Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC#N>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29])[CH2:26][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2cccn2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of pyrazole (93 mg, 1.4 mmol), K2CO3 (180 mg, 1.30 mmol) and 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (193 mg, 0.599 mmol) in MeCN (5 mL) is stirred at RT for 1 h. Additional pyrazole (500 mg, 7.34 mmol) and K2CO3 (200 mg, 1.45 mmol) are added and the mixture is stirred at RT for an additional 15 h. The mixture is partitioned between EtOAc and water and the organic phase is dried over MgSO4. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: S(O[CH2:8][CH3:9])(OCC)(=O)=[O:2].[CH2:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].C(O)C.[OH-].[Na+]>>[OH-:2].[CH2:10]([N+:12]([CH2:8][CH3:9])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11]
Reactant: CCN(CC)CC
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[N+](CC)(CC)CC
Temperature: 140 °C
Reaction time: 4 h
Yield: 410.2 %

Procedure:
To a 1.5 L autoclave equipped with a stirrer and a heating means were added 154 g (1.0 mol) of diethyl sulfate, 101 g (1.0 mol) of triethyl amine and 690 g (15 mol) of ethanol. Stirring was initiated after the autoclave was sealed. The autoclave was heat to 140° C., and pressure was 1.0 MPa. The reaction was kept at 140° C. for 4 h. Then the reaction mixture was cooled to room temperature and discharged into a 1 L three-necked flask. 80 g (2.0 mol) of sodium hydroxide was added thereto. The reaction mixture was heated to 45° C. for 4 h while stirring. After filtration, part of ethanol was distilled off from the filtrate. Then 500 g of water was added while ethanol was distilled off (part of water was entrained out), to give 604 g of tetraethyl ammonium hydroxide solution. The content of tetraethyl ammonium hydroxide was found as 23.3 wt.-% and the total reaction yield was 95.7%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O:23][C:24](=O)[C:25](=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C>C(O)C>[OH:33][C:25]1[C:24](=[O:23])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C1C(O)=C(c2ccccc2)C(c2ccc3[nH]ccc3c2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 1H-Indole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethylester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)=[CH:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:20][C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:10]([C:9]2[CH:8]=[N:7][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:14][CH:13]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2ccsc2)nc1
Product: O=C(c1ccc(-c2ccsc2)nc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D using 6-thiophen-3-yl-nicotinic acid and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine to give the title compound (35 mg). MS (ES+) 342.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:22][CH2:21][CH2:20][Cl:19])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: ClCCCI
Reactant: O=C1COc2cc(Cl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2cc(Cl)ccc2N1CCCCl
Yield: 79.2 %

Procedure:
7-Chloro-4H-benzo[1,4]oxazin-3-one (81MF2271a) (1.74 g, 9.47 mmol), Cs2CO3 (4.63 g, 14.2 mmol) and 3-chloro-1-iodopropane (2.13 g, 10.4 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2271b) (1.95 g, 79%). 1H NMR (CDCl3) δ 7.03-6.96 (m, 3H), 4.59 (s, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H), 2.17-2.10 (m, 2H); 13C NMR (CDCl3) δ 164.0, 146.0, 129.1, 127.3, 123.0, 117.8, 115.5, 67.7, 42.4, 39.2, 30.0.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
Trimethylacetyl chloride (35 g) was added drop wise to a solution of 4-chloroaniline (31.9 g) in dry pyridine and the reaction was stirred under nitrogen overnight. About half of the pyridine was removed by rotary evaporation, then the mixture was treated with 6M hydrochloric acid and extracted with ethyl acetate. The extracts were washed with saturated aqueous NaHCO3 and with water, then were dried (MgSO4), filtered and concentrated by rotary evaporation. The resulting crystalline product was vacuum filtered and dried at high vacuum to constant weight, resulting in a good yield of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide as fine needles. EDC (10 g) and 2-methyl-nicotinic acid (7.15 g) were magnetically stirred in acetonitrile-THF with N,O-dimethylhydroxylamine hydrochloride (9.75 g) and triethylamine (25 mL). After stirring overnight at ambient temperature, the resulting white suspension was added to ice water and extracted with ethyl acetate (3×100 mL). The extracts were dried, filtered, and concentrated to give a light amber oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[Mg].[Cl-].[NH4+].C([O:22][CH2:23][CH3:24])C>O1CCCC1.O>[OH:22][CH:23]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1)[CH2:24][CH2:4][CH2:3][CH2:2][CH2:16][CH2:6][CH2:7][CH2:10][CH2:11][CH3:12]
