Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H](C)C(N[C@H]1C[C@@H](N2C=NC3C2=NC(N2CC[C@@H](NC(NC4C=NC=CC=4)=O)C2)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O)=O)[C:2]1C=CC=CC=1.[NH2:60][C@@H:61]1[CH2:65][CH2:64][N:63]([C:66]2[N:74]=[C:73]3[C:69]([N:70]=[CH:71][N:72]3[C@@H:75]3[CH2:79][C@H:78]([NH:80][C:81](=[O:92])[C@H](OCC4C=CC=CC=4)C)[C@@H:77]([OH:93])[C@H:76]3[OH:94])=[C:68]([NH:95][CH2:96][CH:97]([C:104]3[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=3)[C:98]3[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=3)[N:67]=2)[CH2:62]1.C1(O[C:117](=[O:127])[NH:118][CH2:119][C:120]2[CH:125]=[CH:124][CH:123]=[C:122]([OH:126])[CH:121]=2)C=CC=CC=1.C1(OC(=O)NC2C=NC=CC=2)C=CC=CC=1>>[C:98]1([CH:97]([C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=2)[CH2:96][NH:95][C:68]2[N:67]=[C:66]([N:63]3[CH2:64][CH2:65][C@@H:61]([NH:60][C:117]([NH:118][CH2:119][C:120]4[CH:125]=[CH:124][CH:123]=[C:122]([OH:126])[CH:121]=4)=[O:127])[CH2:62]3)[N:74]=[C:73]3[C:69]=2[N:70]=[CH:71][N:72]3[C@@H:75]2[CH2:79][C@H:78]([NH:80][C:81](=[O:92])[CH2:2][CH2:1][OH:8])[C@@H:77]([OH:93])[C@H:76]2[OH:94])[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NCc1cccc(O)c1)Oc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: O=C(Nc1cccnc1)Oc1ccccc1
Product: O=C(CCO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4) and (3-Hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate ZD) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[I-:19].[K+]>Cl.O>[I:19][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)c(C)c([N+](=O)[O-])c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(I)c(C)c([N+](=O)[O-])c1
Yield: 73.6 %

Procedure:
To a suspension of methyl 3-amino-4-methyl-5-nitrobenzoate (36.0 g) in 6-normal hydrochloric acid (276 mL) was added dropwise a solution nitrite (13.0 g) in water (35 mL) under ice-salt-cooling over 20 minutes, and the mixture was stirred under ice-cooling for 1 hour. Then, thereto was added dropwise a solution of potassium iodide (34.1 g) in water (280 mL) under ice-cooling over 20 minutes, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with chloroform. The organic layer was sequentially washed with aqueous saturated sodium thiosulfate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/1) to give methyl 3-iodo-4-methyl-5-nitrobenzoate [REx(14-1)] (40.5 g) as a yellow powder.
Reaction SMILES: [P:1]([O:19][C:20]1[CH:32]=[CH:31][C:30]2[NH:29][C:28]3[CH:27]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:25]4[C:39](=[O:43])[NH:40][C:41](=[O:42])[C:24]=4[C:23]=3[C:22]=2[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.O1CCCC1.[Pd]>[P:1]([OH:3])([OH:11])([O:19][C:20]1[CH:32]=[CH:31][C:30]2[NH:29][C:28]3[CH:27]=[C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:25]4[C:39](=[O:43])[NH:40][C:41](=[O:42])[C:24]=4[C:23]=3[C:22]=2[CH:21]=1)=[O:2]
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccc(OP(=O)(OCc4ccccc4)OCc4ccccc4)cc3c21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccc(OP(=O)(O)O)cc3c21
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A solution of the dibenzyl phosphate (336) (100 mg, 0.17 mmol) prepared as described in example 447 in methanol/tetrahydrofuran (3:1, 70 mL) was hydrogenated at 60 psi over Pd-C (5%, catalytic) with stirring for 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. Trituration from ethyl acetate/hexane gave the phosphate (337) (49 mg, 71%) as a yellow solid, mp 285–295° C. 1H NMR δ [(CD3)2SO] 12.01 (br s, 1H), 11.09 (br s, 1H), 8.66 (br s, 1H), 7.63 (m, 3H), 7.57 (br d, J=8.6 Hz, 1H), 7.50–7.44 (m, 4H). Found: C, 55.19; H, 3.29; N, 6.34; P, 6.84. C20H13N2O6P.1/2H2O requires: C, 55.18; H, 3.71; N, 6.43; P, 7.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.2 %

