Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10](I)[N:5]2[N:4]=1)[CH3:2].[C:15]([NH2:18])(=[O:17])[CH3:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([NH:18][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CCc1cc2c(C=O)ccc(I)n2n1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1cc2c(C=O)ccc(NC(C)=O)n2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
The compound of Example 130 (100 mg), acetamide (23.6 mg), tris(dibenzylideneacetone)dipalladium (15.3 mg), Xantphos (28.9 mg) and cesium carbonate (152 mg) were suspended in dioxane (3.00 mL) in an argon atmosphere. The suspension was stirred at 100° C. for 5 hours. Subsequently, the mixture was diluted with methylene chloride and filtered through Celite. The filtrate was evaporated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the title compound as a yellow powder (62.5 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1.[N:19]1[N:20]=[CH:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=12.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[N:19]1[N:20]=[CH:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][C:23]=12
Reactant: c1nnc2n1CCNC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CN2CCn3cnnc3C2)cc1

Procedure:
A solution of (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate (127 mg, 0.47 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (91 mg, 0.56 mmol) and DIPEA (183 mg, 1.41 mmol) in DMSO (2.3 mL) was heated at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). After separation, the aqueous phase was washed with EtOAc (2×15 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude product was used to next step without further purification.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1)[CH3:10]>C(#N)C>[CH2:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:19]=1[I:1])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cn2ccccc2n1
Solvent: CC#N
Product: CCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
As shown in FIG. 8, N-iodosuccinimide (8.37 g, 57.25 mmol) was added to a solution of 2-ethyl-imidazo[1,2-α]pyridine 70 (Example 27) (12.88 g, 57.25 mmol) in dry acetonitrile (100 mL) at 0° C. The reaction was warmed to room temperature and then stirred for 12 hours. The mixture was then concentrated and purified on silica gel (CombiFlash, Heptane/EtOAc elution) to afford 2-ethyl-3-iodo-imidazo[1,2-α]pyridine 72, as photosensitive yellow crystals with a yield of 5.6 g, 35%.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH2:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>[F:27][C:28]([F:42])([F:43])[C:29]1[CH:30]=[C:31]([NH:39][C:40](=[O:41])[N:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH2:20][C:21]3[N:22]=[N:23][NH:24][N:25]=3)=[CH:15][CH:14]=2)[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(O)Cc3nn[nH]n3)cc2)CC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Resin bound 1-{4-[(4-tert-butylcyclohexylamino)methyl]phenyl}-2-(2H-tetrazol-5-yl)ethanol (50 mg) was suspended in DCP (500 μl) and N,O-bis(trimethylsilyl)acetamide (100 μl) was added. The mixture was shaken at room temperature for 1 hour, then a solution of 3,5-bis(trifluoromethyl)phenylisocyanate (48 mg, 0.19 mmol) in DCP (500 μl) was added. The resin mixture was shaken overnight at room temperature, then drained and washed with DCM (3×2 ml); DMF (3×2 ml); water (2×2 ml, each 20 min washes), THF (3×2 ml) and finally DCM (6×2 ml). The resin was then treated with 50% TFA in DCM for 30 min. Solvent was collected by filtration, and taken to dryness by evaporation in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[C:31](Cl)=[N:32][CH:33]=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C1N2CCN(CC2)C1>>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[C:30]([Cl:29])[C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:33]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl 5,6-dichloronicotinate and DABCO (17 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:35]([CH:32]3[CH2:31][CH2:30][N:29]([C:26](=[O:28])[CH3:27])[CH2:34][CH2:33]3)=[O:36])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)c(Cl)c3)[C@@H](N(C)C(=O)Oc3ccc(F)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-(1-acetyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-acetylpiperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a brown oil. MS m/e: 536.1 [M]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16].[Br:17]Br>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([Br:17])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16]
Reactant: CSc1nc(-c2ccncc2)cc(=O)n1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CSc1nc(-c2ccncc2)c(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Methyl-6-(4-pyridyl)-2-methylthio-4(3H)-pyrimidinone (1.00 g 4.29 mmol) was dispersed in acetic acid (24 ml) and to the clear solution Bromine (0.5 ml, 1.5 g 9.38 mmol) was added. The reaction mixture stirred at room temperature for 24 h. The mixture was concentrated and the residue was co-evaporated with toluene until all bromine is removed. The crude compound is ready to use in next step. MS(m/z): 312 and 314. C10H11BrN3OS requir. 311 and 313. 1H-NMR(DMSO-d6):d 8.75 (m, 2H, pyridyl) 8.19 (m, 2H, pyridyl), 3.67 (s, 3H, N—CH3), 2.80 (s, 3H, S—CH3).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCOCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1.30 g of 4-(diphenylmethoxy)piperidine was dissolved in 10 ml of N,N-dimethylformamide; 0.52 ml of 2-(2-chloroethoxy)ethanol, 0.73 g of sodium iodide and 0.81 g of potassium carbonate were added, followed by stirring at 100° C. for 1 hour. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected and concentrated to yield 1.47 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3I)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][CH:24]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:23]3[CH:24]=[C:19]([NH2:18])[CH:20]=[CH:21][CH:22]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Fc1ccc(-c2ccc3c(I)cnn3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)ccc23)c1
Temperature: 90 °C
Yield: 44.2 %

