Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[Cl:27])[C:8]=1[CH3:28]>C1COCC1.CO>[Cl:27][C:18]1[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:17]=1[CH2:16][N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[C:8]1[CH3:28]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2Cl)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 45 °C
Reaction time: 1 h

Procedure:
1M Aqueous NaOH (15 ml) is added to a stirring suspension of [1-(2-chloro-4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (2.6 g, 6.39 mmol) in 1:1 THF/MeOH (40 ml). After stirring at 45° C. for 1 hour, the reaction mixture is filtered to remove any undissolved material and is evaporated to dryness. The resulting solid is dissolved in water (30 ml) and acidified to pH 2-3 using concentrated HCl. The resulting suspension is collected by filtration and dried in vacuo at 50° C. to yield a solid which is purified by recrystallisation from IPA/water (1:3) to afford the titled product. (MH+ 393)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])=[N:8][C:9]([CH3:18])=[CH:10][C:11]=1[NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:14]([CH:13]([N:12]1[CH2:2][C:3](=[O:4])[NH:5][C:6]2[C:7]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:8][C:9]([CH3:18])=[CH:10][C:11]1=2)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)N1CC(=O)Nc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of 2-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide (170 mg, 0.42 mml) in 2 ml of dry THF was added a solution of 1 M lithium bis(trimethylsilyl)amide in THF (0.84 ml, 0.84 mmol) at −78° C. The mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. An additional 0.42 ml of 1M lithium bis(trimethylsilyl)amide in HF was added at −78° C. and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give 160 mg of yellow solid. The solid residue was purified through silica gel column chromatography using 15% ethyl acetate (EtOAc) in hexane as eluent to give 91 mg (59%) of the title compound as white crystals. 1H NMR (CDCl3) δ 7.84 (s, 1H), 6.88 (s,2H), 6.22 (s,1H), 3.82(s,2H), 3.58(m,1H), 2.30(s,3H), 2.18(s,3H), 2.08(s,6H), 1.63(m,4H), 0.95(m,6H) ppm.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11](O)=[N:10][CH:9]=[CH:8][N:7]3[C:13]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:11]1[C:6]2[N:7]([C:13]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:5]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(O)nccn34)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Temperature: 110 °C
Yield: 94.7 %

Procedure:
[step 5] To (E)-2-{8-[(2-cyclopropyl-8-hydroxyimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (3.8 g, 8.3 mmol) obtained in step 4 was added phosphorus oxychloride (19 mL, 207 mmol), and the mixture was stirred with heating at 110° C. for 4 hr. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E)-2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (3.7 g, 96%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[C:6]([O:14][CH2:15][O:16][CH3:17])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:13][O:12][CH2:11][O:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([O:14][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: COCOc1cc(OCOC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCOc1cc(CO)cc(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of 3,5-bis-methoxymethoxybenzoic acid methyl ester (11.1 g, 43.3 mmol) in Et2O (150 mL) was treated with LiAlH4 (2.46 g, 65.0 mmol) at 0° C. The suspension was stirred at room temperature for 1 h. The reaction mixture was slowly quenched by water and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=2:3) to afford the title compound (9.16 g, 93%). 1H NMR (300 MHz, CDCl3) δ 6.71 (s, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 5.15 (s, 4H), 4.62 (d, J=6.0 Hz, 2H), 3.47 (s, 6H), 1.93 (t, 1H).
