Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].[O:34]1[CH:38]=[CH:37][C:36]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:35]1.C1COCC1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:39][C:36]2[CH:37]=[CH:38][O:34][CH:35]=2)[C:24]=1[CH3:32]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)OCc2ccoc2)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccoc2)c2ncccc12
Reaction time: 0.5 h

Procedure:
BEMP (182 μL, 0.63 mmol) is added to a stirring solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.39 mmol) in DMF (1.2 ml). After 30 minutes, a solution of toluene-4-sulfonic acid furan-3-ylmethyl ester in THF (1.4 ml, 0.45 mmol) is added. After 18 hours, the reaction is partitioned between water and ether. The organic layer is washed with brine then reduced in vacuo. The residue is purified by flash column chromatography (3:1 iso-hexane/EtOAc elution) to furnish (1-furan-3-ylmethyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester; MH+=285.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=3[C:39]=2[C:38]([CH:51](OC(=O)C2C=CC=CC=2)[CH2:52][C:53]2[C:58]([Cl:59])=[CH:57][N:56]=[CH:55][C:54]=2[Cl:60])=[CH:37][CH:36]=1>O1CCCC1.CN(C1C=CN=CC=1)C>[Cl:59][C:58]1[CH:57]=[N:56][CH:55]=[C:54]([Cl:60])[C:53]=1[CH2:52][CH:51]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([F:17])[F:18])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1)[C:38]1[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[C:40]([O:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)[CH:39]=1
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (268 mg, 1.04 mmoles) is dissolved in dry tetrahydrofuran (30 mL) and EDC (237 mg, 1.24 mmoles), HOBT (190 mg, 1.24 mmoles), TEA (0.172 mL, 1.24 mmoles), DMAP (30 mg) are added to the solution. The mixture is stirred at room temperature for 40 minutes, then Benzoic acid 1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester is added and the reaction mixture is stirred at 70° C. for 32 hours. The solvents are then evaporated and the crude mixture is purified by chromatography on SiO2 (hexane:AcOEt from 10:1 to 7:3) to afford 300 mg of the pure title compound.
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:14]=1)=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:14]=1)=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: N=C(N)NC(=O)c1cn(-c2ccc3ncccc3c2)c2ccccc12
Temperature: 22 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
0.256 g (11.1 mmol) of sodium is added at 22° C. under an argon atmosphere to 40 cm3 of methanol. After complete dissolution, 1 g (10.5 mmol) of guanidine hydrochloride is added. After stirring at 22° C. for 3 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 10 cm3 of 1,2-dimethoxyethane. 1 g of 3-chlorocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride, suspended in 40 cm3 of 1,2-dimethoxyethane, is subsequently added at 22° C. under an argon atmosphere. After stirring at 22° C. for 48 hours and after 2 hours at reflux, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 15 cm3 of water. After stirring at 22° C. for 1 hour, a few drops of 10N hydrochloric acid solution are added. After stirring at 22° C. for 12 hours, the suspension is filtered and dried to give 0.52 g of 3-guanidinocarbonyl-1-(quinol-6-yl)-1H-indole hydrochloride in the form of a yellow solid melting at 268° C. IR spectrum (KBr): 3343, 3168, 2174, 1693, 1597, 1543, 1502, 1454, 1236, 1199, 772 and 751 cm−1.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH:44]1[CH2:48][N:47]([CH2:49][CH3:50])[N:46]([CH2:51][CH3:52])[CH2:45]1>ClCCl>[CH2:51]([N:46]1[CH2:45][CH:44]([NH:43][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH2:48][N:47]1[CH2:49][CH3:50])[CH3:52]
Reactant: CCN1CC(N)CN1CC
Reactant: CC(C)=CCC/C(C)=C/COc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN1CC(NC(=O)c2ccccc2OC/C=C(\C)CCC=C(C)C)CN1CC
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
2-geranyloxybenzoic acid (1.36 g) was dissolved in dichloromethan (20 ml) and 1-hydroxybenzotriazole (0.80 g) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.14 g) were added thereto while being cooled with ice. After the resulting mixture was stirred for 30 minutes, 4-amino-1,2-diethyl pyrazolidine (0.71 g) was added thereto and the mixture was stirred for one night at room temperature. The reaction liquid was washed with brine and then dried over sodium sulfite anhydride. Thereafter, the solvent was evaporated under a vacuum. The residue was purified by silica gel column-m chromatography (chloroform:methanol=30:1), thereby yielding 1.71 g (87%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:7]([O:14][CH3:13])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (1.29 g, 6.23 mmol) and dry MeOH (2 mL), a 25 wt % solution of sodium methoxide in MeOH (10 mL) was added and the mixture stirred for 6 h at 100° C. in a sealed tube. The mixture was cooled to 23° C., poured into water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (25 mL), dried, filtered, and concentrated under reduced pressure to afford the titled compound (0.700 g, 56%). The crude material was used without further purification in the next reaction.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:23])[N:5]([C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=O)[CH3:20])=[CH:13][C:12]=2[F:22])[CH:6]=[CH:7][C:8]=1OC)#[N:2].[OH2:24].[NH2:25][NH2:26].C(O)C>O1CCCC1>[NH2:2][C:1]1[C:3]2[C:4](=[O:23])[N:5]([C:11]3[C:12]([F:22])=[CH:13][C:14]([NH:18][C:19](=[O:24])[CH3:20])=[CH:15][C:16]=3[F:17])[CH:6]=[CH:7][C:8]=2[NH:26][N:25]=1
