Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[C:25]([O:29][C:30]([N-:32][S:33](N1C=CC(=[N+](C)C)C=C1)(=[O:35])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C:25]([O:29][C:30]([NH:32][S:33]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:35])=[O:34])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 116.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in acetonitrile (2 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (181 mg) prepared by the method described in Organic Letters, 2001, 3 (14), 2241-2243, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (172 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:25])=[O:24])=[O:20])[N:10]=1.[CH2:30]=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH2:18][CH3:30])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:25])=[O:24])=[O:20])[N:10]=1
Reactant: CN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Reactant: C=O
Product: CCN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1

Procedure:
Compound 82 was prepared according to the procedure described for the synthesis of compound 81 by replacing formaldehyde with acetadehyde. LCMS (+ESI) m/z=421.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)#[N:2].[H][H]>N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(C#N)c1CNc1cccn2c(C)c(C)nc12
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: Cc1cccc(CN)c1CNc1cccn2c(C)c(C)nc12
Yield: 12.3 %

Procedure:
To a solution of 8-(2-cyano-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.42 g, 1.44 mmol) in ammonia saturated ethanol/methanol (10/2.5)(30 ml) was added Raney nickel (50% in water)(0.45 g) The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Following filtration through celite, the solvents were evaporated under reduced pressure and the residue was purified by by column chromatography on silica gel using methylene chloride:methanol (10:2) as eluent. Recrystallization from methylene chloride/diethyl ether gave 0.052 g (12%) of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:38]C1C=CC(B(O)O)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([CH3:38])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-methylphenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=511, obsd.=511).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[CH:22]=[C:21]([CH3:24])[N:20]=[C:19]([NH2:25])[C:18]=2[N:17]=[C:16]1[CH2:26][O:27][CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:25][C:19]1[C:18]2[N:17]=[C:16]([CH2:26][O:27][CH2:28][CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[CH:22]=[C:21]([CH3:24])[N:20]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
4-Morpholinecarbonyl chloride (202 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435, 1.57 mmol) in a mixture of triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was stirred at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine. The resulting glassy solid was triturated with acetonitrile to provide 0.417 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}morpholine-4-carboxamide as an off white powder, m.p. 156.5-159.5° C. Analysis: C19H30N6O3.0.20 HCl: %C, 57.37; %H, 7.65; %Cl, 1.78; %N, 21.13; Found: %C, 57.19; %H, 7.56; %Cl, 1.84; %N, 21.14. 1H NMR (300 MHz, CDCl3) δ6.51 (s, 1 H), 5.46 (bs, 2 H), 4.71 (s, 2 H), 4.45 (bs, 1 H), 4.17 (t, J=7.5 Hz, 2 H), 3.68 (t, J=4.9 Hz, 4 H), 3.57 (quartet, J=7.1 Hz, 2 H), 3.32 (m, 6 H), ), 2.49 (s, 3 H), 1.86 (quintet, J=7.5 Hz, 2 H), 1.58 (quintet, J=7.3 Hz, 2 H), 1.22 (t, J=7.2 Hz, 3 H); MS(CI) m/e 391 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>ClCCl>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
1-(4-Nitro-phenyl)-piperazine (2 g, 9.65 mmol) is dissolved in dichloromethane (50 mL) and (BOC)2O is added (2.10 g, 9.65 mmol). The mixture is stirred at room temperature overnight. Solvent removal affords a yellow solid (2.96 g, 100% yield, ES+(m/z) 308 [M+H]).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][N:11]=[N:10]2)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].Cl.O1CCOCC1>CO>[N:15]1([CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:5]=3)[N:10]=[N:11][N:12]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(-n2nnnc2CN2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-({1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (Intermediate 25, 532 mg, 1.22 mmol) in methanol (8 mL) was added hydrochloric acid in dioxane (5 mL, 20.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the white solid was dissolved in methanol and poured onto a 5 g SCX cartridge, washed with methanol (2 CV) and eluted with 10% ammonia) in methanol (2 CV). The ammonia in methanol fraction was concentrated under vacuum to leave a white solid, 4-[5-(1-piperazinylmethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (402 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=3)[C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)n3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:40](=[O:41])[CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Temperature: -20 °C
Yield: 107 %