Reaction SMILES: N1C(C)=CC=CC=1C.[F:9][C:10]([F:23])([F:22])[S:11]([O:14]S(C(F)(F)F)(=O)=O)(=[O:13])=[O:12].[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[C@H:25]([CH3:27])O>ClCCl>[F:9][C:10]([F:23])([F:22])[S:11]([O:14][C@@H:25]([CH3:27])[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:13])=[O:12]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 90 %

Procedure:
In a 500 ml round-bottomed flask, 3.00 g of tert-butyl L-lactate (ee>99%) was dissolved in 165 ml of absolute dichloromethane and cooled to 0° C. under argon. Thereafter, first 3.10 ml of 2.6-lutidine and then slowly 4.15 ml of trifluoromethanesulphonic anhydride were added in succession and the reaction was stirred for 50 min at 0° C. Thereafter, the reaction mixture was diluted with 400 ml of petroleum ether, washed 4 times with 250 ml of a 3:1 mixture of saturated aqueous sodium chloride solution and 1 N hydrochloric acid, dried over MgSO4 and concentrated in vacuo. The residue was applied to a silica gel filter and washed off said filter with a 1:1 mixture of petroleum ether and dichloromethane. After removal of the solvent, the pure tert-butyl (S)-2-trifluoromethanesulphonyloxypropionate (ee>99%) was obtained in a yield of 90%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[C:22]([C:25]1[N:26]=[N:27][N:28]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=1)([OH:24])=[O:23].[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][CH2:34][CH:30]([N:28]5[CH:29]=[C:25]([C:22]([OH:24])=[O:23])[N:26]=[N:27]5)[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=C(O)c1cn(C2CCNC2)nn1
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (140 mg, 0.49 mmol), 3-(4-carboxy-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (269 mg, 1.23 mmol) and diazobicycloundecane (187 mg, 1.23 mmol) in acetonitrile (5 ml) was heated at 80°-90° C. for four days. The reaction mixture was concentrated, diluted with water (10 ml) and pH brought down to 4.0 using 1M HCl. The separated solid was filtered and washed with water and crystallized from MeOH/ether to yellow solid. Yield 29 mg (13.2%), m.p. 222°-225° C. 1H NMR (CDCl3 +CD3OD) δ: 1.11-1.42 (m, 4H), 3.88-4.30 (m, 4H), 4.40-4.48 (m, 1H), 5.35-5.55 (m, 1H), 7.8 (d, 1H), 8.41 (s, 1H), 8.79 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.C(N(CC)CC)C>CS(C)=O>[NH2:12][C:13]1[N:14]=[C:15]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 100 °C
Yield: 34.9 %

Procedure:
To a solution of (R)-ethyl piperidine-3-carboxylate (1 g, 6.33 mmol) in dimethylsulfoxide (15 mL) were added 2-amino-3-nitro-6-chloropyridine (1.098 g, 6.33 mmol) and triethylamine (1.921 g, 18.99 mmol) at room temperature. The mixture was heated to 100° C. for 18 h, then was poured into ice water and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (100-200 mesh silica, 30% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (650 mg, 93.5%). MS (ES+APCI) (M+H) 295.1; LCMS retention time 2.832 min (Method G).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33][CH:34]=[O:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO.[BH4-].[Na+]>>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33][CH2:34][OH:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CCO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)acetaldehyde (0.164 g, 0.314 mmol) was dissolved in methanol (5.00 mL, 123 mmol) under an atmosphere of argon and cooled to 0° C. Sodium tetrahydroborate (0.0291 g, 0.754 mmol) was added and the reaction was stirred for 10 minutes. Additional sodium tetrahydroborate (0.0143 g, 0.377 mmol) was added, and the reaction mixture was stirred for another 30 minutes. The reaction was quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of 0 to 100% EtOAc in methylene chloride, to afford the title compound (0.0694 g, 45%). LC/MS: Rt=1.65 min, ES+ 494 (FA standard).
