH:19]([OH:20])[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Clc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-6,7-dihydro-4H-spiro[1,3-benzoxazole-5,2′-[1,3]dioxolane] (12.5 g) in a mixed solvent of THF (60 mL)-methanol (30 mL)-water (30 mL) was added 6 M hydrochloric acid (34.5 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (1.31 g), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.63 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][NH2:58])=[CH:53][CH:52]=1>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([NH:58][CH2:57][C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)=[O:15])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: O=C(NCc1ccc(F)cc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and (4-fluorophenyl)methanamine, the title compound was obtained in 92% purity by HPLC.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[Br:13]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]2[NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCCc2ccccc2N1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(Br)ccc2N1

Procedure:
To a solution of the title compound from Example 2 Step B (17.0 g, 106 mmol) in N,N-dimethylformamide (500 mL) was added N-bromosuccinimide (25.2 g, 141 mmol) at room temperature, and then the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate (1 L), and the separated organic layer was washed with 0.1 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate=12:1 to 3:1) provided a crude product that was recrystallized from ethyl acetate and petroleum ether (v:v=1:10) to give the title compound: LCMS m/z=241 [M+2+H]+. 1H NMR (400 MHz, d6-DMSO): δ 9.56 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 2.65 (m, 2H), 2.12-2.07 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C=CC(=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)/C=C\c1ccccc1CBr

Procedure:
A mixture of 2 g (12.34 mmol) of (E) 2-methyl cinnamic acid, 2.19 g (12.34 mmol) of N-bromosuccinimide (NBS) and a catalytic amount of benzoyl peroxide in 6 ml of CCl4 are heated under reflux for 6 hours. The residue is filtered and washed with ether. The organic phase is successively washed with a 1N HCl aqueous solution then with water. It is dried on MgSO4, filtered and evaporated to dryness.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=S)[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:35]>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([NH2:35])=[N:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=S)c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12

Procedure:
A solution of 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-4-thioxo-3,4-dihydro-2(1H)-quinazolinone (1.2 g) in chloroform (25 ml) and 20% ammonia in methanol (30 ml) was heated in an autoclave for 15 hours at 100° C. The reaction mixture was concentrated in vacuo and the residue was purified by subjecting to a column chromatography on silica gel using 5% methanol in chloroform for elution to give an oily residue. This oily residue was dissolved in methanol and this solution was acidified with conc.hydrochloric acid solution and then concentrated in vacuo to give a crystal of the object compound, which was recrystallized twice from a mixture of water and isoporpyl alcohol to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-4-amino-2(1H)-quinazolinone.2HCl.H2O (0.6 g).
Reaction SMILES: CS(C)=O.[OH-:5].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10](F)[C:9]=1[N+:16]([O-:18])=[O:17].Cl>CCOCC.O>[F:7][C:8]1[C:9]([N+:16]([O-:18])=[O:17])=[C:10]([OH:5])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
Dimethylsulfoxide (which will hereinafter be abbreviated as “DMSO”) (50 ml) and 10N NaOH (12 ml, 120 mmol) were added to 1,3,5-trifluoro-2-nitrobenzene (10.0 g, 56.5 mmol). The mixture was stirred at room temperature for 15 hours. Water (100 ml) and ether (200 ml) were added to separate the reaction mixture into layers. The water layer thus obtained was acidified with 1N HCl, followed by extraction with ether (2×200 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (10:1) eluate fractions, the title compound (7.97 g, 81%) was obtained as a yellow crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([CH3:23])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Br[CH2:26][C:27]1[C:31]2[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=2[S:29][N:28]=1.C([O-])([O-])=[O:39].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:23][C:16]=2[N:15]([CH2:26][C:27]2[C:31]3[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=3[S:29][N:28]=2)[C:14]1=[O:39])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C)ccc1[N+](=O)[O-])c1ccccc1
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2cnccc21
Temperature: 100 °C
Yield: 19.3 %

Procedure:
To a solution of (R)-3-(2-oxo-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl)-3-phenyl-propionic acid ethyl ester (refer to example 2) (50 mg, 0.16 mmol) in DMF (10 mL) were added 3-Bromomethyl-4,6-dimethyl-benzo[d]isothiazol (62 mg, 0.24 mmol) and K2CO3 (44 mg, 0.32 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100° C. for 2 hours. The solution was cooled and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and concentrated. The residue was purified by silica gel flash column chromatography with 20% EtOAc in Hexane as the eluent to afford the title compound (15 mg, 90%) as colorless foam.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)(=[O:24])=[O:23]
Reactant: COc1cccc(C(C#N)=NO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(C(C#N)=NOS(C)(=O)=O)c1
Yield: 47.8 %

