Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.[Si:21]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[O:14]=[C:1]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:30]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OC1CCCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)N1CCCC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve lauric acid (0.77 g) in methylene chloride (50mL) and cool to 0° C. Add oxalyl chloride (0.37 mL) and dimethylformamide (3 drops). Allow to warm to room temperature and stir for 1 hour. Add, by dropwise addition, to a solution of 3-(O-tert-butyldimethylsilyloxy)piperidine (0.76 g, 3.5 mmol) and triethylamine (1 mL) in methylene chloride (20 mL). Stir overnight. Dilute with methylene chloride (50 mL) and separate the organic phase. Wash twice with 10% sodium hydroxide, once with 10% hydrochloric acid, and once with saturated sodium hydrogen carbonate and once with brine. Dry (Na2SO4) and evaporate the solvent in vacuo to give 1-oxododecyl-3-(O-tert-butyldimethylsilyoxy)piperidine.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:13](=[O:15])[CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7]>O1CCOCC1>[CH3:2][O:3][N:4]=[C:5]([C:13](=[O:15])[CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CON=C(C(C)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CON=C(C(C)=O)C(=O)O
Reaction time: 13 h
Yield: 86.4 %

Procedure:
A 200 ml portion of the above 4N hydrogen chloride solution in 1,4-dioxane was added to 35.0 g of tert-butyl 2-methoxyimino-3-oxobutyrate and the thus-obtained solution was stirred at 23° to 25° C. for 13 hours. The supernatant was concentrated, 200 ml of methylene chloride was added to the residue for dissolution of the latter, 30 ml of 20% aqueous sodium chloride was added to the thus-obtained supernatant, the mixture was shaken, and the organic layer was separated, dried over 12 g of anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 21.8 g of 2-methoxyimino-3-oxobutyric acid.
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=[C:9]=[S:10].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH3:35])([CH3:34])[C:32]#[N:33])=[CH:26][CH:25]=1.ClCCl.CC(C)=O>C1COCC1>[OH:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:31]([CH3:34])([CH3:35])[C:32](=[NH:33])[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:22])[F:21])[CH:12]=3)[C:9]2=[S:10])=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CC(C)(C#N)Nc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
Triethylamine (0.101 g, 1 mmol) was added to a solution of 1a (0.456 g, 2 mmol) and 3a (0.352 g, 2 mmol) in dry THF (5 ml). The reaction mixture was stirred at 0° C. for 48 h and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 85:15) to afford 4-[3-(4-hydroxyphenyl)-5-imino-4,4-dimethyl-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 3b (0.274 g, 0.68 mmol, 34%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10](O)(=[O:14])[C:11]([CH3:13])=[CH2:12]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH3:9][O:8][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:2]=1[CH3:1])[C:10](=[O:14])[CH:11]([CH3:13])[CH2:12]2
Reactant: COc1ccccc1C
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc2c(cc1C)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-methylanisole (30 g, 0.25 mol) and methacrylic acid (27 g, 0.31 mol) was added at 60° C. to a well stirred Eaton reagent (69 g P2O5 and 350 mL of methanesulfonic acid). After 30 min of stirring the reaction mixture was cooled, poured into ice water, and filtered. The residue was recrystallized from hexane/benzene (10:1). Yield=22 g (46%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[CH3:27][N:28]1C(=O)CCC1>O.[Ni](Br)Br>[OH:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]#[N:28])[CH:7]=3)[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(-c2nc(-c3ccnc(Cl)c3)c3sccc3n2)c1
Reactant: CN1CCCC1=O
Agent: Br[Ni]Br
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Temperature: 200 °C

Procedure:
A mixture of 3-[4-(2-chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-2-yl]-phenol (90 mg), sodium cyanide (26 mg), nickel (II) bromide (58 mg) and NMP was heated under microwave irradiation at 200° C. for 30 minutes. The mixture was cooled, diluted with water and the precipitate collected by filtration. The title compound was isolated following flash column chromatography (31 mg).
Reaction SMILES: [C:1]([O:9][C:10]1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(OC)OC.C(=O)(OC1C=CC=CC=1)OC.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[Ti+4]>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1
Agent: [Ti+4]
Agent: COC(=O)Oc1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: COC(=O)OC
Product: COC(=O)c1ccccc1
Yield: 80 %

