Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][NH2:14])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[C:24]1([CH:23]=[CH:22][C:21]([NH:14][CH2:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCCCOc1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cccc(CCNC(=O)C=Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 95.6 %

Procedure:
To a solution of 2-(3-butyloxyphenyl)ethylamine (1.0 g) in acetonitrile (40 cm3) was added powdered potassium carbonate (0.80 g). Cinnamoyl chloride (1.03 g) was then added portionwise over a period of fifteen minutes and the reaction mixture was then stirred at room temperature for 6.5 hours after which distilled water (40 cm3) was added. The mixture was left to stand overnight and was then filtered and extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed successively with potassium bicarbonate solution, water and 0.5M hydrochloric acid before drying over sodium sulphate and then evaporating down to give the product as a tan coloured oil (1.60 g).
Reaction SMILES: [CH2:1]([O:5][P:6]([O:13]P(OCCCC)(OCCCC)=O)(=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O-].[K+:31]>O1CCCC1>[CH2:8]([O:7][P:6]([O-:13])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:12])[CH2:9][CH2:10][CH3:11].[K+:31]
Reactant: CCCCOP(=O)(OCCCC)OP(=O)(OCCCC)OCCCC
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOP(=O)([O-])OCCCC
Yield: 171.1 %

Procedure:
The procedure of Example 1 was followed using tetrabutylpyrophosphate (4 mL, 10.5 mmol) in dry tetrahydrofuran (10 mL), potassium trimethylsilanolate (2.68 g, 21 mmol) in dry tetrahydrofuran (50 mL), and a 24 h reaction time. The product, potassium dibutylphosphate (4.46 g, 90% yield), was isolated as a white solid by concentrating the filtrate under vacuum: 1H NMR (D2O, DSS) δ 0.8-1.05 (dist. t, CH3, 6H), 1.18-1.8 (m, CH2, 8H), 3.74-4.0 (q, CH2, 4H). Anal. Calcd. for C8H18KO4P: C, 38.70; H, 7.31. Found: C, 38.63; H, 7.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].C([Li])CCC.[Br:21]C(Cl)(Cl)C(Cl)(Cl)Br.Cl>O1CCCC1>[Br:21][C:3]1[C:2]([Cl:1])=[C:10]([O:11][C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of 3-chloro-4-trifluoromethoxybenzoic acid (4.15 g) in dry tetrahydrofuran was treated with n-butyl lithium (15.1 ml of 2.5M solution in hexanes) at −78° C. under an inert atmosphere. After stirring overnight at this temperature, a solution of 1,2-dibromotetrachloroethane (839 g) in tetrahydrofuran was added. After 30 minutes, the solution was allowed to slowly warm to ambient temperature, then treated with 2M hydrochloric acid. The mixture was extracted with ether, the ethereal solution itself extracted with sodium bicarbonate solution and the latter acidified with dilute hydrochloric acid. This solution was extracted with ether and evaporated in vacuo to give 2-bromo-3-chloro-4-trifluoromethoxybenzoic acid (5.5 g) as a brown solid, NMR (CDCl3) 7.3(m,1H), 7.8(d,1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:4]([C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: CCCCOC(=O)CC(=O)OCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C(=O)OCCCC)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A 0.5-liter three-neck flask equipped with a stirrer was purged with nitrogen gas, and 7.2 g (0.3mols) of sodium hydride and 250 ml of dewatered tetrahydrofuran were put thereinto in a nitrogen stream atmosphere. With stirring, the mixture was cooled to 0° C., and, while its temperature was kept cooled, 66 ml (0.3 mols) of di-n-butyl malonate was dropwise added thereto over a period of 30 minutes. After the addition, the mixture was heated up to room temperature, and 32 ml of cyclopentyl bromide was dropwise added thereto, and refluxed for 5 hours. After this was cooled to room temperature, 10 g of sodium hydride and 32 ml of cyclopentyl bromide were added thereto, and refluxed further for 8 hours. The resulting reaction mixture was washed with 200 ml of water, and subjected to distillation under reduced pressure to obtain 20 g of di-n-butyl cyclopentylmalonate. The yield was 23.5%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:17]3[C:12]([O:11][C:4]=2[CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccccc2oc2cc(Br)ccc12
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a suspension of 4-bromo-2-phenoxy-benzoic acid (35.1 g, 120 mmol) in CH2Cl2 (350 mL) at 0° C. was added trifluoroacetic anhydride (20.3 mL, 144 mmol), dropwise, and the reaction was stirred for 15 min. At that time, boron trifluoride diethyl etherate (1.46 mL, 12.0 mmol) was added, dropwise. The reaction became homogeneous upon stirring for 1 h at room temperature. Upon completion, the reaction was poured into 1 N NaOH, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to give Compound 3a (32.14 g, 116 mmol). MS m/z (MH+) 275.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)C.Br[C:22]1[CH:27]=[C:26]([N+:28]([O-])=O)[C:25]([CH3:31])=[CH:24][C:23]=1[CH3:32]>>[CH3:31][C:25]1[C:24]([N:11]2[C:10]3[N:6]([N:7]=[C:8]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:9]=3)[CH:5]=[CH:4]2)=[C:23]([CH3:32])[CH:22]=[CH:27][C:26]=1[NH2:28]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Product: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
200 mg (0.72 mmol) of the compound of Example 4A together with 200 mg (0.87 mmol) of 1-bromo-2,4-dimethyl-5-nitrobenzene were reacted and worked up analogously to the procedure of Example 10A/Step 1. This gave 200 mg (86% pure, 56% of theory) of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[N:19]=3)[N:14]=[CH:13][C:12]=2[C:22](=[O:24])[CH3:23])[CH2:6][CH2:5]1.[C:25]([O:29][C:30]([NH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]([CH:37]([CH3:38])[CH3:39])[C:34]([NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[N:19]=3)[N:14]=[CH:13][C:12]=2[C:22](=[O:24])[CH3:23])[CH2:6][CH2:5]1)=[O:35])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(N)CC1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)CC1