Procedure:
A cold (0° C.) solution of 4-(3-bromophenyl)butan-1-ol (1.08 g, 4.7 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.3 mmol) in THF was treated slowly with triethyl amine (1.8 mL, 12.3 mmol), stirred at room temperature for 4 hours, poured into cold saturated aqueous NH4Cl and extracted with ether. The organic extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) as the eluting solvent afforded toluene-4-sulfonic acid 4-(3-bromophenyl)-butyl ester as a colorless oil (2.4 g, 76% yield). m/e (M+NH4)+ 400.1. 1H NMR (400 MHZ, DMSO-d6) δ ppm, 1.4-1.6 (m, 4 H), 2.4 (s, 3 H), 2.4-2.5 (m, 2 H), 4.0 (t, J=6.0 Hz, 2 H), 7.2 (t, J=7.8 Hz, 1 H), 7.3-7.3 (m, 1 H), 7.3-7.3 (m, J=8.0, 1.0 Hz, 1 H), 7.4-7.5 (m, J=8.6 Hz, 2 H), 7.7-7.8 (m, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[CH:3][CH:2]=1.O1CCOCC1.O1CCCC1.[Br:27][CH2:28][CH2:29][C@H:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([NH2:41])=[O:40])[CH2:31]1>CO>[Br-:27].[C:39]([N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:30]([CH2:29][CH2:28][N+:1]2[CH:6]=[CH:5][C:4]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][CH:11]=[CH:10]4)=[CH:3][CH:2]=2)[CH2:31]1)(=[O:40])[NH2:41]
Reactant: c1cc(-c2ccc3[nH]ccc3c2)ccn1
Reactant: NC(=O)N1C[C@@H](CCBr)c2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=O)N1C[C@@H](CC[n+]2ccc(-c3ccc4[nH]ccc4c3)cc2)c2ccccc21
Product: [Br-]
Yield: 82 %

Procedure:
A mixture of 5-(pyridin-4-yl)-1H-indole (2.6 g, 0.13 mol), 1,4-dioxane (250 mL), tetrahydrofuran (20 mL) and methanol (10 mL) was heated to reflux temperature, and (S)-3-(2-bromoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid amide (3.9 g, 0.015 mol) was added. The resulting mixture was boiled under reflux for 96 h. The mixture was cooled, and the liquid decanted off. The residue was washed with ethyl acetate and then dissolved in methanol (500 mL) under heating. The organic phase was concentrated in vacuo to give 1-[2-((S)-1-carbamoyl-2,3-dihydro-1H-indol-3-yl)ethyl]-4-(1H-indol-5-yl)pyridinium bromide (5.7 g, 75%). This compound was suspended in methanol (130 mL), and sodium borohydride (1.48 g, 0.039 mol) was added over a period of 10 min at 12-20° C. The resulting mixture is stirred at 10° C. for 30 min and then poured onto a mixture of brine (500 mL) and 28% aqueous sodium hydroxide (50 mL). The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/ethanol/triethylamine 85:10:5) to give crude title compound (3.5 g). Starting from 0.7 g of crude compound, the hydrochloric acid salt was prepared (0.63 g). Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].[S:25](Cl)([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]>O>[CH3:35][N:34]([CH3:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:32]=1[CH:31]=[CH:30][CH:29]=[C:28]2[S:25]([NH:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])(=[O:27])=[O:26]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
Pyridine (5 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) and dansyl chloride (0.81 g, 3.0 mmol) and stirred under an inert atmosphere at room temperature. After 20 hours, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with water then saturated brine, then dried over MgSO4 and stripped of solvent under reduced pressure to afford the product (1.3 g); m.p. 231-232° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH:4]=1.C(Br)(Br)(Br)[Br:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:17][CH2:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1cc(CO)ccn1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1cc(CBr)ccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Hydroxymethyl-1-phenyl-1H-pyridin-2-one from Step 4 (1.0 g, 5 mmol) was dissolved in CH2Cl2. CBr4 (6 mmol, 2 g) was added and the reaction mixture was cooled to 0°. PPh3 (6 mmol, 2.0 g) was added dropwise in CH2Cl2. The reaction mixture was stirred at 0° for 15 minutes and then warmed to room temperature. The reaction mixture was concentrated and purified on a column of silica eluting with (30% EtOAc/hexane to 50% EtOAc/hexane) to give 4-bromomethyl-1-phenyl-1H-pyridin-2-one (8, x=H) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:6]=[CH:5][CH:4]=1)#[N:2].NC(N)=[O:21].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][N+:6]([O-:21])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: NC(N)=O
Reactant: COC(=O)c1c(C#N)ccnc1-c1cnn(C)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C#N)cc[n+]([O-])c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (470 mg, 1.940 mmol) in DCM (10 mL) was added urea-hydrogen peroxide compound (1/1, 913 mg, 9.70 mmol), and 2,2,2-trifluoroacetic anhydride (1.370 mL, 9.70 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. More urea-hydrogen peroxide compound (1/1, 400 mg) was added and the mixture was stirred at RT for an additional 3 h after which was added saturated aq NaHCO3 solution and CHCl3. The aqueous phase was extracted with CHCl3 (3×), and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to obtain crude 4-cyano-3-(methoxycarbonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine 1-oxide, which was combined with phosphorus oxychloride (2 mL, 21.46 mmol). The resulting mixture was stirred at 80° C. for 5 h and then concentrated to a residue, which was neutralized with 2N NaOH. The organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2(Hexane/EtOAc=1/1) to give the title compound as a white solid (155 mg, 41.3%). 1H NMR (500 MHz, CDCl3) δ ppm 3.96 (s, 3H), 4.03 (s, 3H), 7.41 (s, 1H), 7.81 (s, 1H), 7.94 (s, 1H). [M+H] calc'd for C12H9ClN4O2, 277. found, 277.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[C:17]([CH3:30])=[C:16]([CH3:31])[N:15]=1>CN(C)C=O>[ClH:13].[CH3:30][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[N:19][C:14]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:15][C:16]=1[CH3:31]
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NCC(C)C)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 28.8 %