Procedure:
Into an autoclave made of SUS316 having an internal volume of 100 ml were charged above-prepared phenyl benzoate 5.64 g (28.4 mmole), dimethyl carbonate 20 g (222 mmole) and titanium tetraphenoxide 0.13 g (0.30 mmole). The pressure was elevated to 20 kg/cm2 with nitrogen, and then the contents were reacted for three hours at 150° C. After completing the reaction, the reaction mixture was analyzed by gas chromatography. As a result, the yield of methyl phenyl carbonate was 75%, and the yield of diphenyl carbonate was 5%. Furthermore, at the same time, methyl benzoate was produced as a by-product with a yield of 80% (the yield is given in terms of phenyl benzoate)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (80 mg, 0.27 mmol) in pyridine (5 mL) was added 4-fluorobenzene-1-sulfonyl chloride (57 mg, 0.30 mmol) with ice cooling. Upon completion of the addition, the resultant mixture was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 74 mg of 2-(4-(4-fluorophenyl-sulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow powder. Yield: 63%; MS (ESI+APCI) M+1=455.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:20])[C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]1>O1CCCC1.[Ni]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C@:11]2([CH3:20])[C:16]([F:17])([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12]2)[CH:4]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])ccc2Cl)N=C(N)OCC1(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: C[C@]1(c2cc(N)ccc2Cl)N=C(N)OCC1(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
Under an inert atmosphere of argon a solution of (R)-4-(2-chloro-5-nitro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate X-3) (50 mg, 0.16 mmol) in tetrahydrofurane (1 ml) was treated at 0° C. with Raney nickel (50% in water, 0.07 ml). The mixture was stirred under hydrogen atmosphere at 0° C. for 15 minutes. The catalyst was filtered off and the filtrate was evaporated at reduced pressure to give the (R)-4-(5-amino-2-chloro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (42 mg, 93% of theory) as a yellow oil which was used without further purification. MS (ISP): m/z=276.1 [M+H]+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C=O>C(O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Reactant: C1CCNC1
Agent: C=O
Solvent: CCO
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Temperature: 25 °C

Procedure:
(3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H) (1 g, 3.8 mmol) is added to ethanol (7 ml). Pyrrolidine (312 μl, 3.8 mmol) and aqueous formaldehyde (393 μl, 5.3 mmol) are added. The mixture is heated at reflux for 3 h. The mixture is next cooled to room temperature and concentrated in vacuo to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (2-a, R1=methylpyrrolidin). Spectroscopic data as reported in Example 19.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:18]([NH2:21])=[CH:19][CH:20]=1)[CH:16]=O.Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[C:18]([NH2:21])=[CH:19][CH:20]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: Nc1ccc(Cl)cc1C=O
Agent: Cl
Solvent: CO
Product: Nc1ccc(Cl)cc1C=C1Oc2cc(O)ccc2C1=O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-chloro-6-aminobenzaldehyde 1.24 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 1.42 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH2:9][CH2:10][N:11]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:12]([NH:14][C:15]2[S:16][C:17]([Cl:35])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([Si](C)(C)C)[N:28]=[N:27]4)=[CH:22][CH:21]=3)[N:19]=2)=[O:13])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)[CH2:9][CH2:10][N:11]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:12]([NH:14][C:15]2[S:16][C:17]([Cl:35])=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)=[CH:24][CH:25]=3)[N:19]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1cn(-c2ccc(-c3nc(NC(=O)N(CCc4ccccn4)CCC(c4ccc(F)cc4)c4ccc(F)cc4)sc3Cl)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(-c2ccc(-n3ccnn3)cc2)c(Cl)s1)N(CCc1ccccn1)CCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(3,3-bis(4-fluorophenyl)propyl)-3-(5-chloro-4-(4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)thiazol-2-yl)-1-(2-(pyridin-2-yl)ethyl)urea 71, prepared in the previous step, at room temperature was added tetrabutylammonium fluoride (1 M in THF, 3.0 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 40° C. for 3 h, and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 30% to 70% EtOAc in hexanes) gave 1-(3,3-bis(4-fluorophenyl)propyl)-3-(5-chloro-4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1,3-thiazol-2-yl)-1-(2-(2-pyridinyl)ethyl)urea. Mass spectrum, calculated for C34H28ClF2N7OS 655.2; found 656.1 (M++1).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:30][CH2:29][CH2:28]1>CN(C1C=CN=CC=1)C.CC#N>[N:27]1([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC3)ccc2n1CC1CCC(F)(F)CC1
Yield: 68.9 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (122 mg, 0.3 mmol), azetidine (41 uL, 34 mg, 0.6 mmol) and DMAP (73 mg, 0.6 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 88 mg (69%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.49-1.63 (m, 2 H), 1.65 (s, 9 H), 1.69-1.93 (m, 4 H), 1.98-2.19 (m, 4 H), 2.21-2.34 (m, 1 H), 3.73-3.82 (m, 4 H), 4.51 (d, J=7.42 Hz, 2 H), 7.84 (dd, J=8.59, 1.76 Hz, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 8.13 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=426.2.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)[C:7]3[N:8]([C:10]([C:13](O)=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH:46]12[NH:53][CH:50]([CH2:51][CH2:52]1)[CH2:49][O:48][CH2:47]2.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)[C:7]3[N:8]([C:10]([C:13]([N:53]4[CH:46]5[CH2:52][CH2:51][CH:50]4[CH2:49][O:48][CH2:47]5)=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc2c(-c3cnco3)cc(C3CC3)cn12
Reactant: C1CC2COCC1N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cnc2c(-c3cnco3)cc(C3CC3)cn12)N1C2CCC1COC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
6-Cyclopropyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (135 mg) was dissolved in DMF (4 mL), and HATU (229 mg), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (113 mg) and triethylamine (91 μL) were added thereto. The reaction mixture was stirred at room temperature for 1 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (43 mg).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[C:1]1([C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=[C:9]([C:16]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:18])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc(-c2ccccc2)c2sccc2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(-c2ccccc2)c2sccc2c1)N1CCCCC1

