Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH:12](=O)[CH:13]([CH3:15])[CH3:14]>>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([N:8]=[CH:12][CH:13]([CH3:15])[CH3:14])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)C=O
Product: CC(C)C=NC1CC(C)(C)NC(C)(C)C1

Procedure:
21.0 g (0.10 mol) of 2,2,6,6-tetramethyl-4-(isobutylideneamino)-piperidine (b.p. 42°-43°/0.05 mm Hg), obtained by condensation of an equimolecular mixture of 2,2,6,6-tetramethyl-4-aminopiperidine with isobutyraldehyde at 0°, and 13.8 g (0.10 mol) of diethyl phosphite and 0.02 g of sodium ethylate (dissolved in 0.3 ml of ethanol) are heated for 31/2 hours at 90°. The reaction product is dissolved in ether, washed with a saturated sodium chloride solution, dried over potassium carbonate and, after removal of the solvent by distillation, distilled (b.p. 133°/0.4 mm Hg). Diethyl-1-[(2,2,6,6-tetramethyl-4-piperidyl)-amino]-isobutyl-phosphonate is obtained in this manner.
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.N1CCC[CH2:20]1>>[N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]2)[CH2:20][CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCC2)CC1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CCCC2)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 227, on a 2.34 mmol scale utilising pyrrolidine (Aldrich; 250 μL, 3.04 mmol), as a white solid (175 mg, 44%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([CH:35]=O)[C:32]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][CH:40]=3)=[N:31]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([CH2:35][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:32]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][CH:40]=3)=[N:31]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (2.74 ml) in tetrahydrofuran (50 ml), sodium hydride (60%, oily, 552 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-carbaldehyde (6.31 g) in tetrahydrofuran (100 ml) was added slowly, and the solution was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained crystals were collected by filtration, and ethyl 3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyloxy)-1H-pyrazol-4-yl]propionate (6.79 g, yield: 95%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].B(F)(F)F.[CH3:16][C:17]1[S:18][C:19]([CH3:27])=[CH:20][C:21]=1[C:22](O)([CH:24]=[CH2:25])[CH3:23].C(O)=C>O1CCOCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]2[C:3]=1[O:11][C:22]([C:21]1[CH:20]=[C:19]([CH3:27])[S:18][C:17]=1[CH3:16])([CH3:23])[CH2:24][CH2:25]2
Reactant: Cc1cc(O)c(Cl)c(C)c1O
Reactant: C=CC(C)(O)c1cc(C)sc1C
Agent: C=CO
Agent: FB(F)F
Solvent: C1COCCO1
Product: Cc1cc(C2(C)CCc3c(C)c(O)c(C)c(Cl)c3O2)c(C)s1
Temperature: 120 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
To a solution of 2-chloro-3,5-dimethyl-benzene-1,4-diol (520 mg) and BF3 etherate (1.28 g) in dioxane (10 mL) at 120° C. was added slowly a solution of the vinyl alcohol 2-(2,5-dimethyl-thiophen-3-yl)-but-3-en-2-ol (600 mg) in 2 mL of dioxane in 30 min. After completion, the solution was stirred at 120° C. for 3 h. Workup and purification by silica gel column chromatography eluting with 10% EtOAc in hexane gave 50 mg off-white solid 4-Chloro-6-(2,5-dimethyl-thiophen-3-yl)-1,3,6-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol. 1H NMR (300 MHz, CDCl3) δ: 6.52 (s, 1H), 4.29 (s, 1H, OH), 2.63-2.33 (3s+m, 12H), 2.06-2.01 (s+m, 4H), 1.62 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3 δ: 145.40, 143.98, 139.90, 134.97, 132.28, 125.68, 121.24, 120.34, 119.97, 119.57, 78.05, 32.85, 28.52, 21.74, 15.49, 14.96, 13.49, 11.77 ppm. MS m/z: 337 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:16]([O:19][C:20](=O)C)(=O)C>>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([C:6](=[CH:16][O:19][CH3:20])[C:7]#[N:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC(=O)c1cc(F)c(F)c(F)c1F
Product: COC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 150 °C
Yield: 95.3 %

