Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][CH2:18][C:19]([CH3:25])([C:21]([O:23]C)=[O:22])[N:20]=1.[OH-].[Na+]>CO.O>[OH:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][CH2:18][C:19]([CH3:25])([C:21]([OH:23])=[O:22])[N:20]=1
Reactant: COCCOCCOc1cccc(C2=NC(C)(C(=O)OC)CN2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCCOc1cccc(C2=NC(C)(C(=O)O)CN2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of methyl 2-(2-hydroxy-3-(2-(2-methoxyethoxy)ethoxy)phenyl)-4-methyl-4,5-dihydro-1H-imidazole-4-carboxylate (0.85 g, 0.25 mmol) in MeOH (5 mL) was added NaOH (20 mg, 0.5 mmol) and water (one drop). The resulting mixture was stirred for 2 h at room temperature. The solvent was evaporated under vacuum and the residue was purified by Combi Flash to obtain the title compound as colorless oil (50 mg, 60%). 1H NMR (300 MHz, CD3OD, n=2): δ 7.40-7.50 (m, 1H), 7.10-7.25 (m, 1H), 6.75-6.95 (m, 1H), 4.30-4.40 (m, 1H), 4.15-4.25 (m, 2H), 3.75-3.95 (m, 2H), 3.45-3.75 (m, 5H), 3.35 (s, 3H), 1.67 (s, 3H). LC-MS (ES, m/z): 339 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][S:8]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:30][CH:31]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
From p-chlorostyrenesulphonyl chloride and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate; colourless oil, nD20 =1.5625;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2].[H-].[Na+].[CH:28](I)([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:28]([CH3:30])[CH3:29])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(C)c(C)cc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC(C)C)nc2cc(C)c(C)cc2c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-chlorophenyl)-1,2-dihydro-6,7-dimethyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (2.0 g) in DMF (20 ml) was added sodium hydride (60% in oil) (270 mg), followed by stirring at room temperature for 30 minutes. To this solution was added isopropyl iodide (0.9 ml), followed by stirring at 70° C. for 5 hours. After the mixture was cooled, ethyl acetate was added, and this mixture was washed successively with dilute hydrochloric acid, aqueous potassium carbonate and water and then dried, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1), to yield 4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylic acid ethyl ester as colorless crystals (1.72 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>O1CCCC1.CCOCC>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH:13]1[C:12](=[O:16])[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][C:10]=2[CH2:15][CH2:14]1)[CH3:31]
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2onc(-c3ccccc3)c2C1=O
Temperature: -78 °C

Procedure:
In 115 ml anhydrous tetrahydrofuran was dissolved 2.44 g of 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one under nitrogen. The solution was cooled to -78° C. and 11.5 ml lithium diisopropylamide was added dropwise. The resultant solution was stirred for 15 minutes at -78° C. and ethyl bromoacetate (2.6 ml) was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted three times with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Flash column chromatography (30% ethyl acetate/hexane) gave 2.94 g of 4,5,6,7-tetrahydro-4-oxo-3-phenyl-1,2-benzisoxazol-5-acetic acid ethyl ester
Reaction SMILES: [Bi:1].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([OH:7])=[O:6])[CH3:3].[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([O-:17])=[O:16])[CH3:13].[NH4+]>CO>[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3].[Bi+3:1].[CH2:12]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([O-:17])=[O:16])[CH3:13].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3]
Reactant: CCCCC(CC)C(=O)O
Reactant: [Bi]
Agent: CCCCC(CC)C(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: [Bi+3]

Procedure:
The electrolyzer of FIG. 1 was used to assist the reaction. The anolyte contained a solution formed from 10 ml of 2-ethylhexanoic acid, 1.6 g of ammonium 2-ethylhexanoate, and 90 ml of methanol. The anode was a bismuth plate having a surface area of 10 cm2. The catholyte solution contained 3 ml of 2-ethylhexanoic acid, 0.5 g of ammonium 2-ethylhexanoate, and 27 ml of methanol. A graphite cathode having a surface area of 10 cm2 was utilized. Electrolysis was conducted using a current of 0.100 amps for 20 hours. A 2 ml quantity of 2-ethylhexanoic acid was added to the catholyte solution every 3 hours. The anolyte solution was removed from the electrolyzer and filtered. The mother liquor was cooled to a temperature ranging from about 0-2° C. to precipitate crystals. The crystals were isolated by filtration, washed with methyl alcohol, and dried in a vacuum heater at a temperature ranging from about 50-60° C. for a duration of 7-8 hours. The product included 14.3 g of a viscous transparent liquid, namely, Bi(C7H15COO)3. Table 2 presents the analytical data for the product.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CN1C2C(=C(N)C=CC=2)C=C1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)Cn1ccc2c(N)cccc21
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (4-amino-indol-1-yl)-acetic acid ethyl ester (prepared in two steps from 4-nitroindole) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.47 (1H, s), 7.84 (1H, d), 7.47 (2H, m), 7.27 (1H, m), 7.15 (1H, t), 7.05 (1H, d), 6.96 (1H, d), 6.87 (1H, t), 5.69 (1H, d), 4.75 (4H, m), 4.57 (1H, d), 4.25 (1H, d), 2.79 (1H, m), 1.99-1.09 (19H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.46; H, 7.08; N, 9.78%; C32H37N5O5.C7H17NO5.1.6H2O.0.5C4H8O2 requires: C, 58.64; H, 7.35; N, 10.01%.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].[CH:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:18])=O.BrC[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O>[C:24]([O:23][C:21](=[O:22])[CH2:7][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:1]=[O:2])=[C:10]1[CH3:18])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc2ccccc2n1C=O
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C=O)c2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 95.1 %

Procedure:
K2CO3 (15 mmol, 2.07 g) and 1-formyl-2-methyl indole (10 mmol, 1.59 g) were stirred in 50 mL DMF. t-Butyl bromoacetate (12 mmol, 1.77 mL) was added and the reaction was heated to 80° C. for 1 h. The reaction was cooled, diluted with 100 mL EtOAc, and washed with water (3×50 mL). The organic solution was dried over MgSO4 and concentrated to give the sub-title compound as a yellow solid (2.6 g).
Reaction SMILES: [CH2:1]([C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1)[CH:2]=C.[O:17]=[O+][O-]>ClCCl>[O:17]=[CH:2][CH2:1][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]#[N:16])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCC2)O1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-9-(2-propenyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage =90 V) is when passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 2.5 g of pure (±)-cis-9-(2-oxoethyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C@H:3]1[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[CH2:25]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:25]([O:32][C:33]([NH:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][C@H:3]1[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:38])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
A solution of tert-butyl 3-((1R,2S,5R)-2-amino-5-(tert-butoxycarbonylamino)cyclohexyl)propanoate (90 mg) and 2-(benzyloxycarbonylamino)acetic acid (55 mg) in dichloromethane (2 mL) was treated sequentially with diisopropylethylamine (92 μL), 1-hydroxybenzotriazole hydrate (45 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg). The mixture was stirred at rt for 20 h, then was diluted with dichloromethane, washed sequentially with 1 M aqueous HCl, saturated aqueous NaHCO3 and water, dried over Na2SO4 and concentrated under vacuum to provide tert-butyl 3-((1R,2S,5R)-2-(2-(benzyloxycarbonylamino)acetamido)-5-(tert-butoxycarbonylamino)cyclohexyl)propanoate as a pale yellow gum (125 mg). MS found: (M+H)+=534.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[N:18]=2)[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[H][H]>[Pd].C(O)C.C([O-])(=O)C.[Na+]>[ClH:23].[N:20]1[CH:21]=[CH:22][C:17]([N:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH3:16])=[N:18][CH:19]=1
Reactant: [H][H]
