Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.C(=O)([O-])N.C12OC(CC1)CN(C1C=C(CS(C)(=O)=O)N=C(C3C=CC(N)=CC=3)N=1)C2.[CH:35]12[O:42][CH:39]([CH2:40][CH2:41]1)[CH2:38][N:37]([C:43]1[CH:48]=[C:47]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[N:46]=[C:45]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61](=[O:82])[NH:62][C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:74][CH2:73][N:72](C(OC(C)(C)C)=O)[CH2:71][CH2:70]5)=[CH:65][CH:64]=4)=[CH:56][CH:55]=3)[N:44]=1)[CH2:36]2.FC(F)(F)C(O)=O>ClCCl>[CH:39]12[O:42][CH:35]([CH2:41][CH2:40]1)[CH2:36][N:37]([C:43]1[CH:48]=[C:47]([CH2:49][S:50]([CH3:53])(=[O:51])=[O:52])[N:46]=[C:45]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61]([NH:62][C:63]4[CH:68]=[CH:67][C:66]([N:69]5[CH2:70][CH2:71][NH:72][CH2:73][CH2:74]5)=[CH:65][CH:64]=4)=[O:82])=[CH:56][CH:55]=3)[N:44]=1)[CH2:38]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(CS(C)(=O)=O)cc(N5CC6CCC(C5)O6)n4)cc3)cc2)CC1
Agent: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1
Agent: NC(=O)[O-]
Agent: NC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(NC(=O)Nc3ccc(N4CCNCC4)cc3)cc2)n1

Procedure:
tert-Butyl 4-(4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)ureido)phenyl)piperazine-1-carboxylate was obtained according to the general procedure for formation of urea or carbamate compounds from 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)aniline (44). Removal of the Boc group in tert-butyl 4-(4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)ureido)phenyl)piperazine-1-carboxylate (85.2 mg, 0.126 mmoles) by treatment with trifluoroacetic acid in dichloromethane gave the title compound. Yield: 70.0 mg (38% over 2 steps). RT 1.64, M+H=578.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:10]([N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCN
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Yield: 97 %

Procedure:
Heat a solution of ethyl 3-aminopropanoate hydrochloride (80.0 g, 0.52 mol), benzylbromide (186.7 g, 1.1 mol) and K2CO3 (179.4 g, 1.3 mol) in acetonitrile (1 L) at 40° C. overnight. Concentrate the mixture to dryness, treat with water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography chromatography (Pet Ether/EtOAc, 50:1) to afford the title compound (150 g, 97% yield). 1H NMR (400 MHz, CDCl3): δ 7.35-7.21 (m, 10H), 4.09 (q, J=7.2 Hz, 2H), 3.58 (s, 4H), 2.82 (t, J=7.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:15].[C:16](OC(=O)C)(=[O:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1CCNC1=O>>[C:16]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NC(c2ccccc2)CN1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1NCCN1
Product: CC(=O)OCCN1CC(c2ccccc2)NC1=O

Procedure:
Approximately 9.2 g of 1-(2-hydroxyethyl-4-phenyl-2-imidazolidone is stirred with acetic anhydride (25 ml.) and p-toluenesulfonic acid (200 mg.) for 4 hours, during which time the imidazolidone completely dissolves. The solution (100 ml.) from which a white solid precipitates. The solid is extracted with methylene chloride (3×100 ml.). The organic layer is separated, dried and the solvent removed to give a pale yellow solid. Recrystallization from ether gives the title compound as a white crystalline solid; m.p. 88°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:6](=NNC(OC)=O)[CH3:7])[CH3:2].O.C(OCC)(=[O:28])C>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[C:6](=[O:28])[CH3:7])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=NNC(=O)OC
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Titanium trichloride (10% solution in 20-30% HCl) was added to a solution of 3-(methoxycarbonylhydrazono)-2-(3-nitrophenylamino)butyric acid ethyl ester (compound 1c-51a) (5.0 g, 14.78 mmol) in acetone (50 mL), and the mixture was stirred at room temperature for 1 hour. Water was then added to the reaction mixture, extraction was performed with ethyl acetate, and the organic extract was washed with water and saturated saline. After drying over magnesium sulfate, it was concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (3.75 g, 95%) as a yellow oil.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:22].[Na+].O.Cl>C(O)(=O)C>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:5]2[C:4](=[O:20])[NH:3][C:2](=[O:22])[NH:10][C:9]=2[N:8]=[CH:7]1)#[N:19]
Reactant: O=N[O-]
Reactant: N#Cc1ccccc1Cn1cnc2nc(N)[nH]c(=O)c21
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccccc1Cn1cnc2[nH]c(=O)[nH]c(=O)c21