Procedure:
After isobutylamine(0.27 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 180 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13](=O)[CH3:14])[CH2:8][CH2:7][CH2:6]2.[CH2:16]([NH2:18])[CH3:17].Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]([NH:18][CH2:16][CH3:17])[CH3:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2C(C)=O
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)C1CCCc2cc(OC)ccc21
Reaction time: 48 h

Procedure:
The product of Example 93(2 g) was dissolved in anhydrous MeOH (20 ml) and EtNH2 (3 ml) and the pH adjusted to ca. 8 with methanolic HCl. Sodium cyanoborohydride (500 mg) was added and an additional 2 ml methanolic HCI dropwise. The reaction was stirred under N2 for 48 h then 6N HCl added to pH<2. The methanol was removed under vacuum and the aqueous layer extracted with CH2Cl2 (2×100 ml). The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated giving 0.18 g of an oil. The neutral CH2Cl2 extract was dried (MgSO4), filtered and evaporated then partitioned between 2N HCl and a mixture of ether/hexane. The organic layer was separated and discarded. The acidic layer was basified and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and evaporated giving an additional 1.12 g of product.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH2:19].O>CN1CCCC1=O>[CH3:18][NH:19][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-fluoro-5-nitroaniline (5 g, 32 mmol) in 40 ml N-methylpyrrolidinone in a sealed reaction vessel was added potassium carbonate (9.0 g, 50.0 mmol) and a solution of methyl amine (32 ml, 2M in THF) and the reaction was heated to 120° C. After 16 h, the reaction mixture was cooled to room temperature and poured into 400 ml of water. The resulting precipitate was filtered and dried to give the title compound as a red solid. 1H NMR (300 MHz, d6-DMSO) δ7.54 (dd, J=8.7 and 2.7 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 6.41 (d, J=8.7 Hz, 1H), 6.13 (s, 1H), 5.08 (s, 2H), 2.83 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.Cl[C:11]1[N:12]=[C:13]([NH2:29])[C:14]2[N:15]=[CH:16][N:17]([C:27]=2[N:28]=1)[C@@H:18]1[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]1[OH:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[S:5][CH:6]=1
Reactant: NCCc1cc(Br)cs1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(NCCc2cc(Br)cs2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Condensation of 2-(4-bromo-2-thienyl)-ethylamine with 2-chloroadenosine essentially according to the procedure in the previous examples yields 2-[2-(4-bromo-2-thienyl)-ethylamino]-adenosine, melting at 136°-144°.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([O:18][C:19]([N:21]([CH3:33])[C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]([CH3:33])[C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCBr
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
2-Bromoacetonitrile (0.200 ml, 2.87 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.183 ml, 1.05 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2K-B) (309 mg, 0.955 mmol) in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-cyanomethyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-B) (272 mg, 78%).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[C:4]=1[CH3:19])=[O:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[OH:2][CH2:1][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[C:4]=1[CH3:19]