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(Cl)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(CC1CCNCC1)c1ccncn1
Product: Cl
Reaction time: 2 h
Yield: 123.1 %

Procedure:
A suspension of 1-t-butoxycarbonyl-4-{[(2-chloropyrimidin-4-yl)(methyl)amino]methyl}piperidine (3.00 g, 8.80 mmol) and 5% palladium on activated carbon (1.87 g, 0.880 mmol) in ethanol (70 mL) and 1N sodium acetate solution (17.6 mL) is stirred rapidly under 1 atmosphere of hydrogen for 2 hours. After the atmosphere of hydrogen is replaced with argon the mixture is filtered through a bed of Celite™ and ethyl acetate, water and saturated sodium bicarbonate are added to the solution. The phases are separated and the aqueous phase is extracted into ethyl acetate (×3). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. The residue is taken into methanol (270 mL) and hydrogen chloride gas is passed through the solution maintaining <20° C. The mixture is kept at this temperature for 2 hours before it is concentrated in vacuo and freeze-dried from water providing 4-{[(pyrimidin-4-yl)(methyl)amino]methyl}piperidine hydrochloride (2.63 g, 100%).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].N1C=CN=C1>O1CCCC1>[C:7]1([C:5]2[N:6]=[C:2]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:3]([CH3:19])[C:4]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -20 °C

Procedure:
A solution of 2-chloro-4,5-diphenyl-1-methylimidazole (1.46 g, 5.4 mmol) from Step B in tetrahydrofuran (THF) (20 mL) under nitrogen was cooled to −70° C. in a dry ice/acetone bath. n-Butyl lithium (1.6 N in hexanes, 10.2 mL, 16.3 mmol) was added via syringe. The reaction was allowed to warm to −20° C. for 2 hr. In a separate round-bottomed flask, a solution of benzyl chloroformate (CBZ-Cl) (4.3 mL, 16.3 mmol) in TBF (10 mL) was cooled to −20° C. The above imidazole reaction was added via a double-tipped needle to the solution of CBZ-Cl and after 20 min the reaction was allowed to warm to rt for 30 min. The reaction was then quenched into an aqueous sodium bicarbonate solution and was then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (5% methylene chloride and 15% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1>>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: CC(=O)N1CCC(NC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)CC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 1-(4-amino-piperidin-1-yl)-ethanone (27 mg, 0.19 mmol). Yield: 39 mg (47%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C(=O)C)=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:22]([O:24]CC)=[O:23]>CO.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Cn2c(C(=O)O)cc3cc(O)ccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
Sodium hydroxide (2M, 1.9 ml) was added to a stirred solution of ethyl N-(3-methoxy-4-chlorobenzyl)-5-acetoxyindole-2-carboxylate (305 mg) in methanol (3 ml) and THF (3 ml). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and then diluted with water (5 ml). The solution was acidified by the addition of aqueous hydrochloric acid (2M), extracted with ethyl acetate, dried and evaporated. The residue was purified by column chromatography eluting 20%-100% ethyl acetate to give the desired product as a solid (177 mg, 70%) NMR (CD3SOCD3): d 3.95 (s, 3H), 5.95 (s, 2H), 6.35 (d, 1H), 6.8 (dd, 1H), 6.9 (d, 1H), 7.0 (d, 1 μl), 7.1 (s, 1H), 7.25 (d, 1H), 7.3 (d, 1H), 9.0 (s, 1H); m/z 332 (M+H+).
Reaction SMILES: CN(C)OCC[O:6][C@@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][C@H:8]1[N:15]1[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[O:40][C:41]1[CH:62]=CC(C(Cl)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[N:63]1[CH:68]=CC=C[CH:64]=1>CN(C)C1C=CN=CC=1>[CH3:64][N:63]([CH3:68])[O:40][CH2:41][CH2:62][C@@:8]1([N:15]2[CH:22]=[C:21]([CH3:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[O:9][C@H:10]([CH2:13][OH:14])[C@@H:11]([OH:12])[C@H:7]1[OH:6]
Reactant: c1ccncc1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1cn([C@]2(CCON(C)C)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