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([CH:7]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]=[C:35]=[O:36].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][C:35](=[O:36])[NH:1][C:2]1[O:6][C:5]([CH:7]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][N:3]=1
Reactant: CN=C=O
Reactant: Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNC(=O)Nc1nnc(C(CCc2ccccc2)NC(=O)OCc2ccccc2)o1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
350 mg of benzyl [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]-carbamate were dissolved in 5 ml of dry dimethyl sulfoxide, treated with 140 mg of potassium carbonate and 140 mg of methyl isocyanate, and stirred at 80° C. for 16 h. The reaction mixture was cooled, treated with ethyl acetate, washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Benzyl {1-[5-(3-methylureido)-[1,3,4]oxadiazol-2-yl]-3-phenylpropyl}carbamate was obtained, which was employed in the next stage (hydrogenolysis) without further purification.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:25](/[C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCCCC
Product: CCCC/C=C/c1nc(N)c2nc(NCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-propylaminoadenosine (9, 400 mg, 0.89 mmol) and (E)-1-borocatechol)-1-hexene (2.67 mmol). The mixture was purified by column chromatography (10% MeOH in CH2Cl2). Yield 43 mg (0.11 mmol, 12%), mp 170–172÷C; Rƒ 0.41 (10% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.93–6.82 (m, 1H, ═CHCH2), 6.29 (d, 1H, J=15.48 Hz, ═CH), 6.04 (d, 1H, J=7.65 Hz, H-1′), 4.79–4.74 (m, 1H, H-2′), 4.29–4.26 (m, 1H, H-3′), 4.13–4.12 (m, 1H, H-4′), 3.81 (q, 2H, J=8.24 Hz, H-5′), 3.37–3.32 (m, 2H, NHCH2), 2.24 (q, 21H, J=7.16 Hz, ═CHCH2), 1.89–1.66 (m, 2H, NHCH2CH2), 1.51–1.35 (m, 4H, CH2CH2), 1.02–0.91 (m, 6H, 2×CH3); MS m/z 407 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=8.10 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=20.25 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:8]=[O:9])[N:5]([CH3:7])[CH:6]=1.[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].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.C1COCC1>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[N:3]=[C:4]([CH:8]=[O:9])[N:5]([CH3:7])[CH:6]=2)=[CH:11]1
Reactant: Cn1cc(Br)nc1C=O
Reactant: OB(O)c1ccoc1
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: [Cl-]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccoc2)nc1C=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
A glass vial was charged with 4-bromo-1-methyl-1H-imidazole-2-carbaldehyde (567 mg, 3.0 mmol), furan-3-boronic acid (504 mg, 4.5 mmol), 1,2-dimetoxyethane (12 mL) and 1M sodium carbonate solution (4.5 mL). The slurry was deoxygenated by bubbling argon through then tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.0675 mmol) was added and the vessel sealed and warmed to 120° C. and stirred at this temperature for 5 hours, then 110° C. for 12 hours. THF (45 mL) was added to the cooled mixture followed by brine (15 mL). The organic layer was separated and the aqueous extracted with EtOAc (2×50 mL). The combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (Gradient: n-heptane/EtOAc=3/1 to n-heptane/EtOAc=1/1) to yield the title compound (326 mg, 62%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:26](O)[CH3:27].OS(O)(=O)=O.CCCCCC>CO.C(OC(=O)C)C>[CH2:26]([O:24][C:23](=[O:25])[CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1)[CH3:27]
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(-c2ccc(Cl)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid (300 g, 840 mmol) and ethanol (3 L) were placed in a flask. Concentrated H2SO4 (2.4 mL, 86.4 meq.) was added with stirring. The reaction was then heated to reflux. After approximately 30 minutes, the suspension dissolved. The reaction was monitored by TLC (silica gel; hexane:ethylacetate:methanol;70:20:10). After refluxing for 9 hours, all starting material was gone and 2 liters of ethanol was removed by distillation. The remaining solution was cooled with stirring to 0° C. and seeded with known ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate. The resulting suspension was stirred at 0° C. for 30 minutes and then filtered, washed with cold ethanol (100 mL) and vacuum dried (room temperature, ca. 5 mm Hg) to give ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate (275.0 g, 85% yield) as a clean white powder (mp=80-81° C.). An additional 27.9 9 of ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate was obtained as a tan powder after reducing the volume of the mother liquor to approximately 100 mL and seeding with known ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](Cl)=[N:15][N:14]=[CH:13]2.[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:15][N:14]=[CH:13]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: OCC(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)(F)COc1nncc2cc(Br)ccc12