Procedure:
A mixture of 6-(4-fluoro-phenyl)-3-iodo-pyrazolo[1,5-a]pyridine (140 mg, 0.41 mmol) and 3-aminophenylboronic acid pinacol ester (120 mg, 0.5 mmol) in DME (2 ml) and 2N Na2CO3 (aq, 2 ml) was deoxygenated by evacuation/refill with N2 (×3). PdCl2ddpf (15 mg, 0.02 mmol) was added and the mixture was deoxygenated again (×2). The reaction was stirred and heated at 90° C. under N2 for 24 hours. After cooling to RT the mixture was partitioned between CH2Cl2/H2O. The layers were separated using a phase separating cartridge. The organic layer was evaporated and the residue was purified by chromatography on silica (25→65% EtOAc/Petrol) to give the title compound (55 mg, solid).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6](O)[C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:10][C:11](=[O:17])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Temperature: 50 °C

Procedure:
To 3.0 g of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-10-hydroxy-1,9(2H,10H)-acridinedione suspended in 30 ml of chloroform is added dropwise 2.1 g of phosphorous trichloride in 20 ml of chloroform. The suspension is warmed at 50° C. for 2 hrs and filtered while warm. The solid is suspended in aqueous ethanol and filtered to give 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)-acridinedione as a cream solid; mp >325° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(F)ccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3F)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1

Procedure:
Following the procedure for Example 221 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2,5-difluorophenyl)thiazole-4-carboxylic acid gave 295 as a dark cream solid (166 mg, 73% over three steps. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.87-7.81 (m, 2H), 7.17-7.09 (m, 1H), 7.07-7.01 (m, 1H), 6.16 (s, 2H), 4.90 (dd, J=47.1, 6.7 Hz, 1H), 3.74 (s, 3H), 3.49-3.32 (m, 3H), 3.23-3.09 (m, 2H), 2.36-2.28 (m, 1H), 2.18-1.81 (m, 3H). Alkyl NH2 not seen. LCMS (ES+) m/z 466 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:48][C:49]1[C:50]([C@H:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=2)[NH2:56])=[N:51][CH:52]=[CH:53][CH:54]=1.Cl.FC(F)(F)C1C=CC([C@@H](C2C(C(F)(F)F)=CC=CN=2)N)=CC=1>O.CN(C=O)C>[F:48][C:49]1[C:50]([C@H:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:65])([F:66])[F:64])=[CH:59][CH:58]=2)[NH:56][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:51][CH:52]=[CH:53][CH:54]=1
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
To a solution of 4-hydroxy-3-nitrobenzoic acid (285 mg, 1.556 mmol) and DMF (5 mL), were added DIPEA (0.69 mL, 3.96 mmol) and HATU (612 mg, 1.611 mmol). After stirring for 45 min, (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (380 mg, 1.239 mmol, Intermediate 2) was added in one portion. The reaction was stirred at room temperature for 5 h and was then diluted with water (50 mL). The aqueous solution was extracted with EtOAc (3×20 mL). The combined EtOAc layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0 to 75% EtOAc in hexane, to provide the title compound as a yellow solid. MS (ESI pos. ion) m/z: 436.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:2]([Cl:1])[C:3]([C:13]([F:14])([F:16])[F:15])=[N:4]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3-c3ccccc3)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.92) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.78–7.84 (m, 2H), 7.36–7.52 (m, 4H), 6.38–6.48 (m, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62–3.78 (m, 4H), 3.18–3.26 (s, 4H). 13C NMR (400 MHz, CDCl3) 164.4, 156, 150.4, 130.4, 130, 128.6, 110.2, 102.4, 56.4, 52, 50.4, 44.6, 42.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.[CH:30]([P:33](Cl)(Cl)=[O:34])([CH3:32])[CH3:31]>CCCCCC.CCOCC.C1CCCCC1>[CH:30]([P:33]1(=[O:34])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)([CH3:32])[CH3:31]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: COc1ccc(NCc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(N2Cc3ccccc3P2(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 16.6 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.0 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of N-(4-methoxyphenyl)-N-benzylamine (12.8 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 16 hours at 26° C. and then cooled to -72° C. using a solid carbon dioxide-acetone bath. A solution of isopropylphosphonic dichloride (10.3 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -25° C. The reaction mixture was allowed to cool to -72° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 2 hours. The reaction was quenched with the rapid addition of 12 ml. of acetic acid. The reaction mixture was concentrated under vacuum and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then with water, dried over magnesium sulfate and concentrated in vacuo to yield a yellow residue. The yellow residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated under vacuum to produce a crude product. The crude product was slurried in ether to yield 1-isopropyl-2-(4-methoxyphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (3.0 g, 17% yield) as a white solid having a melting point of 135°-137° C. and the following analysis:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].N>[Pd]>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1CO
Agent: [Pd]
Agent: N
Product: Nc1ccn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)n1

