Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.OC(C(F)(F)F)=O.[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57](OC(C)(C)C)=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:47]5[CH2:48][CH2:49][CH:43]4[CH2:44][N:45]([CH3:50])[CH2:46]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:64][CH:65]([S:67]([NH2:70])(=[O:69])=[O:68])[CH3:66].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57]([NH:70][S:67]([CH:65]([CH3:66])[CH3:64])(=[O:69])=[O:68])=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:43]5[CH2:49][CH2:48][CH:47]4[CH2:46][N:45]([CH3:50])[CH2:44]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)S(N)(=O)=O
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Temperature: 60 °C
Yield: 14.7 %

Procedure:
CDI (80 mg, 0.49 mmol) was added to a solution of tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate TFA (200 mg, 0.30 mmol) in THF (1.5 mL) and the reaction mixture was heated at 60° C. for 2 h. The reaction was cooled to rt and then ⅓ (˜0.55 mL) of the reaction solution was added to a stirring solution of propane-2-sulfonamide (40 mg, 0.33 mmol) in DBU (0.20 mL, 1.3 mmol) and THF (0.20 mL). The reaction was stirred at rt ON (complete by LCMS), concentrated to an oil, quenched with 1N HCl (˜1 mL) (prec. formed) and extracted with EtOAc (2×1 mL). The combined organics wee concentrated to dryness, dissolved into MeOH (1.5 mL) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (28.5 mg, 0.044 mmol, 43% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ ppm 1.13-2.77 (m, 28H), 2.80-2.93 (m, 1H), 3.93 (s, 3H), 3.90-4.02 (m, 1H), 4.27-4.65 (m, 2H), 5.11-5.31 (m, 1H), 7.04 (s, 1H), 7.11 (d, J=2.6 Hz, 1H), 7.16 (dd, J=8.4, 2.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.67 (dd, J=8.4, 1.5 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 8.18 (br s, 1H). LC-MS retention time: 2.55 min; m/z 643 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:14]([O:15][Si](C(C)(C)C)(C)C)[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:31]([C:33]2[C:42]([NH:43]C(=O)OCC3C=CC=CC=3)=[CH:41][C:40]3[C:35](=[CH:36][C:37]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[CH:38][CH:39]=3)[N:34]=2)=[O:32])[CH2:10]1)=O)(C)(C)C.[H][H]>CO.[Pd]>[NH2:43][C:42]1[C:33]([C:31]([NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([OH:15])[C@H:9]([NH2:8])[CH2:10]2)=[O:32])=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)[CH:36]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-morpholin-4-ylquinolin-3-yl]carbamate (0.0035 g, 0.0042 mmol) in 3 mL of MeOH was hydrogenated under a balloon of hydrogen, in the presence of 3 mg of 10% Pd on carbon, at room temperature for 1 h. The reaction mixture was diluted with 5 mL of MeOH then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was treated with 2 mL of MeOH and 2 mL of 4 M HCl in dioxane at room temperature for 1 h. The volatile solvents were removed under reduced pressure. The residue was dissolved in 4 mL of MeOH and treated with 0.5 mL of NH4OH solution, then filtered. The filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H32N7O3 [M+H]+: m/z=478.3. found: 478.3.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][O:28][CH3:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:8][CH2:7]1)C.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:29][O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:37])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of ethyl{2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (1.04 g), 1M aqueous sodium hydroxide solution (6 mL), tetrahydrofuran (10 mL), and ethanol (10 mL) was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (700 mg, yield 71%) as a white amorphous solid.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[NH2:16][NH2:17]>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:10][CH:11]([C:12]([OH:14])=[O:13])[NH:17][N:16]=1
Reactant: O=C(O)C=CC(=O)c1ccccn1
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(c2ccccn2)=NN1

Procedure:
Potassium hydroxide (3.29 g) is dissolved in 250 ml of methanol and 8.85 g of 4-(2-pyridyl)-4-oxo-2-butenoic acid is added. Hydrazine (1.6 g) is then added and the solution is heated at reflux temperature for 5 hours. Solvent is removed in vacuo and the residue is dissolved in 50 ml of water and treated with 3.0 g of acetic acid yielding the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:15](O)=[O:16])[N:10]=[C:9]1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:32]([O:39][C:40](=[O:53])[C@H:41]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH2:32]([O:39][C:40](=[O:53])[C@H:41]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[NH:42][C:15](=[O:16])[CH:14]([C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[CH:19]=1)[CH2:13][C:11]1[N:10]=[C:9]([CH2:27][CH2:28][CH2:29][CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CCCCc1nc(CC(C(=O)O)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC(C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)OCc2ccccc2)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 30.1 %