Procedure:
In general analogy to the process described under 1.2, 27.7 g (0.157 mol) of α-hydroxyimino-3-methoxybenzylcyanide are reacted in the presence of 23.9 g (0.236 mol) of triethylamine with 19.8 g (0.173 mol) of methanesulfonyl chloride. Recrystallisation from toluene gives 19.1 g (48%) of α-(methylsulfonyloxyimino)-3-methoxybenzylcyanide in the form of white crystals having an m.p. of 105-107° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[C:6]([S:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:9])=[C:6]([S:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylthio)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile to yield 2-[3-chloro-2-(methylsulfonylaminocarbonyl)phenylthio]-4,6-dimethoxyprimidine, Compound 40 of Table 1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:18]=3)=[CH:9][N:8]=2)[CH2:4]1.Cl.O1CCOCC1>[C].[Pd].CCO>[CH3:1][O:2][CH:3]1[CH2:4][N:5]([C:7]2[N:8]=[CH:9][C:10]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:11][N:12]=2)[CH2:6]1
Reactant: COC1CN(c2ncc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2)C1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC1CN(c2ncc(C3CCNCC3)cn2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.3 %

Procedure:
tert-Butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (483 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (100 mg) was added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (5 ml), and 4M hydrogen chloride/dioxane (3.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then mixed with EtOH (5 ml), and potassium carbonate (2.0 g) was added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(3-methoxyazetidin-1-yl)-5-(piperidin-4-yl)pyrimidine (143 mg).
Reaction SMILES: [C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46]SC)[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46][NH:66][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NSC)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NNCc2ccccc2)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 93.2 %

Procedure:
A solution of (R)-N5 -(Cbz)-N5 -[methylthio(Cbz-iminomethyl)]-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide (0.25 g, 0.312 mmol; see Example 35(d) above) and benzylamine (0.05 mL; 0.476 mmol) in DMF (5 mL) was stirred overnight at room temperature. The DMF was removed in vacuo and the residue dissolved in EtOAc. The EtOAc solution was washed with KHSO4 solution, 0.5 N NaOH solution and brine, dried over Na2SO4 and concentrated in vacuo to afford 0.25 g of the sub-title compound. The material was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: NCCCNCCCCNCCCNC(=O)Cc1ccc(O)c(F)c1
Reaction time: 48 h

Procedure:
According to the General Procedure using 3-fluoro-4-hydroxyphenylacetic acid (85 mg, 0.50 mMol), dicyclohexylcarbodiimide (106 mg, 0.31 mMol), and spermine (512 mg, 2.53 mMol) in DME/DMF (4 ml, 3:1), activation during 2 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 12-19 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.19, (39 mg, 22%), lyophilisation gave 30 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.6-2.2 (m, 8H, 4×CH2 --CH2), 2.85-3.2 (m, 10H, 5×CH2 --N), 3.4 (t, J=7, 2H, CON2H--CH2 --CH2), 3.6 (s, 2H, Ar--CH2 --CO), 6.8-7.1 (m, 2H, 2×ArH 5,6), and 7.1 (d, 3 J H--F=11, H, ArH 2)ppm.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[CH2:41][OH:42]>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:36]4[CH2:40][CH2:39][CH2:38][C@@H:37]4[CH2:41][OH:42])[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: OC[C@H]1CCCN1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC[C@@H]4CO)c23)ccc1OCc1cccc(F)c1
Yield: 37 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and (R)-2-pyrrolidinemethanol to give the title compound in 37% yield; NMR Spectrum: 1.50 (m, 1H), 1.64 (m, 2H), 1.80 (m, 1H), 2.32 (q, 1H), 2.59 (m, 1H), 2.78 (dt, 1H), 3.15 (t, 1H), 3.27 (m, 3H), 3.80 (s, 3H), 4.37 (hidden by water, 2H), 4.40 (t, 1H), 4.46 (s, 1H), 5.11 (s, 2H), 7.02 (d, 1H), 7.16 (t, 2H), 7.28 (td, 2H), 7.38 (d, 1H), 7.44 (q, 1H), 8.27 (d, 2H), 8.29 (s, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[SH:17]>>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Sc1ncc[nH]1
Product: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)c(Cl)c1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-imidazolethiol to give a precipitated solid which was partitioned between methylene chloride and 2 h aqueous sodium hydroxide solution. The aqueous phase was acidified by the addition of a concentrated (20%) aqueous citric acid solution and the precipitate was isolated and dried. The material was recrystallised from a mixture of hexane and ethyl acetate to give 2-chloro-4-nitrophenyl 2-imidazolyl sulphide in 13% yield.