Reactant: Brc1ccc2occ(-c3ccccc3)c2c1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC(O)c1ccc2occ(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.5 g. (0.02 mole) of 5-bromo-3-phenylbenzofuran in tetrahydrofuran is added 0.5 g. (0.02 mole) of magnesium, and the mixture is heated at its reflux temperature for three hours. After cooling to 0° C., 3.4 g. of undecyl aldehyde is added. After stirring for 30 minutes at room temperature, the solution is added to ammonium chloride solution. Evaporation provides a residue which is mixed with diethyl ether and water. The ether layer is separated, washed with saturated sodium chloride solution, dried and evaporated. The resulting oil is dissolved in carbon tetrachloride and eluted from a silica gel column with carbon tetrachloride, then with dichloromethane. The later fractions are evaporated to provide 5-(α-hydroxyundecyl)-3-phenylbenzofuran which is dissolved in dichloromethane.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[O:17][C:18]2[C:19]#[C:20][CH:21]=[CH:22][CH:23]=2)C=CC=CC=1>>[OH:17][C:18]1[CH:23]=[C:22]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[C:3]2=[O:9])[CH:21]=[CH:20][CH:19]=1
Reactant: c1cccc(O[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c#1
Reactant: CN1CCCCCC1=O
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
Following the procedure of Example 3, reaction of the lithium anion of N-methylcaprolactam with m-triphenylsiloxybenzyne (from o-chlorotriphenylsilyloxybenzene and lithium tetramethylpiperidide) followed by workup with aqueous acid gives the title compound m.p. 192°-3° C. (ethylacetate).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[H-].[Na+].[Cl:21][C:22]1[S:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1.[NH2:29][OH:30]>CN(C=O)C.CO.O>[Cl:21][C:22]1[S:23][C:24]([CH2:27][N:12]2[C:13]3[CH:1]=[N:2][C:3]([C:14]([NH:29][OH:30])=[O:16])=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:25][CH:26]=1
Reactant: NO
Reactant: ClCc1ccc(Cl)s1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NO)c1cc2c3ccccc3n(Cc3ccc(Cl)s3)c2cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.1 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (300 mg, 1.25 mmol) in DMF (3 mL) under a nitrogen atmosphere was added NaH (50.0 mg, 60% in mineral oil, 1.25 mmol) portionwise, followed by 2-chloro-5-(chloromethyl)-thiophene (151 μL, 1.25 mmol). The stirring was continued for 21 hours at ambient temperature, water (50 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give a solid that was dissolved in methanol (25 mL). To the resulting solution, H2NOH (25 mL, 50 wt. % solution in H2O, 0.38 mol) was added. The suspension was stirred for 4 days at ambient temperature. The mixture was then filtered, and the solid was boiled in methanol (25 mL). After filtration, the desired product (0.26 g, 58%) was obtained. 1H NMR (400 MHz, DMSO-d6): —11.28 (1H, s), 9.15 (1H, s), 9.01 (1H, s), 8.81 (1H, s), 8.44 (1H, d, J=8 Hz), 6.94–7.92 (5H, m) 5.99 (2H, s). HRMS (M+H)+ found: 358.0417. Calcd for C17H13N3O2SCl: 358.0417.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([CH3:20])=[C:18]([C:21]([O:23]C)=O)[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[NH2:2].[Cl-].[NH4+:29]>N.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([CH3:20])=[C:18]([C:21]([NH2:29])=[O:23])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(=O)OC)c(C)c12
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(N)=O)c(C)c12
Yield: 67.3 %

Procedure:
Methyl 4-(4-carbamoyl-2-ethoxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.025 g, 0.06 mmol) and ammonium chloride (0.250 g, 4.67 mmol) in 7N ammonia/MeOH (3.5 mL) were heated at 100° C. in a sealed-tube for 14 days. The solution was cooled and the residue filtered. The precipitate was washed with water to yield white solid (0.015 g, 63%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([NH2:16])=[NH:15].[Cl:17][C:18]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:19]=1[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23]>>[NH2:25][CH2:24][C:21]1[C:22]([NH2:23])=[N:15][C:14]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=2)=[N:16][C:20]=1[C:19]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:18]=1[Cl:17]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc2oc3ccccc3c2c1