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionic acid (250 mg), L-tryptophan benzyl ester hydrochloride (209 mg) and triethylamine (128 mg) in N,N-dimethylformamide (5 ml) was added diphenylphosphoryl azide (198 mg) and the mixture was stirred at ambient temperature for 5.5 hours. The resulting mixture was diluted with ethyl acetate and the organic layer was washed successively with 0.5N hydrogen chloride aqueous solution, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of the solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; n-hexane:ethyl acetate=1:2) to give [3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan benzyl ester (125 mg) as a yellow oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][S:24]([CH3:39])(=[N:26]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)=[O:25])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C.O.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][S:24]([CH3:39])(=[NH:26])=[O:25])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1OCCCS(C)(=O)=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1OCCCS(C)(=N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
Ethyl 4-(isopropylamino)-7-[(RS)-3-{S-methyl -N-[(4-nitrophenyl)sulphonyl]-sulphonimidoyl}propoxy]quinazoline-6-carboxylate (270 mg, 0.47 mmol) is dissolved in acetonitrile (7 ml), treated with caesium carbonate (276 mg, 0.85 mmol) and thiophenol (90 mg, 0.82 mmol) and stirred at room temperature for 20 hours. The reaction batch is diluted with water and methylene chloride. The organic phase is separated off and dried over sodium sulphate. The desired product is obtained after removal of the solvent, preparative HPLC and subsequent repeated trituration of the residue in 45% yield (83 mg).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13](N)=[CH:12][CH:11]=2.Cl.S(=O)(=O)(O)[OH:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][O:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2
Reactant: COc1cnc2ccc(N)cc2c1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COc1cnc2ccc(O)cc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of sodium nitrite (3.49 g, 50.5 mmol, 1.1 eq) in water (20 mL) is added dropwise at 0° C. to a stirred solution of 3-methoxy-quinolin-6-ylamine (8.0 g, 45.9 mmol, 1.0 eq) in hydrochloric acid (160 mL, 321.3 mmol, 7.0 eq). The mixture is stirred at 0° C. for 2 hours before its addition to a vigorously stirred solution of 10% sulfuric acid (600 mL) at 85-90° C. within 20 minutes. The resulting solution is stirred at 90° C. for 1 hour, cooled down to room temperature, neutralized with sodium carbonate and extracted with ethyl acetate (3×250 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:triethylamine, 3:1:0.1, v/v/v) to afford 3-methoxy-quinolin-6-ol as a red solid (2.9 g, 34% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18]#[N:19].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:18]([CH2:17][N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])#[N:19]
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCN1CC(NC(=O)Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 11.6 %

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (408 mg.) and 2-chloroacetonitrile (152 mg.) was dissolved in N,N-dimethylformamide (15 ml.), and to the solution was added sodium hydride (50% oily) (105 mg.) under stirring at ambient temperature, whereafter the reaction mixture was stirred for an hour at room temperature, and ethyl acetate (100 ml.) was added to the reaction mixture. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off from the solution under reduced pressure. The oily residue (0.25 g.) obtained was subjected to column chromatography using silica gel. 1-Cyanomethyl-3-(2-phenylacetamido)-2-azetidinone (56.3 mg.) was obtained from fractions eluted with chloroform. Mp 108° to 109° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=[O:14])[CH2:9][CH2:8]1)=[O:2].C(O)([C:25]([F:28])([F:27])[F:26])=O>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:13]([N:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=2)[CH:1]=[O:2])[CH2:8][CH2:9]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C=O)c2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cccc(OC2CCN(C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-(3-formylphenoxy)piperidine-1-carboxylate (61) (5.55 mmol) was taken in DCM and cooled to 0° C. when TFA (5 ml) was added drop wise and then stirred at rt for 16 h when TLC confirmed completion of reaction. The reaction mixture was concentrated and used directly for the next step. White solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 36.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (150 mg, 0.52 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (208 mg, 0.63 mmol) using Pd(PPh3)2Cl2 (18 g, 1.56 mol) and sodium carbonate (165 mg, 1.56 mmol) in toluene/ethanol/water (10/10/2 ml) to afford 140 mg (83.6% yield) of the titled compound. MS: m/z=677.2 (M+1) (de t-butyl).
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:19][C@H:20]([C:22]([N:24]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:19][C@H:20]([C:22]([N:24]([CH:29]1[CH2:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37]1)[CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
In 6 ml of 1N aqueous sodium hydroxide is dissolved 0.25 g of N-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine.dihydrobromide, and the solution is allowed to stand at room temperature for 30 minutes. The reaction is made weakly acidic with acetic acid and purified by column chromatography on Amberlite XAD-2 (0.1M aqueous ammonia-5% acetonitrile). The effluent is concentrated under reduced pressure and lyophilized to give 0.11 g of N-[N-[(S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1.CN(C)CCN.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[N:14]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Br:19])[N:21]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1c1cccc(Br)n1
Temperature: 120 °C
Reaction time: 48 h
Yield: 40.7 %