Procedure:
A mixture of 16 g of 2,3,4,5-tetrafluorobenzoylacetonitrile, 15.6 g of trimethyl o-formate and 18.8 g of acetic anhydride is heated at 150° C. (bath temperature) for 3 hours. The solvent mixture is distilled off completely under a waterpump vacuum and finally under a high vacuum, at a bath temperature of 120° C. 18.2 g of 2-(2,3,4,5-tetrafluorobenzoyl)-3-methoxy-acrylonitrile are obtained as a dark brown oil.
Reaction SMILES: [I-:1].[Na+].[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:37])[C@H:12]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[CH:13]2[CH2:15][CH2:14]2)[CH2:7][CH2:6]1)#[N:4].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:37])[C@H:12]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([I:1])[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[CH:13]2[CH2:15][CH2:14]2)[CH2:7][CH2:6]1)#[N:4]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(I)cnc21
Temperature: 110 °C
Yield: 79.1 %

Procedure:
In a 5 mL microwave vial were placed copper(I) iodide (5 mg, 0.027 mmol), sodium iodide (120 mg, 0.80 mmol), 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (150 mg, 0.27 mmol), 1,4-dioxane (1 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (8 mg, 0.054 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 20 h. The reaction mixture was cooled to room temperature and quenched with sat'd aqueous NH4OH (3 mL) then diluted with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 80% EtOAc/hexanes to isolate 130 mg (80%) of 2-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as an orange foamy solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][O:30][CH3:31])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Yield: 23.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), para-toluenesulfonic acid (24 mg, 0.13 mmol) and MeOH (53 μL, 1.3 mmol) were dissolved in toluene (2.0 mL) and irradiated in the microwave at 140° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-(methoxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (9.6 mg, 23%). ESI-MS m/z calc. 415.5, found 416.5 (M+1)+; retention time 3.68 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH3:20])[N:14]=1)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH3:20])[N:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1cccc(N(C)Cc2ccc(OC)cc2)n1)c1cncnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCc1cccc(N(C)Cc2ccc(OC)cc2)n1)c1cncnc1
Yield: 73.1 %

Procedure:
A mixture of 6-11 (1.23 g, 2.51 mmol) and 10% Pd/C (0.200 g) in EtOH (25 mL) was stirred under a balloon of hydrogen for 2 days. Filtration through celite and evaporative removal of the solvent followed by purification on silica gel (70:25:5 CHCl3:EtOAc:MeOH) afforded 0.900 g of 6-12.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]1([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[O:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([N:38]3[CH2:37][CH:36]=[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:40][CH2:39]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCC2(C1)OCCO2)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Step A) (99.3 g) and triethylamine (80.8 g) in 1000 mL of dichloromethane is cooled in an ice bath, and treated dropwise with isobutyl chloroformate (80.1 g), dropwise, under nitrogen. After 30 minutes, a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (84.7 g) in 500 mL of dichloromethane is added dropwise over a 2-hour period. The mixture is stirred at room temperature for 2 additional hours. The solvent is removed in vacuo. The residue is suspended in 1000 mL of ethyl acetate, cooled to 0° C., and sequentially washed with ice-cold 1N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product is purified by flash chromatography (silica; hexane:ethyl acetate, 3:1) to give 107.1 g of the title compound as a yellow oil (silica; Rf =0.4; 1% methanol, 99% chloroform); Mass Spectrum (Electron Ionization) (MS (EI)) 327 (M, 26.1%), 141 (100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10]
Reactant: O=C(O)c1cccc(CCCCO)c1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(CCCCO)c1
Reaction time: 65 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzoic acid (100 mg) in dry DMF (10 ml) was treated with diisopropylethylamine (0.134 ml) and benzyl bromide (106 mg) and the reaction mixture was stirred for 65 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl(aq), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient Cyclohexane to cyclohexane-EtOAc 1:1) to give the title compound LCMS RT=3.38 min.
Reaction SMILES: [C:1]([NH2:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CN(C)C=O>O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:10])[CH3:23]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1ccccc1C#N

Procedure:
A mixture of anthranilamide (11.8 g), potassium carbonate (20 g), ethyl bromoacetate (18 g) and dimethylformamide (50 mL) was heated at reflux for 40 min. The reaction mixture was diluted with water and the product was extracted with ether. The organic layer was washed with water and brine, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized from ethanol to afford N-(2-Cyanophenyl)glycine ethyl ester as a colorless solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([O:8][C:9]([C:11]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:12]=1[S:13][C:14]1[C:15]([CH2:28][C:29]([OH:31])=[O:30])=[CH:16][CH:17]=[C:18]([CH2:26][NH2:27])[C:19]=1[N:20]2[CH3:25])=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(Cl)Cl>[C:4]([O:8][C:9]([C:11]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:12]=1[S:13][C:14]1[C:15]([CH2:28][C:29]([O:31][CH3:3])=[O:30])=[CH:16][CH:17]=[C:18]([CH2:26][NH2:27])[C:19]=1[N:20]2[CH3:25])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CN1c2cccc(C(=O)OC(C)(C)C)c2Sc2c(CC(=O)O)ccc(CN)c21
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CN)c2c1Sc1c(C(=O)OC(C)(C)C)cccc1N2C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
1 ml of diazomethane solution (~0.3N in diethyl ether) was added dropwise while cooling with ice to a solution of 80 mg (0.19 mmol) of (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetic acid in 4 ml of methylene chloride. The reaction mixture was brought to room temperature, stirred for 1.5 hours and evaporated. The residue was crystallized from ethyl acetate/hexane, whereupon, after drying in a high vacuum, 72 mg (91%) of methyl (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetate were obtained as a white solid. MS 414 (M+, 64), 358 (100), 343 (15), 314 (15), 238 (15), 57 (16).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]1[N:5]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:7][N:6]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(F)cc2F)no1
Yield: 77.3 %