Product: NCc1c(N)nc(-c2ccc3oc4ccccc4c3c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=434.9 (M+), was prepared from dibenzofuran-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].CC1C=C(C)[N:18]=C(C)C=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[NH2:18]
Reactant: Cc1cc(C)nc(C)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Para-nitrophenyl chloroformate (483 mg, 2.40 mmol) was dissolved in 10 mL dichloromethane (dry, mol. sieve). A solution of amine 18d (1.00 g, 2.31 mmol) in 5 mL dichloromethane (dry, mol. sieve) and 1.8 mL of sym-collidine were added and mixture was stirred at room temperature for 40 min. Dichloromethane was removed under reduced pressure, residue was acidified with acetic acid and purified by RP-HPLC to yield para-nitrophenyl carbamate 18e.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16]C(=O)CC)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(Cl)N=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H](N3[N:80]=[C:79]([CH2:81][OH:82])[CH:78]=[N:77]3)[C@@H](O)[C@H]2O)=C(Cl)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:80]=[C:79]([CH2:81][OH:82])[CH:78]=[N:77]3)[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
(1R,2S,3R,5S)-3-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide by replacing N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide, with (1R,2S,3R,5S)-3-(2,6-dichloro-purin-9-yl)-5-(4-hydroxymethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol (Intermediate FC).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:48]=[CH:49][C:50]=1F)[C:35]([N:37]1[CH2:40][CH:39]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:38]1)=[O:36].[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[F:31][C:32]1[CH:33]=[C:34]([C:35]([N:37]2[CH2:40][CH:39]([O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[CH2:38]2)=[O:36])[CH:48]=[CH:49][C:50]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: O=C(c1ccc(F)c(F)c1)N1CC(OC2CCCCO2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CC(OC4CCCCO4)C3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (150 mg, 0.348 mmol) synthesized in Example (38d) and 1-(3,4-difluorobenzoyl)-3-(tetrahydro-2H-pyran-2-yloxy)azetidine (220 mg, 0.740 mmol) synthesized in Example (42a) were dissolved in dimethyl sulfoxide (5.0 mL), and sodium hydride (60%, 70 mg, 1.75 mmol) was added, followed by stirring at 100° C. for 1.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, saturated brine (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). Subsequently, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=65%-85%) to afford the desired compound (158 mg, yield 75%) as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Brc1ccccn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromopyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:65]=[CH:64][CH:63]=[CH:62][C:4]=1[C:5]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[O:34][PH:35]([O:37][CH2:38][C@H:39]1[O:43][C@@H:42]([N:44]2[CH:52]=[C:50]([CH3:51])[C:48](=[O:49])[NH:47][C:45]2=[O:46])[CH2:41][C@@H:40]1[O:53]C(=O)C1C=CC=CC=1)=[O:36])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.C(N)(C)(C)C>[CH3:1][O:2][C:3]1[CH:65]=[CH:64][CH:63]=[CH:62][C:4]=1[C:5]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[O:34][PH:35]([O:37][CH2:38][C@H:39]1[O:43][C@@H:42]([N:44]2[CH:52]=[C:50]([CH3:51])[C:48](=[O:49])[NH:47][C:45]2=[O:46])[CH2:41][C@@H:40]1[OH:53])=[O:36])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1C(OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[PH](=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)N
Solvent: CO
Product: COc1ccccc1C(OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[PH](=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O)(c1ccccc1)c1ccccc1

Procedure:
Dinucleoside monophosphate 3 (20 mg; 20 μmol) was dissolved in 2 mL of 1:1 CH3OH-t-butylamine. The reaction mixture was maintained at 40°-45° C. for 2 days, then concentrated under diminished pressure. The residue was purified by preparative silica gel TLC; development was with 9:1 CH2Cl2 -CH3OH. Dinucleoside monophosphate 4 was isolated as an off-white gummy solid following lyophilization, yield 15 mg (84%); silica gel TLC Rf 0.50 (10:1 CH2Cl2 -CH3OH); 1H-NMR (CDCl3, (CH3)4Si) & 0.8-0.9 (m), 1.2-1.35 (m), 1.32 (s), 1.81 (s), 2.1-2.9 (m), 3.00 (m), 3.4-4.3 (m), 3.71 (s), 4.4 (m), 4.6 (m), 5.04 (m), 6.07 (t), 6.35 (m), 6.78 (d), 7.2-7.4 (m), 7.50 (s) and 8.46 (br s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:15])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@H:12]([OH:14])[CH3:13])[N:8]=[CH:7]2.[C:16]([O:22]C)(=O)[C:17](OC)=O.[NH3:24]>CO.O.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>[OH:14][C@H:12]([CH3:13])[CH2:11][N:9]1[C:10]2[C:2]3[N:1]=[C:17]([C:16]([NH2:24])=[O:22])[O:15][C:3]=3[CH:4]=[CH:5][C:6]=2[CH:7]=[N:8]1
