Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[N:8][CH:9]=[C:4]2[C:3]([C:10]2[O:19][C:13]3=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[CH:2]1.[I:20]N1C(=O)CCC1=O>CN(C)C=O>[I:20][C:17]1[CH:16]=[N:15][C:14]([NH2:18])=[C:13]2[O:19][C:10]([C:3]3[C:4]4[C:5](=[CH:6][N:7]=[N:8][CH:9]=4)[S:1][CH:2]=3)=[CH:11][C:12]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2cc(-c3csc4cnncc34)oc12
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3csc4cnncc34)oc12
Yield: 88.3 %

Procedure:
A solution of 2-(thieno[2,3-d]pyridazin-3-yl)furo[2,3-c]pyridin-7-amine (30.0 mg, 0.112 mmol) and N-iodosuccinimide (101.6 mg, 0.4516 mmol) in N,N-dimethylformamide (2 mL) was stirred at 40° C. for 45 min. The reaction was removed from the heat and 1.0 M aqueous sodium thiosulfate solution (2 mL) was added. The crude mixture was concentrated in vacuo. The residue was then suspended in water and the fine solid was filtered off and dried, giving 39.0 mg (88%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 10.48 (d, J=1.52 Hz, 1H), 10.02 (d, J=1.52 Hz, 1H), 9.04 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 6.89 (s, 2H); MS (ESI): 395.07 [M+H]+; HPLC: tR=2.83 min.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.O>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:21][CH:22]=4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CC(c3csc(-c4ccncc4)n3)=NO2)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]pyridine (i.e. the product of Example 13, Step A) (0.60 g, 1.95 mmol) in toluene (10 mL) was added benzyl bromide (0.670 g, 3.90 mmol), and the reaction mixture was heated to 100° C. for 12 h. Then the reaction mixture was cooled to room temperature. The solid that precipitated out was filtered and dried. The solid was dissolved in methanol (10 mL), and sodium borohydride (0.072 g, 1.95 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2 h, diluted with water (50 mL), neutralized with 1.5 N aqueous hydrochloric acid solution, and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine (25 mL), and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography using 3% of methanol in chloroform as eluant to give 0.4 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1)[OH:32])[CH3:26].Cl>C1COCC1>[CH2:25]([N:27]([C:5](=[O:7])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:9])[CH3:8])[CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=1)[OH:32])[CH3:26]
Reactant: CC(C)(C)CCC(=O)O
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)C(=O)CCC(C)(C)C
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
A stirred solution of 4,4-dimethylpentanoic acid (2.07 g, 0.0159 mol) and triethylamine (2.28 ml, 0.0163 mol) in THF (120 ml) was cooled to -8° C. and treated dropwise with isobutyl chloroformate (2.12 ml, 0.0163 mol). The mixture was kept at -8° C. for 1.5 hour and treated with a mixture of the product from Example 7 Step II (4.0 g, 0.014 mol), triethylamine (2.28 ml, 0.0163 mol) and THF (160 ml). This mixture was kept at -8° C. for 1.5 hour and then treated slowly with 1N HCl (158 ml) and extracted with EtOAc. The extract was washed with water, dilute NaHCO3 and water, dried (MgSO4) and concentrated to give 4.4 g of N-(4-(4-(ethyl(4,4-dimethylpentanoyl)amino)-1-hydroxybutyl)phenyl)methanesulfonamide. The mass spectrum had m/z 398 (M+).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][CH2:18]3)=[CH:12][CH:13]=1)=[O:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:19][CH2:18]3)=[CH:12][CH:13]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Pd]
Solvent: CO
Product: NCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reaction time: 5 h