Procedure:
To a solution of 32.6 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 750 ml of tetrahydrofuran is dropwise added a solution of 9.5 ml of pyridine and 15.1 ml of phenylacetyl chloride in 144 ml of tetrahydrofuran over a period of 15 minutes while maintaining the temperature at -20° C. and stirring under nitrogen atmosphere. The mixture is stirred for 55 minutes, poured into 700 ml of ice water, stirred for 5 minutes and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium hydrogencarbonate and water, dried on sodium sulfate, and evaporated under reduced pressure to yield 46.4 g of benzyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product in 107% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.[Cl:19]N1CCOCC1>CCOC(C)=O>[Cl:19][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[O:8][N:7]=[C:6]([OH:9])[C:5]=2[CH:10]=1
Reactant: ClN1CCOCC1
Reactant: Cc1ccc2c(O)noc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc2onc(O)c2cc1Cl
Temperature: 0 °C

Procedure:
A 25 ml round-bottom flask equipped with a stir bar was charged with 6-methyl-benzo[d]isoxazol-3-ol (298 mg, 2.0 mmole, 1.0 eq) and TFA (2.0 ml) and cooled to 0° C. in an ice bath. Neat N-chloromorpholine (242 μL, 2.0 mmoles, 1.0 eq, Organic Syntheses, CV 8, 167) was added dropwise and the reaction mixture was allowed to warm to room temperature over the period of 30 minutes. EtOAc was added, the crude product was partitioned in a separatory funnel (EtOAc/1.0M aqueous HCl), the organic layer was dried with MgSO4 and excess solvent was removed from the filtrate in vacuo. Crystallization of the crude product (383 mg) from a mixture of 20 ml of toluene and 6 ml of EtOAc provided 206 mg (94% purity determined by HPLC) as a white solid. (1H DMSO-d6, 400 MHz) δ 12.41 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 2.43 (s, 3H); (13C DMSO-d6, 100 MHz) δ 164.46, 161.87, 138.53, 128.08, 120.59, 113.78, 111.83, 20.49.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3](=[O:37])[C@@H:4]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)[C@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[CH2:9]1)=[O:7].[OH:39]O.[OH-].[Na+].Cl>C1COCC1.O>[C:17]([O:16][C:15](=[O:21])[NH:14][C@H:5]([C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[CH2:9]1)=[O:7])[C@H:4]([C:22]1[CH:27]=[CH:26][C:25]([OH:39])=[CH:24][CH:23]=1)[C:3]([N:2]([CH3:1])[CH3:38])=[O:37])([CH3:19])([CH3:18])[CH3:20]
Reactant: CN(C)C(=O)[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the material from Step A (0.5 g, 0.94 mmol) in THF (10 mL) at 0° C. was added sequentially 30% hydrogen peroxide (0.16 mL, 1.4 mmol) and 3N aqueous sodium hydroxide (0.31 g, 0.94 mmol). After 1.5 h at this temperature, the mixture was allowed to warm to ambient temperature, and then water (50 mL) was added, and the resulting solution was adjusted to pH 5 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with 10% aqueous sodium thiosulfate until the organic phase showed a negative peroxide test. The combined organics were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% methanol in ethyl acetate) to give the title compound as a white foam. LC/MS 424.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[CH:19]=[C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]4=[CH:16][C:15]=3[N:14]([CH2:25][C:26]3[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[C:13]2=[O:35])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:31]([F:34])([F:33])[C:28]1[O:27][C:26]([CH2:25][N:14]2[C:15]3[CH:16]=[C:17]4[O:24][CH2:23][CH2:22][O:21][C:18]4=[CH:19][C:20]=3[C:12]3([C:3]4=[CH:4][C:5]5[O:10][CH2:9][CH2:8][O:7][C:6]=5[CH:11]=[C:2]4[O:1][CH2:36]3)[C:13]2=[O:35])=[CH:30][CH:29]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C12COc1cc4c(cc12)OCCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one was obtained (76%) as a colorless solid: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 6.75-6.67 (m, 2H), 6.49-6.43 (m, 2H), 6.37-6.31 (m, 1H), 6.22-6.16 (m, 1H), 4.87 (ABq, 2H), 4.69 (ABq, 2H), 4.26-4.04 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.0, 152.0, 151.9, 144.6, 144.0, 140.1, 138.3, 135.2, 124.3, 120.9, 113.7, 112.6, 112.6, 111.5, 109.1, 99.3, 98.9, 80.0, 64.6, 64.5, 64.0, 63.9, 57.8, 37.0; MS (ES+) m/z 501.9 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([NH:12][NH:13][C:14]([CH:16]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:15])=[O:11])[N:3]1[O:27][S:28]([OH:31])(=[O:30])=[O:29].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:18]1[CH2:17][CH:16]([C:14]([NH:13][NH:12][C:10]([C@H:7]2[CH2:6][CH2:5][C@H:4]3[CH2:9][N:8]2[C:2](=[O:1])[N:3]3[O:27][S:28]([OH:31])(=[O:30])=[O:29])=[O:11])=[O:15])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NNC(=O)[C@H]2CC[C@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OS(=O)(=O)O)C1CNC1
Reaction time: 1 h