Procedure:
Prepared by treating 16.68 g of 2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin-6-one with 17.00 g of sodium nitrite in a mixture of 375 ml of conc. acetic acid, 84 ml of water and 5.2 ml of conc. hydrochloric acid at 50° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=4)[N:28]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[H-].[Na+].I[CH3:40]>CN(C=O)C>[CH3:40][N:9]([CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=4)[N:28]=3)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: CI
Reactant: O=C(NCCN1CCCC1=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN1CCCC1=O)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
A solution of N-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (obtained as described in Example 639) (150 mg, 0.30 mmol) in DMF (2 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil) (13.16 mg, 0.33 mmol) in DMF (1 mL) under nitrogen. The resulting suspension was stirred at ambient temperature for 5 minutes, then iodomethane (0.028 mL, 0.45 mmol) was added and the mixture was stirred at ambient temperature for a further 10 minutes. The reaction was quenched with MeOH (0.5 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-methyl-N-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (84 mg, 55%) as a solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([OH:14])=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
p-Trifluromethoxy aniline (49.60g) was added rapidly dropwise to vigorously stirred 9N aqueous H2SO4 (500 mL) at 40° C. The mixture was heated to dissolve the solid, then cooled to 0° C. To the fine white suspension, a solution of sodium nitrite (19.46 g in 50 mL of H2) was added portionwise until an immediate positive KI/starch test result was obtained. This cold solution of diazonium salt was added rapidly dropwise to 9N aqueous H2SO4 (500 mL) at 110° C. Stirring and heating was continued for 2.5 hours. The mixture was cooled to 10° C. and extracted with diethyl ether (3×500 mL). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo, then flash chromatographed on SiO2 using diethyl ether as eluant to give 35.0 g of the desired phenol as a light brown oil was distilled (b.p.=75°-80° C. at 20 torr.) to afford a yellow liquid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][N:10]([CH2:20][C:12]1[S:11][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc2sc(CN(Cc3nc4ccccc4s3)c3ccc4[nH]cnc4c3)nc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), (benzo[d]thiazol-2-yl)methylbromide (502 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.037 g (8.7%); 428.1 MS m/z: [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 5.22 (s, 4H); 6.96 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.02 (br s, 1H); 7.38-7.43 (m, 3H); 7.47-7.51 (m, 2H); 7.96-7.98 (m, 2H); 8.02-8.03 (m, 3H); 12.35 (br s, 1H); HPLC (METHOD [A]): rt 14.45 min (92.1%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:10][CH:9]=3.C[Li].C([Li])CCC.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].B(F)(F)F.CCOCC>C1COCC1>[CH:19]1([CH2:18][CH2:17][O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([CH2:29][C:30]([CH3:32])([OH:33])[CH3:31])=[CH:15][C:14]3=2)[CH2:21][CH2:20]1
Reactant: Brc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Reactant: CC1(C)CO1
Agent: FB(F)F
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of 3-bromo-6-(2-cyclopropylethoxy)phenanthrene (11 mmol) from Step 1 above in THF (75 mL) at −78° C. was successively added methyllithium (1.6 M in diethyl ether, 1 mL) and butyllithium (2.5 M in hexanes, 5.3 μL). The mixture was stirred at −78° C. for 30 minutes, after which isobutylene oxide (2.9 mL, 33 mmol) was added, followed by BF3.OEt2 (4.2 mL, 33 mmol). The reaction mixture was stirred at −78° C. for 1 h, then quenched with 1 M HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (10% ethyl acetate in hexanes) to afford 1-[6-(2-cyclopropylethoxy)-3-phenanthryl]-2-methylpropan-2-ol (1.33 g) as a yellow oil.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]([O:22][CH3:23])=[O:21])#N>ClCCl>[CH3:23][O:22][C:20]([C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1)=[O:21]
Reactant: COC(=O)C#N
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: COC(=O)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.9 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (4.0 g, 16.2 mmole) and methyl cyanoformate (2.75 g, 32.4 mmole) in 30 mL of dichloromethane was stirred at room temperature for 21 h. The precipitate was filtered and washed with dichloromethane to give 3.36 g (84%) of 3-(methoxycarbonyl)-1,2,4-thiadiazolo [4,5-a]benzimidazole as a colourless solid: mp 208-209° C.; 1H NMR (CDCl3)δ 8.61 (d, 1H), 7.82 (d, 1H), 7.51 (t, 1H), 7.31 (t, 1H), 4.17 (s, 3H) ppm; 13C NMR (CDCl3)δ 164.02, 156.51, 150.67, 140.89, 129.34, 125.93, 122.41, 119.48, 115.41, 54.04 ppm; IR (KBr)ν 1733 cm-1 ; HRMS calcd for C10H7N3O2S 233.0259, found 233.0262. Anal. Calcd. for C10H7N3O2S: C, 51.50;H, 3.02; N, 18.02. Found: C, 51.41;H. 2.89; N, 18.16.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:26])C>>[O:26]1[C:19]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: CCC(=CCCC(C)=CCOc1ccc2c(c1)OCCC2)CC
Product: CCC1(CC)OC1CCC(C)=CCOc1ccc2c(c1)OCCC2