Reaction time: 0.17 h

Procedure:
A solution of 2,2,2-trifluoroethanol (329 mg, 3.28 mmol) in 3.0 mL of THF and 3.0 mL of DMF at 0° C. was treated with sodium hydride (60% wt) (131 mg, 3.28 mmol) and the resulting mixture was stirred for 10 min, then solid 6-bromo-1-chlorophthalazine (400 mg, 1.64 mmol) was added in one portion. The mixture was stirred at RT for 1 h, poured into iced-cold saturated NH4Cl solution, and extracted with EtOAc twice. The combined organic layers were dried over sodium sulfate, concentrated under vacuum. The residue was put on an ISCO 40 g column (eluted with 20-70% EtOAc in Hexanes) and purified to give title compound as a tan amorphous solid. MS (ESI, pos. ion) m/z: 309.0 (M+1).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COC1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)COC1CCC(N)CC1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
Tert-butyl 2-[4-(dibenzylamino)cyclohexoxy]acetate (6 g, 15 mmol, 1 eq.) was dissolved in methanol (200 mL) and pumped through the H-Cube® hydrogenation instrument containing a 10% Pd(OH)2 catalyst cartridge (CatCart) and using full hydrogen flow, ambient pressure, at 40° C. for 3 hours. The solvent was removed under vacuum to provide tert-butyl 2-(4-aminocyclohexoxy)acetate (3.3 g, 98%); (CI, m/z): [M+H]+ 230; 1H NMR (400 MHz, CDCl3): δ 3.99 (s, 2H), 3.31 (tt, J=10.7, 4.2 Hz, 1H), 2.71 (tt, J=10.8, 3.9 Hz, 1H), 2.00-2.11 (m, 2H), 1.83-1.93 (m, 2H), 1.46-1.51 (m, 9H), 1.29-1.44 (m, 4H), 1.06-1.19 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C@H:51]1([NH2:58])[CH2:56][CH2:55][C@@H:54]([NH2:57])[CH2:53][CH2:52]1>CN(C=O)C.CCOC(C)=O>[NH2:57][C@@H:54]1[CH2:55][CH2:56][C@H:51]([NH:58][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:22])[CH2:52][CH2:53]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: N[C@H]1CC[C@@H](N)CC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](N)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (91 mg, 0.24 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (33 mg, 0.240 mmol), and N,N-diisopropylethylamine (38 μl, 0.22 mmol) were combined with DMF (4 ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 45 min. In a 20 mL round-bottomed flask, cis-cyclohexane-1,4-diamine (249 mg, 2.18 mmol) was dissolved in 0.4 mL DMF to give a colorless solution. The carboxylic acid reaction mixture was added dropwise to the amine solution. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (−50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography over SiO2 with 0% to 10% MeOH in DCM with 0.1% NH4OH to afford 86 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-4-amino-cyclohexyl)amide as a white solid. MS: [M+H]+=554.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:21]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CCOC(C)=O.CCCCCC.CCOC(C)=O>CO>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH2:12][C@H:11]1[CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]#[CH:23])[CH:21]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#C[Si](C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Reaction time: 1.75 h

Procedure:
In a 50 mL round-bottom flask with stir bar, a solution of KOH (174 mg) in methanol (4 mL) was added to a solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(trimethylsilyl)ethynyl]pyridine (560 mg, 1.55 mmol) in methanol (1 mL). The flask was loosely closed with a rubber stopper, and the mixture was stirred at room temperature for 3 h. A TLC taken after 105 min (silica gel, EtOAc/hexane 55:45) showed traces of starting material (Rf 0.6) and a new spot (Rf 0.5). The mixture was evaporated and the residue directly chromatographed on silica gel (24×2.5 cm, EtOAc/hexane 1:1). The product-containing fractions were evaporated, and the residue was dried (35° C./14 torr) to obtain 473 mg (nominally 106%) of the product, an orange-brown oil which darkened upon standing and appeared to be too unstable for more stringent drying. The excess mass balance was represented by EtOAc as shown by 1H NMR. The material was suitable in this form for the subsequent reaction. 1H NMR (CDCl3, TMS, 250 MHz) δ 8.36-8.29 (m, 2H), 7.33 (dd, 1H, J=1.6, 2.7 Hz), 4.51 (m, 1H), 4.34 (m, 1H), 4.13 (dd, 1H, J=2.9, 10.1 Hz), 3.89 (t, 2H, J=7.6 Hz), 3.20 (s, 1H), 2.43-2.20 (m, 2H), 1.43 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 156.0, 154.3 (br), 145.1, 138.4, 123.5, 119.3 (br), 80.4, 80.0, 79.7, 68.7, 59.9, 47.0 (br), 28.3, 18.9.