Procedure:
The reaction is carried out as in Example 1, but starting with 7-phenylbenzo[b]thiophene-5-carboxylic acid (2.5 g) in toluene (25 cc) and thionyl chloride (2.2 cc) and then triethylamine (4.15 cc) and piperidine (0.97 cc) in toluene (25 cc). After two successive chromatographies of the residue on silica gel, the first with a cyclohexane:ethyl acetate (80:10:10 by volume) mixture as the eluent and the second with a cyclohexane:ethyl acetate (70:30 by volume) mixture as the eluent, a residue is isolated, which is stirred for 1 hour in 40°-60° petroleum spirit. After filtering and drying, 1-[(7-phenylbenzo[b]thien-5-yl)carbonyl]piperidine (1.55 g), m.p. 112° C., is isolated.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7](O)[C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1.[CH2:29]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH2:31]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[CH2:31][CH:30]=[CH2:29])[S:5][CH:6]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Solvent: C1CCOC1
Product: C=CCC(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Reaction time: 0.33 h

Procedure:
Boron trifluoride THF complex (0.205 mL, 1.861 mmol) was added to a solution of 7-((4-chlorothiazol-2-yl)(hydroxy)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (870 mg, 2.067 mmol) and allyltri-n-butyltin (0.641 mL, 2.067 mmol) were dissolved in THF (15 mL). The mixture was stirred at room temp. for 20 mins. The reaction mixture was quenched with saturated NaHCO3(aq) and extracted with EtOAc. The organic extracts were washed with 1M KF(aq) (1×), brine (1×), dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 10-60% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [S:1]([O:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1[N:20]1[C:29]2[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=2[N:22]=[CH:21]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36]([NH:25][C:24]2[C:23]3[N:22]=[CH:21][N:20]([C:29]=3[N:28]=[CH:27][N:26]=2)[C@@H:13]2[O:14][C@H:15]([CH2:18][O:19][C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[C@@H:16]([OH:17])[C@H:12]2[O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2[C@H](O)[C@@H](CO)O[C@H]2n2cnc3c(N)ncnc32)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)[C@@H](O)[C@H]2OS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
2'-O-Tosyladenosine (Compound Al) (4.21 g, 10 mmol) and 4,4'-dimethoxytrityl chloride (7.45 g, 22 mmol) were added to anhydrous pyridine (50 ml), and stirred at room temperature for 20 hours. After ice cooling, 50% aqueous pyridine was added, the mixture was extracted with chloroform, and the organic layer was washed successively with aqueous sodium bicarbonate and water, and dried over magnesium sulfate. After distillating away the chloroform, the pyridine was removed by co-evaporation with toluene, and the residue was subjected to silica gel column chromatography [eluant : toluene-ethyl acetate-triethylamine→(9:1:0.1) toluene-ethyl acetate-triethylamine-methanol (9:1:0.1:0.2)]. Fractions containing the desired substance were combined and concentrated to give Compound A2 (7.74 g, yield 75%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([CH3:12])[CH3:11])[CH:5]1[NH2:13])([CH3:3])[CH3:2]>[Pd]>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH2:13])([CH3:12])[CH3:11]
Reactant: CC(C)C1CCCC(C(C)C)C1N
Agent: [Pd]
Product: CC(C)c1cccc(C(C)C)c1N
Yield: 93 %

Procedure:
The procedure described in Example 27 is followed, using a catalyst which contains 1.0% by weight of palladium on a zinc/aluminum spinel and starting from 2,6-diisopropylcyclohexylamine. 2,6-Diisopropylaniline (boiling point=257° C.) is obtained in a yield of 93% of the theory.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:49]([CH3:51])[CH3:50])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([S:23][C:24]3[C@H:25]([CH3:48])[C@@H:26]4[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]4[C:28]=3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[CH2:20]2)[S:17][CH:18]=1)=[O:13])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][N:11]([CH:49]([CH3:51])[CH3:50])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:20][CH:21]([S:23][C:24]3[C@H:25]([CH3:48])[C@@H:26]4[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]4[C:28]=3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[CH2:22]2)[S:17][CH:18]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-[1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (4.47 g, 5.88 mmol) (obtained as described in Example 64(1)) in a mixture of tetrahydrofuran (220 ml) was added to acetic acid (0.40 ml, 7.06 mmol) and 1M tetrabutylammonium fluoride in tetrahydrofuran solution (7.06 ml, 7.06 mmol) and the mixture was stirred at room temperature for 1 day. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (10:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(2-hydroxyethyl)-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.79 g, yield 47%) as a pale yellow solid.