Procedure:
Following general procedure VI, 1-{4-[(4-aminocyclohexyl)amino]-6-chloro-1,5-naphthyridin-3-yl}ethanone dihydrochloride (300 mg, 0.94 mmol) was reacted with 2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (310 mg, 1.4 mmol) to afford the desired product (320 mg, 65%) as a white solid. ESI MS m/z 518 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[C:27]=1[O:28][CH3:29])[C:22]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:23]
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCc2ccccc2)cc([N+](=O)[O-])c1OC

Procedure:
A solution of 1.49 g of 2-phenylethylamine in 100 ml of methylene chloride is treated with 1.26 g of triethylamine. A solution of 3.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of methylene chloride is added dropwise thereto while stirring, whereupon the mixture is stirred for a further 15 minutes. The organic phase is then extracted twice with 50 ml of ice-water each time, dried over sodium sulfate and evaporated in a water-jet vacuum. After recrystallization from methylene chloride/n-hexane there is obtained 3,4-dimethoxy-5-nitro-N-phenethylbenzamide in the form of pale beige needles of m.p. 121°-122°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][C:21]=1[CH3:27].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])=[CH:22][C:21]=1[CH3:27]
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: Cc1cc(O)ccc1Br
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1Br
Temperature: 0 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (300 mg, 1.05 mmol) in toluene (4 mL) are added 4-bromo-3-methyl-phenol (196 mg, 1.05 mmol) and tri-n-butylphosphine (394 μL, 1.58 mmol). The reaction mixture is cooled to 0° C. To the reaction mixture is added 1,1′-(Azocarbonyl)-dipiperidine (399 mg, 1.58 mmol) and the reaction mixture is warmed to room temperature. After 6 h, the reaction mixture is concentrated and the residue is chromatographed eluting with 10% to 20% EtOAc/hexanes to yield the title compound (324 mg, 68%). LC-ES/MS m/e 455.7 (M+1).
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].C1COCC1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>O>[C:24]([O:23][C:21]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)CNCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of iminodiacetic acid (5.1 g, 38.3 mmol) and sodium hydrogen carbonate (NaHCO3, 12.9 g, 153 mmol) were dissolved in 50 mL of water. Once the bubbling subsided, 50 mL of THF was added followed by 10.0 g (46.0 mmol) of BOC2O. The mixture was stirred at ambient temperature for 2 days when starting materials were completely consumed as detected by ESI. The reaction was worked up by removing THF and washing the aqueous layer with Et2O twice. The pH of the aqueous layer was then adjusted to 1 using conc. HCl. The product was extracted with EtOAc and solvent removed in vacuo to provide the product as a white solid. The product was purified by crystallization from EtOAc to give 8.04 g (90%) of clear crystals of 27. ES MS [M−H]−232.1.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]([CH:10]1[CH2:11][CH2:12][N:13]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:14][CH2:15]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1cncc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cncc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)n1
Yield: 47 %