Reactant: O
Reactant: COc1ccn(-c2c(F)cc(NC(C)=O)cc2F)c(=O)c1C#N
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1cc(F)c(-n2ccc3[nH]nc(N)c3c2=O)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A mixture of N-(4-(3-cyano-4-methoxy-2-oxopyridin-1(2H)-yl)-3,5-difluorophenyl)acetamide obtained in Step C (1.10 g), hydrazine monohydrate (0.52 g), ethanol (30 mL) and tetrahydrofuran (15 mL) was stirred at 60° C. for 2 hr. The solvent was evaporated under reduced pressure, and to the residue was added isopropyl ether, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (0.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(CCl)cc1
Product: CCOP(=O)(Cc1ccc(OC)cc1)OCC

Procedure:
4-methoxybenzylchloride and triethyl phosphite were reacted at 150° C. for 5 hours, followed by vacuum distillation for removal of excess triethyl phosphite and by-products to give diethyl 4-methoxybenzylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13](O)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]1=[O:22].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[CH3:23])[CH2:32][CH2:33]2)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:20])[CH3:21])(=[O:17])=[O:18])[C:9]1=[O:22]
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccccc3Cl)CC2)c1

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 519.3 ([M+H]+)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH:32]1([CH2:35][NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][C:14]([C:18]([N:36]([CH2:35][CH:32]3[CH2:34][CH2:33]3)[CH2:37][CH2:38][CH3:39])=[O:20])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: CCCNCC1CC1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)oc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)C(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylic acid i43 (3.18 g, 10.75 mmol, 1 eq) and triethylamine (1.5 ml, 10.75 mmol, 1 eq) in chloroform (70 ml) is cooled to 0° C. Thionyl chloride (2.3 ml, 32 mmol, 3 eq) is then added dropwise. The mixture is refluxed for 2 h 30 and the solvent is evaporated. The residue is taken up in cold dichloromethane (20 ml, 0° C.) and treated with triethylamine (0.6 ml, 4.3 mmol, 2 eq) and N-(cyclopropylmethyl)propan-1-amine (0.29 g, 2.58 mmol, 1.2 eq). The mixture is stirred at room temperature overnight and then washed two times with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.82 g of 2-[4-(3-chloropropoxy)phenyl]-N-(cyclopropylmethyl)-4-methyl-N-propyl-1,3-oxazole-5-carboxamide i44.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[CH2:17]([Mg]Br)[CH3:18].[CH2:21]1COC[CH2:22]1>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:9]2[S:10][C:6]([C:4]([OH:5])([CH2:17][CH3:18])[CH2:21][CH3:22])=[CH:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2s1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: CCC(O)(CC)c1cc2cc(OC)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
5-Methoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (4.13 g, 17.5 mmol) in THF (100 mL) at −78° C. is treated with ethylmagnesium bromide (17.5 mL, 3.0 M). The reaction mixture is allowed to warm to RT over 30 min and is stirred for 10 min. The mixture is quenched with water (40 mL) and acidified with HCl (50 mL, 1.0 M). THF is removed under vacuum, and the residue is extracted with EtOAc (2×40 mL). The organic layer is dried over Na2SO4, concentrated, and purified using silica gel column chromatography (10% EtOAc/Hex) to give the title compound (4.53 g, 97%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:42][CH2:43][CH2:44][CH3:45])[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([OH:41])=[O:40])=[CH:34][CH:33]=3)[CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.[CH3:46]O>>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:42][CH2:43][CH2:44][CH3:45])[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH2:38][C:39]([O:41][CH3:46])=[O:40])=[CH:36][CH:37]=3)[CH:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CO
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)O)cc1)C1CCN(C)CC1
Agent: O=S(=O)(O)O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sulfuric acid (1 mL) was added to the product from step (i) (250 mg) in MeOH (10 mL). The mixture was stirred at rt for 15 h, then the solvent evaporated under reduced pressure. The residue was purified by RPHPLC to afford the title compound, yield 6.2 mg.