Procedure:
To a solution of 2,4-difluoro-N′-hydroxybenzimidamide 5.2 (3.52 g, 33% purity, max. 7.2 mmol) and pyridine (2.32 mL, 28.7 mmol) in anhydrous CH2Cl2 under N2 was added ethyl chlorooxoacetate (1.27 g, 9.32 mmol) dropwise over 5 min at RT. The mixture was stirred under reflux. After 1 h30, the rxn mixt. was concentrated and purified on silica gel using CH2Cl2, furnishing 1.414 g of title product 5a as colorless oil. Yield: 1.414 g (78%). LCMS: P=94%, rt=4.21 nm, m/z=255, 277 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]=O)[C:7](=[O:15])[CH:6]=[CH:5]2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:8]4[C:9]5[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=5)[CH:5]=[CH:6][C:7]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1ccc2c(ccc(=O)n2CC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To 10 mL of a chloroform solution containing 229 mg of (6-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 340 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 55 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 314 mg of sodium triacetoxyborohydride was added and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=50:1], to give 228 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[CH:3][CH:2]=1.[N:15]1[CH:16]=[C:17](B(O)O)[N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[C:17]([C:10]2[CH:9]=[C:8]([NH:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12
Reactant: OB(O)c1cnc2ccccn12
Reactant: Brc1cccc(Nc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(Nc2cccc(-c3cnc4ccccn34)c2)cc1
Temperature: 80 °C
Yield: 2.3 %

Procedure:
To 3-Bromodiphenylamine (0.16 g, 0.6 mmol) was added imidazo[1,2-a]pyridine-3-ylboronic acid (0.1 g, 0.6 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 5 mol %), EtOH (0.5 ml), toluene (0.5 ml) and 2M Na2CO3 (0.9 ml). The reaction mixture was heated at 80° C. for 6 h, before being allowed to cool and then partitioned between EtOAc and H2O. The organic fraction was separated, washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography (20%-100% EtOAc/hexane) to afford the product (4 mg). MS: [M+H]+ 286.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[CH:3][C:2]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(F)c(Br)c1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(F)c(-c2cccnc2)c1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-4-fluorophenylamine (7.92 g, 41.7 mmol), diethyl(3-pyridyl)borane (6.74 g, 45.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol) and potassium carbonate (17.26 g, 125 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (500 mL) and water (500 mL). The organics were washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with dichloromethane on a gradient of ethyl acetate (0%-20%) gave 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 46%) as a colourless oil that solidified on standing to afford a white solid: δH (360 MHz, CDCl3) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4), 8.76 (1H, m).
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@H:11](OS(C(F)(F)F)(=O)=O)[C@H:10]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].[CH3:33][S-:34].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@@H:11]([S:34][CH3:33])[C@H:10]([N:21]2[C:25]3[N:26]=[C:27]([NH2:31])[NH:28][C:29](=[O:30])[C:24]=3[S:23][C:22]2=[O:32])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: C[S-]
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(OC(C)=O)[C@@H]1C[C@@H](SC)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-[(2S,4S,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]propyl acetate (compound 22d, 420 mg, 0.83 mmol) in DMF (7 mL) was added sodium thiomethoxide (84 mg, 1.2 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford crude product of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-methylsulfanyl-tetrahydrofuran-2-yl]propyl acetate (compound 22e), which was used in next step without further purification. MS obsd. (ESI−) [(M−H)−]: 399.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C([S:31][CH2:32][CH:33]([CH3:37])[C:34](O)=[O:35])(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][SH:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 ml.) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vauco. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue, N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester, is purified by column chromatography (silica gel, chloroform), yield 7.9 g. The named product is obtained by following the procedure of Example 17.