Procedure:
KOBut (483 mg, 4.32 mmol, 2.5 eq) was added at room temperature to a solution of tert-butyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-60) (370 mg, 1.72 mmol, 1 eq) and 2-chloro-6-methylpyrazine (244 mg, 1.9 mmol, 1.1 eq) in toluene (50 ml) and the mixture was degassed for 30 min with argon. BINAP (64.5 mg, 0.103 mmol, 0.06 eq) and Pd2(dba)3 (31.6 mg, 0.034 mmol, 0.02 eq) were added and the reaction mixture was refluxed for 16 h. After cooling, concentration under reduced pressure was carried out. The residue was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml) and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure and the crude product so obtained was purified by column chromatography (Alox, 0.5% methanol/dichloromethane). The desired product was in the form of a brown solid. Yield: 47% (250 mg, 0.816 mmol)
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:6]=2[CH:5]=1)([O-])=O.NC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C=C2>>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cc3ccccc3)[nH]c2c1
Agent: Nc1ccc2c(ccn2Cc2ccccc2)c1
Product: Nc1ccc2[nH]c(Cc3ccccc3)nc2c1

Procedure:
The title compound was prepared from 5-nitro-2-benzylbenzimidazole by an analogous reduction method to that described above for 5-amino-1-benzyl-1H-indole; m/z (M+1)+ 224. Also note the published method (J. Het. Chem., 23, 1109-13, (1986)).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][C@@H:21]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([CH3:44])[O:24][C@H:22]2[OH:23])[C@@H:6]1[NH:45][C:46](=[O:51])[C:47]([Cl:50])([Cl:49])[Cl:48])(=[O:3])[CH3:2].[Cl:52][C:53]([Cl:57])([Cl:56])[C:54]#[N:55].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:52][C:53]([Cl:57])([Cl:56])[C:54]([O:23][C@@H:22]1[O:24][C@@H:25]([CH3:44])[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:21]1[O:20][C@@H:7]1[O:8][C@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[NH:45][C:46](=[O:51])[C:47]([Cl:50])([Cl:49])[Cl:48])=[NH:55]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
The hemiacetal 318 (539 mg, 0.68 mmol) was dissolved in CH2Cl2 (50 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.6 mL, 6.8 mmol), then DBU (10 μL, 70 μmol) were added. The mixture was stirred at 0° C. for 30 min. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 7:3 cyclohexane-EtOAc and 0.2% of Et3N to give 306 (498 mg, 78%) as a colourless foam; [α]D−18° (c 1, CHCl3). 1H NMR: δ 8.48 (s, 1H, NH), 7.40-7.15 (m, 10H, Ph), 6.75 (d, 1H, J2,NH=8.5 Hz, NHD), 6.18 (d, 1H, J1,2=1.1 Hz, H-1A), 5.15 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.07 (pt, 1H, J4,5=9.5 Hz, H-4D), 4.82-4.50 (m, 4H, CH2Ph), 4.62 (d, 1H, J1,2=8.5 Hz, H-1D), 4.20-4.03 (m, 2H, J5,6=4.5, J6a,6b=12.3 Hz, H-6aD, 6bD), 3.98 (m, 1H, H-2D), 3.85 (dq, 1H, J4,5=9.5, J5,6=6.2 Hz, H-5A), 3.84 (dd, 1H, J2,3=3.3 Hz, H-2A), 3.83 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.55 (m, 1H, H-5D), 3.45 (pt, 1H, H-4A), 1.98, 1.96, 1.93 (3s, 9H, OAc), 1.23 (d, 3H, H-6A); 13C NMR: δ 171.1, 170.0, 169.6, 162.1 (C═O), 138.4-127.2 (Ph), 101.7 (C-1D), 97.2 (C-1A), 92.6 (CCl3), 80.5 (C-4A), 79.1 (C-3A), 76.2 (C-2A), 76.2, 74.1 (2C, CH2Ph), 74.4 (C-3D), 74.1 (C-5D), 71.3 (C-5A), 68.6 (C-4D), 62.3 (C-6D), 56.3 (C-2D), 21.1, 21.0, 20.9 (3C, OAc), 18.2 (C-6A). Anal. Calcd for C36H40Cl6N2O13: C, 46.93; H, 4.38; N, 3.04%. Found: C, 46.93; H, 4.52; N, 2.85%.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][CH:2]2[CH:6]3[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]3[CH2:4][CH2:3]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@@H]2C1
Reactant: Clc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CCC(Oc3ccc(Cl)cn3)C2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(8R*,8aS*)-tert-Butyl 8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Example 35D, 0.969 g, 4.0 mmol) and 2,5-dichloropyridine (0.651 g, 4.40 mmol) were treated with potassium tert-butoxide (0.987 g, 8.80 mmol) in dry tetrahydrofuran (5 mL). The mixture was heated to 80° C. and stirred for 16 hours. After the mixture cooled to room temperature, the mixture was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=222 nm) to give the tert-butoxycarbonyl protected product, tert-butyl 8-(5-chloropyridin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate. This