Reaction SMILES: [N:1]1([C:6]2[CH:20]=[CH:19][C:9]([C:10]([C:12]3[NH:13][C:14](=[O:18])[NH:15][C:16]=3[CH3:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]=[O:22]>>[OH:22][CH2:21][C:2]1[N:1]([C:6]2[CH:20]=[CH:19][C:9]([C:10]([C:12]3[NH:13][C:14](=[O:18])[NH:15][C:16]=3[CH3:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2)cc1
Reactant: C=O
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2CO)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
1,3-Dihydro-4-[4-(1H-imidazol-1-yl)benzoyl]-5-methyl-2H-imidazol-2-one (5.85 g, 21.8 mmol) (Example I) is combined in a pressure tube containing a magnetic stir bar with 37% aqueous formaldehyde (300 mL) and the mixture heated with stirring at 120° C. for 18 hr. The mixture is cooled, the tube opened and the solution evaporated in vacuo. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:35][N:36]([CH3:50])[C:37]([C:39]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:38]>ClCCl>[CH3:35][N:36]([CH3:50])[C:37]([C:39]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][N:41]([C:12]([C:8]2[CH:9]=[N:10][O:11][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:14])[CH2:40]1)=[O:38]
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)c2cnoc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a solution of 5-phenylisoxazol-4-carboxylic acid (15 mg, 0.08 mmol) in dichloromethane (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (15 mg, 0.08 mol), triethylamine (33 μL, 0.24 mmol) and finally N,N-dimethyl-3-phenylpyrrolidine-3-carboxamide hydrochloride (15 mg, 0.06 mmol) and allowed to stir at ambient temperature overnight. The residue was purified using straight phaseHPLC (1:1 hexane/ethyl acetate) to afford the title compound (4 mg). HRMS (ESI, pos. ion) m/z calcd for C23H23N3O3: 389.1739, found 389.1744.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.C(=O)([O-])[O-:25].[K+].[K+].OO.Cl>O.CS(C)=O>[CH3:23][S:22][C:4]1[NH:3][C:2](=[O:25])[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[N:5]=1
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Nc2cccc(S(C)(=O)=O)c2)c(C(N)=O)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a mixture of 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (Preparation Example 298) (1.95 g) and DMSO (30 mL), potassium carbonate (1.81 g) and 30% hydrogen peroxide solution (2.65 mL) were added and stirred at 50° C. for 1.5 hours. The reaction liquid was ice-cooled, and 1M hydrochloric acid (25 mL) and thereafter water (150 mL) were added and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water to give 2-(methylsulfanyl)-4-{[3-(methylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (1.40 g) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:27][NH2+:28][CH3:29]>C(O)C>[N:11]1([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:28]([CH3:29])[CH3:27])[CH2:6][CH2:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: ClCCCN1CCC(n2ccc3ccccc32)CC1
Reactant: C[NH2+]C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)CCCN1CCC(n2ccc3ccccc32)CC1
Yield: 107.8 %

Procedure:
A mixture of 1-N-[1-N-(3-chloro-propyl)-piperidin-4-yl]-indole (900 mg, 3.25 mmol), anhydrous potassium carbonate (440 mg, 3.25 mmol) and dimethylammonium hydrochloride (260 mg, 3.25 mmol) in absolute ethanol (10 mL) was refluxed for 6 hours, evaporated and suspended in water. The mixture was extracted with methylene chloride, dried over anhydrous potassium carbonate, and evaporated to yield 1 g of the desired compound (100% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[N:7][O:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:10]1([C:9]2[O:8][N:7]=[C:6]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[C:5]=2[CH2:3][OH:2])[CH2:12][CH2:11]1
Reactant: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a 0° C. solution of 5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole-4-carboxylic acid methyl ester (0.80 g, 2.6 mmol) in THF (8 mL) is added a 1M DIBAL solution in toluene (5.66 mL). The reaction is stirred one hour. An additional 1M DIBAL solution in Toluene (5.66 mL) is added and the reaction is stirred for an additional hour. The reaction is quenched with methanol and is acidified with aqueous HCl solution (1M). The aqueous solution is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed under reduced pressure to yield the title compound (0.68 g, 93%). ES/MS m/e 284.0 (M+1).