Procedure:
2-Azido-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide (500 mg) was dissolved in methanol (100 ml) and 10% palladium on charcoal (125 mg) was added. Starting material was hydrogenated for 5 hours at room temperature to give 2-amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide. The product was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 10.7 (s, 1H), 8.35 (d, 1H, J 2.6 Hz), 8.17 (bs, 3H), 8.01 (dd, 1H, J 2.6, 8.9 Hz), 7.47-7.32 (m, 51), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (dd, 1H, J 1.90, 10.1 Hz), 3.79 (q, 2H, J 5.6 Hz), 3.01-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.20-2.15 (m, 1H), 2.05-1.94 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](O)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][OH:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CO)COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
N-(tert-Butyloxycarbonyl)-O-benzyl-D-serine 10 (7.56 g, 25.63 mmol) was dissolved in dry THF and cooled to -20° C. under argon atmosphere. To this cold stirred solution was added TEA (3.03 g, 30 mmol) and isobutyl chloroformate (4.08 g, 30 mmol). The stirring was continued for 30 min at -20° C. under argon atmosphere. The reaction mixture was filtered immediately under a blanket of argon, the precipitate was washed with dry THF (50 ml). The combined filtrate was added slowly into a cold (0° C.) solution of NaBH4 (7.4 g, 200 mmol) in THF/water (80:20, 200 ml) during 10 min period. After the addition, the reaction mixture was stirred for 2 h at 0° C. and the pH adjusted to 7 with acetic acid. The solution was evaporated to dryness, partitioned between ethyl acetate/water (300:150 ml) and extracted in ethyl acetate. The organic extract was washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure product was pooled together and evaporated to dryness to give 6.68 g (92%) of the pure product as an oil. 1HNMR (CDCl3): δ1.41 (s, 9H, Boc), 3.60-3.70 (m, 4H), 3.82 (d, 2H), 4.53 (s, 2H, OCH2Ph), 5.20 (bs, 1H, NH) and 7.30-7.40 (m, 5H, Ph).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.[C:32]([Cu])#[N:33]>N1C=CC=CC=1>[C:32]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)#[N:33]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 160 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (41 mg), CuCN (80 mg), and pyridine (0.2 mL) was heated with stirring to 160° C. for 4 hours. The pyridine distilled off during the course of the heating. The cooled dark mass was dissolved in 2 mL of 20% aqueous KCN by heating to 50° C. for 15 minutes. Acetic acid (2 mL) (Caution! HCN is evolved.) was added and the mixture was extracted (2×EtOAc). The organic layers were dried (Na2SO4), concentrated, and purified (SiO2, 80/20/1 CH2Cl2 --MeOH--NH4OH) to give 26 mg of the title compound as a solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:27]C[O-].[Na+].CCO.O>C(O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC[O-]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute ethanol (10 mL) and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72 hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.35; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.69; S, 7.97.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C(O)C.Cl.[NH2:19][OH:20]>CCCCCC>[OH:20]/[N:19]=[C:4](\[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])/[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1ccccc1C
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)/C(=N/O)c1ccccc1C
Yield: 68 %

Procedure:
To a solution containing 19.2 g of ethyl 2-methylbenzoylformate (0.1 mol) and 100 ml of ethanol, 7.6 g of hydroxylamine hydrochloride (0.11 mol) was added and the resulting mixture was heated under reflux for 5 hours. Afterwards, the solvent was distilled off under reduced pressure as a work-up procedure to give a solid. The solid, to which hexane was added, was pulverized and 14.1 g of ethyl (E)-α-hydroxyimino-o-tolylacetate (yield; 68%) was filtered off. Furthermore, the concentrated residue of the filtrate, to which ethanol and a catalytic amount of thionyl chloride were added, was heated under reflux for 5 hours. The same work-up procedure as shown above was then employed to give 4.5 g of the objective product (yield; 21%). mp 88.0-89.0° C.
Reaction SMILES: [CH2:1]1[C:15](=O)[C:14]2[C:5](=[C:6]([OH:20])[C:7]3[C:12]([C:13]=2[OH:17])=[C:11]([OH:18])[CH:10]=[CH:9][C:8]=3[OH:19])[C:3](=O)[CH2:2]1.[CH2:21]([NH2:23])[CH3:22].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:32][N:33]([CH2:35][CH2:36][CH2:37][NH2:38])[CH3:34]>CO>[CH3:32][N:33]([CH3:34])[CH2:35][CH2:36][CH2:37][NH:38][C:15]1[C:14]2[C:13](=[O:17])[C:12]3[C:7](=[C:8]([OH:19])[CH:9]=[CH:10][C:11]=3[OH:18])[C:6](=[O:20])[C:5]=2[C:3]([NH:23][CH2:21][CH3:22])=[CH:2][CH:1]=1
Reactant: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Reactant: CCN
Reactant: CN(C)CCCN
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCNc1ccc(NCCCN(C)C)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 50 °C