tert-butoxycarbonyl compound was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and then purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.72-1.86 (m, 1H), 2.08-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.69-2.80 (m, 2H), 2.87-2.98 (m, 1H), 2.99-3.21 (m, 3H), 5.51 (ddd, 1H, J=7, 4, 2 Hz), 6.77 (d, 1H, J=9 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 8.07 (d, 1H, J=2 Hz); MS (DCI) m/z 254 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]1[CH:26]2[CH:22]([CH2:23][CH:24]([CH2:27][OH:28])[CH2:25]2)[C:21](=[O:29])[C:20]=1[C:30]1[C:35]([CH2:36][CH3:37])=[CH:34][C:33]([CH3:38])=[CH:32][C:31]=1[CH2:39][CH3:40])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH2:11]([O:18][C:19]1[CH:26]2[CH:22]([CH2:23][CH:24]([CH:27]=[O:28])[CH2:25]2)[C:21](=[O:29])[C:20]=1[C:30]1[C:35]([CH2:36][CH3:37])=[CH:34][C:33]([CH3:38])=[CH:32][C:31]=1[CH2:39][CH3:40])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1cc(C)cc(CC)c1C1=C(OCc2ccccc2)C2CC(CO)CC2C1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C)cc(CC)c1C1=C(OCc2ccccc2)C2CC(C=O)CC2C1=O
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
At −78° C., 1.31 g (16.8 mmol) of dimethyl sulphoxide are slowly added dropwise to 1.067 g (8.4 mmol) of oxalyl chloride in 40 ml of dichloromethane, and the mixture is stirred at this temperature for 20 min. 1.70 g (4.20 mmol) of 3-(benzyloxy)-2-(2,6-diethyl-4-methylphenyl)-5-(hydroxymethyl)-4,5,6,6a-tetrahydropentalen-1(3aH)-one (Example I-a-1), dissolved in 30 ml of dichloromethane, are then slowly added dropwise, and the mixture is stirred for another hour. 2.13 g (21 mmol) of triethylamine are then added slowly, and the mixture is brought to room temperature. Addition of 50 ml of saturated ammonium chloride solution, separation, washing of the organic phase with water, drying (magnesium sulphate), concentration on a rotary evaporator and chromatographic purification of the resulting crude product on silica gel (mobile phase ethyl acetate/hexane 1:5) gives 1.24 g (73%) of the title compound as a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][N:20]([CH3:32])[C:21](=[O:31])[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:22]([CH3:24])([CH3:23])[C:21]([N:20]([CH3:32])[CH3:19])=[O:31])[CH2:30][CH2:29]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C)C(=O)C(C)(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.8 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (146 mg, 0.42 mmol) in DMF (5 mL) were added N,N-dimethyl-2-piperazin-1-yl-isobutyramide (100 mg, 0.50 mmol), cesium carbonate (273 mg, 0.837 mmol) and water (23 μL, 1.26 mmol). The resulting mixture was stirred at RT for 17 h. The reaction mixture was loaded directly onto an Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography to give the title compound as an off-white solid (131 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][S:12][CH2:13][CH2:14][OH:15])[CH:5]=1)([O-])=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][S:12][CH2:13][CH2:14][OH:15])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(CSCCO)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c(CSCCO)c1
Reaction time: 0.33 h

Procedure:
0.085 moles (19.5 g) of 4-nitro-2-[(β-hydroxyethylthio)methyl]phenol are added to a solution of 16 g of sodium hydroxide (NaOH) pellets in 135 ml of water, followed portionwise, so as to maintain the temperature between 70° C. and 75° C., by 55 g of sodium hydrosulphite. After the end of addition stirring is continued for 20 minutes at 75° C. After cooling, the expected product is precipitated by neutralizing the reaction mixture with acetic acid. After filtering off, followed by washing with water and drying, the product obtained is recrystallized from acetonitrile. It melts at 121° C.
Reaction SMILES: [CH3:1][CH:2]([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].[N+](=[CH2:17])=[N-]>>[CH3:17][O:13]/[C:12](/[CH3:14])=[C:2](/[CH3:1])\[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4]
Reactant: CC(=O)C(C)C(=S)Nc1ccccc1
Reactant: C=[N+]=[N-]
Product: CO/C(C)=C(/C)C(=S)Nc1ccccc1

Procedure:
2-methylthioacetoacetanilide [formed from α-chloroacetoacetanilide and sodium methylmercaptan] was reacted with diazomethane to obtain 3-methoxy-2-methylthio-crotonanilide melting at 155° C.