Procedure:
To a solution tert-butyl 3-[(2-{[(2R,5S)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate 262 (0.18 g, 0.39 mmol) in DCM (18 mL) was added trifluoroacetic acid (1.45 mL, 18.79 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOH:ether (1:5, 6×) and the white solid was collected by centrifugation to give (2R,5S)—N′-(azetidin-3-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide Compound 112 (Table 2) (0.04 g, 28%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccn2cc(-c3ccc(C#CCCOS(C)(=O)=O)cc3)nc2c1
Temperature: 10 °C
Yield: 66.4 %

Procedure:
The product of Step B (0.135 g) in dichloromethane (3 mL) was treated with pyridine (0.37 g) and cooled to 10° C. The cold solution was treated with methanesulfonyl chloride (0.112 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with 1% H2SO4 solution, saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.115 g).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1>>[Cl:57][C:50]1[N:51]=[C:52]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: NN1CCCCC1c1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared according to method A as described in Example 1 was obtained as a solid (0.25 g, 26%) by the reaction of 1-amino-2-phenylpiperidine (Overberger, C. G. and Herin, L. P. Journal of Organic Chemistry, 1962, 27, 417) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine, followed by deprotection (as described in Example 5) to give the title nucleoside (a ca. 60:40 mixture of diastereoisomers): m.p. 186°-210° C.; 1H NMR (400 MHz, Me2SO-d6) δ 3.47-3.20 (2H, m, 5'-CH2), 3.82-3.97, 4.04-4.14 (2H, 2m, H-3' and H-4'), 4.46-4.56 (1H, 2q, H-2'), 5.33, 5.73 (1H, 2d, H-1'), 8.26, 8.48 (1H, 28, H-8).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Cl-].[OH:30][CH:31]1[CH2:34][NH2+:33][CH2:32]1>>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:33]4[CH2:34][CH:31]([OH:30])[CH2:32]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OC1C[NH2+]C1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Agent: [Cl-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CC(O)C4)cn3)nc2n1C1CCCC1
Yield: 47 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and 3-hydroxy-azetidinium chloride (73 mg, 0.667 mmol) gave 7-cyclopentyl-2-[5-(3-hydroxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a light yellow solid (0.131 g, 47%) [following SiO2 chromatography, eluting with 0-5% (2M NH3 in MeOH)/DCM). MS(ESI) m/z 436.2 (M+H)+ (method B).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([CH:14]([OH:17])[CH2:15][OH:16])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>ClCCCl>[Si:28]([O:16][CH2:15][CH:14]([C:4]1[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:18])[OH:17])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 80 %

Procedure:
1-[5-Chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-fluorophenyl]ethanone (700 mg, 2 mmol) (from Step 2, peak 2) was stirred in 1,2-dichloroethane (6 mL) with N,N-diisopropylethylamine (4.0 mL, 23 mmol) and a 1.0 M solution of tert-butyldimethylsilyl chloride in 1,2-dichloroethane (7.6 mL) was added. The mixture was heated to 80° C. for 3 hours and cooled to rt. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound 800 mg, 80%. LCMS calculated for C18H28ClFO4SiNa (M+Na)+: m/z=413.1; found: 413.1.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:35])([F:34])[F:36])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.