Procedure:
A mixture of 2.74 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone, 0.45 g. of ethylamine, a trace of sodium hydrosulfite and 60 ml. of aqueous methanol was stirred and warmed to 50° C. for one hour. To this was added 1.1 g. of dimethylaminopropylamine and the mixture was stirred and warmed at 50°-60° C. for 2 hours. Air was bubbled through this mixture while heating on a steambath for 6 hours. The mixture was cooled and the title product was collected.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CO>[F:19][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: CO
Product: COC(=O)c1ccc2c(F)c[nH]c2c1

Procedure:
A solution of methyl 1H-indole-6-carboxylate 20a (11.4 mmol, 2.0 g) and N-fluoro-2,4,6-trimethylpyridinium triflate (14.8 mmol, 4.3 g) in MeOH (100 mL) was heated at reflux for 18 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 15-20% EtOAc/hexanes) to give compound 20b as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:3]1[OH:21]>C(O)C.[C].[Pd]>[CH3:22][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:3]1[OH:21]
Reactant: CCN(CC)C1c2cc(N)c([N+](=O)[O-])cc2OC(C)(C)C1O
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)C1c2cc(N)c(N)cc2OC(C)(C)C1O
Yield: 82.6 %

Procedure:
0.20 g (0.65 mmol) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-diethylamino-6-amino-7-nitro-2H-benzo[b]pyran were dissolved in 34.9 g of ethanol and hydroge gas blown in in the presence of 0.15 g of 5% palladium-carbon, as a catalyst, for at room temperture for 2.5 hours under one atmospheric pressure while stirring. The reaction liquid was filtered under suction to remove the catalyst therefrom, and the solvent was distilledoff to obtain 0.15 g (yield: 83%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-diethylamino-6,7-diamino-2H-benzo[b]-pyran as a dark brown oil.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH:23]=[O:24])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].CC(=CC)C.[O-:34]Cl=O.[Na+]>CC(O)(C)C>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([OH:34])=[O:24])([CH2:20][CH2:21]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: [O-][Cl+][O-]
Reactant: CCCn1c(=O)c2nc(C34CCC(CC=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCn1c(=O)c2nc(C34CCC(CC(=O)O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 14 h