Reactant: COC(=O)C(=O)OC
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(N)c21
Reactant: N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CO
Solvent: O
Product: C[C@@H](O)Cn1ncc2ccc3oc(C(N)=O)nc3c21
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a solution of the product from Step C (1.61 g, 7.76 mmol) in methanol (20 mL) was added dimethyl oxalate (9.16 g, 77.6 mmol), p-toluene sulfonic anhydride hydrate (50 mg), and the mixture was heated to distill off liquids with a bath temperature of 120° C. for 5 h. The dark residue was treated with methanolic ammonia (7 M, 22 mL, 0.15 mol) and heated at reflux temperature for 1 h. Additional ammonia (7 M in methanol, 20 mL) was added and heating continued for another hour. The reaction mixture was cooled to room temperature, filtered, and evaporated to a brown solid that was purified by chromatography to give a tan solid (0.91 g, 45%): LC/MS m/z 279.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]2[CH2:8][CH2:9][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][CH:15]1[C:20]([CH3:22])([CH3:21])[CH:19]2[CH2:23][CH2:24][CH:16]1[CH2:17][CH2:18]2.[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][NH2:31].[H][H]>C(O)C.[Pt]=O>[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][NH:31][CH:12]([CH2:13][CH2:14][CH:15]1[C:20]([CH3:22])([CH3:21])[CH:19]2[CH2:23][CH2:24][CH:16]1[CH2:17][CH2:18]2)[CH2:11][CH2:10][CH:3]1[C:2]([CH3:26])([CH3:1])[CH:7]2[CH2:8][CH2:9][CH:4]1[CH2:5][CH2:6]2
Reactant: CC1(C)C2CCC(CC2)C1CCC(=O)CCC1C2CCC(CC2)C1(C)C
Reactant: [H][H]
Reactant: NCC(O)CN
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)C2CCC(CC2)C1CCC(CCC1C2CCC(CC2)C1(C)C)NCC(O)CN

Procedure:
A solution of 1,5-di-(3,3-dimethylbicyclo[2.2.2]oct-2-yl)-3-pentanone (14.8 g., 0.04 mole) in 50 cc of anhydrous ethanol is added dropwise over about 20 minutes to a stirred solution of 1,3-diamino-2-hydroxypropane (25 g., 0.27 mole) in 200 cc of ethanol. The resulting mixture is then heated at reflux for about two hours, allowed to cool, 1.0 g. platinum oxide added, and the mixture reduced under a 40 psi hydrogen atmosphere until hydrogen uptake ceases. The mixture is then filtered from the catalyst, concentrated in vacuo to remove the ethanol, the oily residue taken up in ether (250 cc.), washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product 1-amino-3-[1,5-di-(3,3-dimethylbicyclo[2.2.2]oct-2-yl)-3-pentylamino]-2-propanol.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:9]=1)#[N:3].[Br:20][C:21]([Cl:27])([S:25]Cl)[CH:22]([Br:24])[Cl:23].[Cl:28][C:29]([Cl:36])([S:34]Cl)[C:30]([Cl:33])([Cl:32])[Cl:31]>>[C:2]([C:4]1[C:5](=[O:19])[N:6]([S:25][C:21]([Br:20])([Cl:27])[CH:22]([Br:24])[Cl:23])[C:7](=[O:18])[N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:9]=1)#[N:3].[C:2]([C:4]1[C:5](=[O:19])[N:6]([S:34][C:29]([Cl:36])([Cl:28])[C:30]([Cl:33])([Cl:32])[Cl:31])[C:7](=[O:18])[N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:9]=1)#[N:3]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Br)C(Cl)Br
Reactant: ClSC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Na]
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Br)C(Cl)Br)c1=O
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)C(Cl)(Cl)Cl)c1=O

Procedure:
The sodium salt of 5-cyano-1-(2,6-dimethylphenyl)uracil is reacted with each of 1,2-dibromo-1,2-dichloroethanesulphenyl chloride and pentachloroethanesulphenyl chloride to yield 5-cyano-1-(2,6-dimethylphenyl)-3-(1,2-dibromo-1,2-dichloroethanesulphenyl)uracil and 5-cyano-1-(2,6-dimethylphenyl)-3-pentachloroethanesulphenyluracil.
Reaction SMILES: [Br:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([S:8][CH:14]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(Br)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ncccc2Br)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromopyridine-2-thiol (0.30 g, 1.6 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (0.79 g, 3.2 mmol) and K2CO3 (438 mg, 3.20 mmol) in DMF (12 mL) was stirred at rt for 4 h. The reaction mixture was concentrated to dryness and the residue subjected to FCC purification to give partially purified title compound (1.05 g, 63% purity).