Procedure:
Following the procedure of Example 17, 7-(3-methyl-7-ethyl-2,6-nonadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-methyl-7-ethyl-2-nonenyloxy)-chromane, nD20 = 1.5303.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38]>C1COCC1>[CH:13]1([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:46][CH:43]4[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]4)[N:7]=3)=[C:9]([C:17]3[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(C4CCC4)nc3-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)n2)CC1
Yield: 59 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.33 g, 1.9 mmol) in THF (2 mL) the title compound was obtained (0.075 g, 0.11 mmol, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.08-7.97 (m, 1H), 7.59-7.18 (m, 7H), 6.17-5.73 (m, 1H), 3.84 (quin, J=8.4 Hz, 1H), 3.60-3.39 (m, 2H), 2.93-2.62 (m, 7H), 2.43-2.12 (m, 4H), 2.10-1.68 (m, 3H), 1.64-1.29 (m, 2H), m/z (ESI): 679 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7]>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% 1HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](O)=[O:13])[CH:7]=1.C[N:25](C)CCCN=C=NCC.N1C2C(=NC=CC=2)N(O)N=1.C(NC(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:25])=[O:13])[CH:7]=1
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CNc1cc(OC)c(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture containing 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylic acid (1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (1.5 eq), and diisopropylamine (5 eq) in tetrahydrofuran was stirred at room temperature for 1 hour. To this was then added ammonium chloride (2 eq) and the resulting mixture was stirred together for 48 hours. Reaction concentrated. Purification on silica gel, 50% acetone in hexanes to yield 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide as a bright yellow solid. HPLC=3.70 min; MS: MH+=319.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([I:11])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 7-Chloro-imidazo[1,2-a]pyridine (30.9 g, 186 mmol, 1.0 equiv) in DMF (280 ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The thin brown slurry was diluted with water (840 ml), brine (280 ml) and extracted with EtOAc (560 ml). The aqueous layer was further extracted with EtOAc (3×280 ml). The combined organic phases were washed with water (2×280 ml), 10% w/v sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO4), filtered and concentrated in vacuo to give a brown residue. The residue was triturated with ether (200 ml), filtered and the solid was washed with ether (2×50 ml) and dried on the filter to give 39 g of product. MS: [M+H]+=279.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]1=[O:27]>N1C=CC=CC=1>[CH:1]([O:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]1=[O:27])=[O:2]
Reactant: O=C(O)c1nc2ccccc2n(CCO)c1=O
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=COCCn1c(=O)c(C(=O)O)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Formic acid (3 ml., 98%) was added dropwise to acetic anhydride (6 ml) which was cooled below 5°. The mixture was heated at 50° for 15 minutes and cooled to below 5° and added slowly to a cold (5°-10°) solution of 3,4-dihydro-4(2-hydroxyethyl)-3-oxo-2-quinoxalinecarboxylic acid (3.2 g) in pyridine (40 ml). The solution was allowed to warm to room temperature, stirred for 6 hours and the pyridine was distilled off under reduced pressure. Hydrochloric acid (50 ml., 2N) was added to the residue and the solid was filtered off and dried, m.p. > 100°. Attempts to recrystallise this compound from dimethylformamide resulted in the loss of the formyl group.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH:64]([S:81][S:82][CH:83]([CH3:85])[CH3:84])[CH2:65][C@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67](OCC#N)=[O:68])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH:64]([S:81][S:82][CH:83]([CH3:85])[CH3:84])[CH2:65][C@@H:66]([NH:73][C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[C:67]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:68])=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)SSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)SSC(CN=[N+]=[N-])C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 40.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 43.6 mg, 0.069 mmol) in water (0.3 mL) and a solution of (2S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 45) (83 mg, 0.206 mmol) in tetrahydrofuran (0.2 mL) were added to buffer A (12 mL), and the mixture was stirred at room temperature for 55 minutes. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 46) (27.7 mg, 41%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.C[O:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=O>>[OH:1][CH:2]1[CH2:5][N:4]([C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[C:23]([NH:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)=[CH:22][CH:21]=[C:20]([CH:31]4[CH2:33][CH2:32]4)[N:19]=3)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=2)=[O:7])[CH2:3]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: OC1CNC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CC(O)C2)n1
Yield: 13 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-hydroxy-azetidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (13%) as sticky yellow solid.