Procedure:
To a solution of [4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acetaldehyde (170 mg, 0.440 mmol) in t-BuOH (10 ml) and 2-methyl-2-butene (10 eq, 4.4 mmol, 470 μL), cooled with the aid of an ice bath, was added NaClO2 (1.5 eq, 0.66 mmol). The resulting yellow solution as allowed to reach ambient temperature over a period of 14 h then concentrated in vacuo. The resulting oily residue was partitioned between water (10 ml) and CH2C (10 ml). The aqueous phase was acidified by the dropwise addition of concentrated HCl and the resulting precipitate was collected, washed with water and dried to afford 105 mg (59%) as a white powder. 1H NMR (400 MHz, CDCl3); d 0.91 (t, 3H), 0.93 (t, 3H), 1.63 (m, 2H), 1.77 (m, 2H; partially-obscured), 1.82 (m, 6H), 2.01 (m, 6H), 2.32 (s, 2H), 3.95 (m, 2H), 4.07 (m; 2H), 12.74 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])(=O)=O>ClCCl.C(OCC)(=O)C>[Si:54]([O:37][CH2:36][C:35]([CH3:39])([CH3:38])[O:34][C:31]1[CH:30]=[CH:29][C:28]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:33][CH:32]=1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.49 g) and 2,6-lutidine (0.33 mL) in dichloromethane (10 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.32 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.50 g, 85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:28]C(=O)OC(C)(C)C)[CH2:12][NH:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=2)=[CH:2]1.Cl>ClCCl.O1CCOCC1>[NH2:28][C@@H:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1cncc(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H](CNc1cncc(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
A solution of Example 11C (40 mg, 0.085 mmol) in dichloromethane (3.0 mL) at room temperature was treated with 4N HCl in dioxane (0.5 mL), stirred for 1 hour, and concentrated to provide the desired product as the hydrochloride salt (30 mg, 74%). MS (DCI/NH3) m/e 370 (M+H)+; 1H NMR (DMSO-d6) δ 11.09 (br s, 1H), 8.90 (d, J=5.8 Hz, 2H), 8.47 (br s, 2H), 8.33 (s, 1H), 8.22 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.8 Hz, 2H), 7.98 (s, 1H), 7.94 (d, J=16.5 Hz, 1H), 7.86 (d, J=16.5 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.37 (d, J=4.5 Hz, 1H), 7.36 (s, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 3.71 (m, 1H), 3.67 (m, 1H), 3.54 (m, 1H), 3.15 (m, 2H).
Reaction SMILES: I[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[C:27]1([C:33]#[CH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C:17]1([CH3:20])[O:16][C@H:15]2[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:12][C@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[C@H:14]2[O:18]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNS(N)(=O)=O)O[C@H]2n1cnc2c(CCc3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of N-{[(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide (0.14 g, 0.28 mmol) in DMF was added phenylacetylene (0.115 g, 1.13 mmol), CuI (10.6 mg, 0.056 mmol), DIPEA (98 μL, 0.56 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.028 mmol) The solution was stirred for 1 h at r.t. and concentrated. The residue was taken up in DCM, washed with saturated aq EDTA.Na2 (3×20 mL), dried (Na2SO4) concentrated and purified by flash chromatography (20 to 60% EtOAc/DCM) to give the title compound (0.08 g, 60%).
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:10][N:9]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[C@H:8]([CH2:24][O:25][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCOCC1.[Pd]>[C:1]([O:5][C@H:6]1[CH2:10][N:9]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@@H]1C[C@@H](COC/C=C/c2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)O[C@@H]1C[C@@H](COCCCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 93.5 %

Procedure:
Hydrogenation: A solution of (E)-(2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-2-(3-phenyl-allyloxymethyl)-pyrrolidine (2.3 g) in ethanol/dioxane 1:2 (75 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.50 g) at 1.1 bar and room temperature for 4 h. The reaction mixture was filtered over a pad of celite and washed with ethanol. The filtrate was concentrated, and the residue was chromatographed on silica gel using EtOAc/hexane 1:4 as eluent to obtain (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-2-(3-phenyl-propoxymethyl)-pyrrolidine (2.16 g) as a gum, MS: 482 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:15]S(C)(=O)=O)([C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([Br:14])[CH:8]=1)[CH3:6])=[N+]=[N-].[CH:20]1[CH:25]=[CH:24][C:23]([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C1COCC1>[Br:14][C:9]1[CH:8]=[C:7]([C:5]2([CH3:6])[CH2:4][NH:1]2)[C:12]([F:13])=[CH:11][N:10]=1.[P:26]([C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(CN=[N+]=[N-])(OS(C)(=O)=O)c1cc(Br)ncc1F
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ncc2F)CN1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methanesulfonic acid 2-azido-1-(2-bromo-5-fluoro-pyridin-4-yl)-1-methyl-ethyl ester (2.1 g, 6.09 mmol) and PPh3 (1.597 g, 6.09 mmol) in THF (20 mL) was stirred at rt for 30 min. The reaction mixture was evaporated to dryness, the residue was taken up with TBME and 10% aq. citric acid soln. The aq. phase was reextracted with TBME, the combined org. phases were washed with H2O. The combined aq. phases were basified using 2N aq. NaOH soln. and three times extracted with TBME. The combined org. phases were dried over Na2SO4, filtered and concentrated to yield 2-bromo-5-fluoro-4-(2-methyl-aziridin-2-yl)-pyridine in a mixture with Ph3PO that was used for the next step without further purification, HPLC RtH4=0.96 min; ESIMS: 231, 233 [(M+H)+].