Procedure:
The synthesis of several new 3'-azido and 3'-amino nucleosides is outlined above. Tritylation of 2'-deoxyuridine (I) with trityl chloride in pyridine gives the corresponding 5'-O-trityl derivative, (II), which is then converted to the 3'-O-methanesulfonyl analog, (III), with methanesulfonyl chloride in pyridine. The replacement of the mesyloxy group at the 3'-position in (III) with net inversion to yield 1-(2'-deoxy-5'-O-trityl-β-D-lyxosyl)uracil (V), is accomplished by refluxing compound (III) with excess sodium hydroxide solution. Mesylation of compound (V) affords the sulfonate (VI). This compound is then treated with lithium azide in N,N-dimethylformamide followed by detritylation by o refluxing with 80% aqueous acetic acid to yield 3'-azido-2,3'-dideoxyuridine (VIII). Catalytic hydrogenation of compound (VIII) in the presence of 10% palladium on charcoal in ethanol gives 3'-amino-2',3'-dideoxyuridine (IX). Acetylation of compound (VIII) with acetic anhydride in pyridine at 4° C. yields 5'-O-acetyl-3'-azido-2',3'-dideoxyuridine (X). Reaction of compound (X) with thionyl chloride and N,N-dimethylformamide in absolute chloroform at reflux temperature for 6 hours affords the corresponding 4-chloro derivative (XI) which is then converted to 3'-azido-2',3'-dideoxycytidine (XII) by treatment with saturated methanolic ammonia at room temperature for 6 days. Hydrogenation of compound (XII) using 10% palladium on charcoal as a catalyst gives 3'-amino-2',3'-dideoxycytidine (XIII). Compounds (VIII) and (IX) are key intermediates for the synthesis of various 5-substituted 3'-azido and 3'-amino nucleoside analogs.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.C(O[CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)C>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[NH:1][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nncs1
Solvent: CCO
Product: CCOC(=O)C(=CNc1nncs1)C(=O)OCC

Procedure:
2-amino-1,3,4-thiadiazole (5 g) was reacted with diethyl ethoxymethylenemalonate (26.5 g) in ethanol (20 ml) at the reflux temperature for 23 hours. After cooling the precipitate was filtered and purified with hexane to give diethyl N-(1,3,4-thiadiazol-2-yl)-aminomethylenemalonate, m.p. 107°-111° C. (10 g), which was treated with polyphosphoric acid (57.6 g; 30.8 g of 99% H3PO4 and 26.8 g of P2O5) and POCl3 (25 g) under stirring at 120° C. for 30 minutes.