Reactant: CCOC(=O)c1cn(C)c2c(C)c(C=O)sc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)c2c(C)c(CO)sc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a 0° C. mixture of ethyl 2-formyl-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (695 mg, 2.49 mmol) and glacial acetic acid (0.71 mL, 12.5 mmol) in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride (1.06 g, 4.98 mmol). After stirring for 5 min at 0° C., the reaction was stirred at room temperature for 3.5 hours. The reaction was poured into sat. aqueous. sodium bicarbonate (50 mL) and methylene chloride (30 mL), stirred vigorously for 5 minutes, and filtered. The collected solid was washed with water and methylene chloride, then dried in vacuo, leaving an off-white solid (665 mg, 93%).
Reaction SMILES: C(OC([N:9]1[C:13]2[CH:14]=[C:15]([O:20]C)C=[C:17](C#N)[C:12]=2[N:11]=[C:10]1[CH3:22])(OCC)C)C.[OH-:23].[K+].C(O)[CH2:26][O:27][CH2:28][CH2:29]O>>[CH3:26][O:27][C:28]1[CH:29]=[C:14]([C:15]([OH:20])=[O:23])[C:13]2[N:9]=[C:10]([CH3:22])[NH:11][C:12]=2[CH:17]=1
Reactant: OCCOCCO
Reactant: [OH-]
Reactant: CCOC(C)(OCC)n1c(C)nc2c(C#N)cc(OC)cc21
Agent: [K+]
Product: COc1cc(C(=O)O)c2nc(C)[nH]c2c1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(1,1-diethoxy-ethyl)-6-methoxy-2-methyl-1H-benzoimidazole-4-carbonitrile (2.5 g, 8.2 mmol), diethylene glycol (5 mL) and 6 N KOH aqueous solution (2.5 mL) was stirred at 150° C. for 16 hours. The mixture was poured into ice water (15 mL) and washed with ethyl acetate (3×100 mL). The water layer was then adjusted to pH 7-6 with 6 N HCl aqueous solution. The resulting mixture was washed with EtOAc and the water layer was concentrated down to a volume of 10 mL. The crude product was purified by preparative HPLC to obtain 350 mg of dark colored sticky gum product. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.98 (bs, 1H) 7.55 (d, J=2.5 Hz, 1H) 7.51 (d, J=2.5 Hz, 1H) 4.20 (bs, 1H) 3.9 (s, 3H) 2.77 (s, 3H). LRMS for C16H21N3O3 m/z 205 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[C-:10]#[N:11].[K+].O>CS(C)=O>[C:10]([CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: Cc1ccnc(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccnc(CC#N)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 1112.3 %

Procedure:
2-chloromethyl-4-methylpyridine (3.70 g, 2.17 mmol) was dissolved in dimethyl sulfoxide (9 ml) and herein potassium cyanide (1.70 g, 2.60 mmol) was added. After stirring for 17 hours at room temperature, water was added and it was extracted twice with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to get crude product. The residue was separated and purified by column-chromatography over silica gel to obtain the desired product (3.19 g, yield=95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=3)[NH:11][C:10]=2[CH3:21])=[CH:4][CH:3]=1.[CH3:22][Si](Cl)(C)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:22])=[O:19])[CH:16]=3)[NH:11][C:10]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1Sc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)c1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Reaction time: 8 h

Procedure:
To a solution/suspension of the product from part (i) (1 g) in methanol (50 ml) was added trimethylsilylchloride (12.6 ml). After stirring at room temperture overnight the mixture was concentrated in vacuo to give sub-title compound in quantitative yield.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH2:25][CH2:26][CH2:27][O:28][C:2]([Cl:1])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
In a four necked round bottom flask, triphosgene (5.45 g, 55.1 mmol) was dissolved in toluene (80 mL) under argon. After cooling at 0° C., pyridine (4.8 mL, 58.8 mmol) was added dropwise during 1 h and the resulting suspension stirred for further 1 h at 0° C. 3-phenyl-1-propanol (5 mL, 36.8 mmol) was added dropwise in 30 min. After stirring at rt for 24 h, the solid was filtered off and the solvent removed under vacuum, yielding the title compound (6.2 g, 85%) as pale yellow oil, which was used in the next step without further purification. FTIR (cm−1): 3086, 3065, 3027, 2995, 2932, 2862, 1776, 1743, 1603, 1496, 1454, 1262, 1148, 745, 699.