Reaction SMILES: [P:1](=[O:90])([S:84][CH2:85][S:86][C:87](=[O:89])[CH3:88])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[O:59]C(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1>C(O)(=O)C.O.CO>[P:1](=[O:90])([S:84][CH2:85][S:86][C:87](=[O:89])[CH3:88])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[OH:59])[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)OP(=O)(OC(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)SCSC(C)=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(=O)SCSP(=O)(OC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O)O[C@]1(O)C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C

Procedure:
The totally protected phosphorothioate dinucleoside (3c) is dissolved in an acetic acid/water/methanol mixture (8:1:1, v:v:v) (5 ml) and left with stirring at ambient temperature all night. The following day, the reaction mixture is evaporated and coevaporated several times with water and with toluene. The residue is then chromatographed on a column of silica gel using a gradient of methanol (0 to 10%) as eluent. The fractions containing the detritylated phosphorothioate triester dinucleoside (4c) are collected and concentrated under reduced pressure. The residue is coevaporated with dioxane and then lyophilized in dioxane. (4c) is obtained in the form of a white powder (20 mg, 85%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl[CH2:26][O:27][CH3:28].[CH3:29]N(C)C=O>>[CH2:3]([C:4]1[N:8]([CH2:26][O:27][CH3:28])[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:29]
Reactant: COCCl
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(COC)c1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Sodium hydride (50% in mineral oil; 220 mg, 4.76 mmol) was added to a solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (1 g, 3.18 mmol) in dimethylformamide (15 mL) at 0° C. and then the mixture stirred for 30 min at ambient temperature. The mixture was cooled to 0° C. and chloro-methoxy-methane (0.3 ml, 3.8 mmol) was added and the whole refluxed for 6 h. The reaction mixture was cooled, washed with water (2×25 ml) and extracted with ethyl acetate (4×25 ml). The combined ethyl acetate extracts were washed with water (2×25 ml), brine (25 ml), dried over anhydrous sodium sulphate and concentrated to afford diethyl 5-ethyl-1-(methoxymethyl)-3-phenyl-pyrrole-2,4-dicarboxylate (1 g, 88%) as a pale yellow liquid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@@:6]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[CH:4]=[CH2:5].[CH3:35]I>C1COCC1>[CH2:3]([C@@:6]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:35])[CH:22]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)[nH]c3)cc2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of NaH (330 mg, 8.24 mmol) in THF (20 mL) was added a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (891 mg, 0.174 mmol) in THF (30 mL) at 0° C., and the resulting mixture was stirred for 1 h. CH3I (2 ml) was added and the mixture was stirred overnight. The reaction was quenched by aqueous NH4Cl solution. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (634 mg, 69%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.16-2.35 (m, 3H), 2.52-2.64 (m, 2H), 2.94 (m, 1H), 3.61 (s, 3H), 5.00-5.11 (m, 2H), 5.66-5.74 (m, 2H), 6.64 (d, 1H), 6.90 (d, 2H), 7.02 (t, 2H), 7.11-7.14 (d, 2H), 7.25-7.28 (m, 2H), 7.41 (m, 1H), 7.53 (m, 1H).