2′-O-(dimethylaminooxyethyl)-5-methyluridine (750 mg, 2.17 mmol) was dried over P2O5 under high vacuum overnight at 40° C. It was then co-evaporated with anhydrous pyridine (20 mL). The residue obtained was dissolved in pyridine (11 mL) under argon atmosphere. 4-dimethylaminopyridine (26.5 mg, 2.60 mmol), 4,4′-dimethoxytrityl chloride (880 mg, 2.60 mmol) was added to the mixture and the reaction mixture was stirred at room temperature until all of the starting material disappeared. Pyridine was removed under vacuum and the reside chromatographed and eluted with 10% MeOH in CH2Cl2 (containing a few drops of pyridine) to get 5′-O-DMT-2′-O-(dimethylamino-oxyethyl-5-methyluridine (1.13 g, 80%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[O:26][C:27]([CH3:30])=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1nnc(N)o1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)o1
Yield: 23.2 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-methyl-1,3,4-oxadiazole (33.7 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(5-methyl-1,3,4-oxadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][CH2:9][C@H:10]([CH3:24])[C@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:12]([CH3:15])[CH2:13]O)=[CH:5][CH:4]=1.CCN(CC)CC.[H-].[Na+].[CH3:36][CH2:37][O:38][C:39]([CH3:41])=[O:40].CCCCCC>>[CH2:37]([O:38][C:39](=[O:40])/[CH:41]=[CH:13]/[C@H:12]([CH3:15])[C@@H:11]([O:16][Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:19])[CH3:18])[C@@H:10]([CH3:24])[CH2:9][O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=1)[CH3:36]
Reactant: CCOC(C)=O
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)COCc1ccc(OC)cc1
Yield: 63 %

Procedure:
The procedure for 10 was used with the aldehyde from 21 (17.5 g, 31.6 mmol), Py.SO3 (15.2 g, 95.5 mmol) and Et3N (13.3 mL, 95.5 mmol), NaH (0.90 g, 39.7 mmol) and triethylphosphonoacetate (7.2 mL, 40.3 mmol) to yield 8.96 g (63% for 3 steps) of the ester 22 by flash column chromatography (EtOAc/Hexane 1:9) as a colorless oil: IR (CHCl3) 2957, 2931, 2856, 1720, 1651, 1613, 1513, 1463, 1366, 1250, 1180, 1093, 1077, 837 cm−1; 1H NMR (300 MHz, CDCl3) ε7.31-7.27 (m, 2H), 7.03 (dd, J=15.8, 7.8 Hz, 1H), 6.93-6.91 (m, 2H), 5.83 (dd, J=15.8, 1.3 Hz, 1H), 4.48b -4.40 (m, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.67 (m, 1H), 3.52 (m, 1H), 3.30 (dd, J=9.1, 7.2 Hz, 1H), 2.59 (m, 1H), 2.00 (m, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H), 0.94 (s, 9H), 0.08 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 166.5, 159.0, 152.7, 130.6, 129.0, 120.4, 113.6, 76.8, 72.5, 71.8, 60.0, 55.1, 40.2, 38.0, 26.0, 18.2, 14.8, 14.3, 14.2, −4.0, −4.2; LRMS (ESI) 473.2 [M+Na]+; HRMS (ESI) calcd for C25H42O5SiNa 473.2699 [M+Na]+, found 473.2716; [α]20D−28.3 (c 0.41, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:11][CH3:12])=[N:9][NH:10][C:4]=2[CH:3]=1.[CH3:13][N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:16]([NH:25][C:26]([NH2:28])=[O:27])[CH2:15]1.CC(C)([O-])C.[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1COCC1>[CH3:12][O:11][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:28][C:26]([NH:25][C@H:16]3[C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:18][N:14]([CH3:13])[CH2:15]3)=[O:27])=[CH:3][C:4]=2[NH:10][N:9]=1
Reactant: COc1n[nH]c2cc(Cl)ncc12
Reactant: CN1C[C@@H](NC(N)=O)[C@H](c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1n[nH]c2cc(NC(=O)N[C@@H]3CN(C)C[C@H]3c3ccccc3)ncc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
6-Chloro-3-methoxy-1H-pyrazolo[4,3-c]pyridine (50 mg, 0.272 mmol), 1-((3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl)urea (Intermediate 17B; 90 mg, 0.409 mmol), BrettPhos pre-catalyst (21.75 mg, 0.027 mmol), and potassium tert-butoxide (1 M in THF, 0.817 mL, 0.817 mmol) were dissolved in THF (1 mL). The vial was degassed with argon for 5 min and the reaction stirred at 60° C. for 16 h. The reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (0-20% CH2Cl2/MeOH with 1% ammonia) gave 1-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-[(3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl]urea. MS ESI calc'd. For C19H22N6O2 [M+1]+ 367. found 367. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 7.72 (s, 1H), 7.43 (s, 1H), 7.31-7.26 (m, 3H), 7.22-7.18 (m, 2H), 4.22-4.14 (m, 1H), 3.98 (s, 3H), 3.16-3.04 (m, 1H), 2.64-2.58 (m, 2H), 2.48 (s, 3H), 2.38-2.28 (m, 2H).