Procedure:
Copper (I) iodide (0.047 g, 0.25 mmol) was added to a stirred suspension of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.3 g, 1.23 mmol), 2,6-dibromopyridine (0.58 g, 2.46 mmol), N,N-dimethylethylenediamine (0.08 mL, 0.74 mmol) and K2CO3 (0.34 g, 2.46 mmol) in toluene (12 mL). The reaction mixture was stirred at 120° C. for 48 hours. Then 2,6-dibromopyridine (0.146 g, 0.62 mmol), The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with pentane to yield 2-(benzyloxy)-5-(6-bromopyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.20 g, 39% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:21]([F:24])([F:23])[F:22])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.Cl[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N+:27]=1[O-:32].Cl.[H-].[Na+].[OH-].[Na+].[Cl-].[Na+]>CS(C)=O.C(OCC)(=O)C.CO.C(OCC)(=O)C>[CH3:1][C:2]1([C:21]([F:24])([F:22])[F:23])[CH2:7][N:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N+:27]=2[O-:32])[C:5]2[CH:8]=[C:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C(F)(F)F)CNc2cc(S(=O)(=O)c3ccccc3)ccc2O1
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CO
Product: CC1(C(F)(F)F)CN(c2cccc[n+]2[O-])c2cc(S(=O)(=O)c3ccccc3)ccc2O1
Reaction time: 18 h

Procedure:
A solution of 2-methyl-2-trifluoromethyl-6-phenylsulfonyl-3,4-dihydro-2H-1,4-benzoxazine (200 mg) and 2-chloropyridine N-oxide.HCl (121 mg;) in dimethylsulfoxide (8 mL) was treated with sodium hydride (60% dispersion in oil, 58 mg), and stirred under a nitrogen atmosphere for 18 hours. The mixture was then poured into a solution containing aqueous sodium hydroxide (0.5N, 150 mL) and saturated sodium chloride (20 mL.) and extracted with ethyl acetate. (3×150 mL). The combined organic portions were washed with aqueous sodium hydroxide (0.5N, 30 mL) and saturated sodium chloride (5 mL) and evaporated to yield a black semi-solid. Chromatography of this solid on silica gel eluting with ethyl acetate then ethyl acetate/methanol (97:3) yielded the title compound (110 mg) as a white solid; mp 192°-193° C.; NMR (250 MHz, d6-DMSO): 1.55 (s,3), 3.98 (dd,2), 6.81 (s,1), 7.20 (d,1), 7.40 (dd,1), 7.45 (m,2), 7.62 (m,4) 7.85 (dd,2), 8.42 (d,1); MS: m/z=451(M+1). Analysis for C21H17F3N2O4S: Calculated: C, 56.00; H, 3.78; N, 6.22; Found: C, 56.10; H, 3.88; N, 6.02.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.8 %

Procedure:
Following general procedure II, (R)-tert-butyl(1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (175 mg, 0.34 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (140 mg, 0.51 mmol) to afford the desired product (120 mg, 57%) as a solid: ESI MS m/z 621 [M+H]+.
Reaction SMILES: O.[Na].[N+:3]([CH:6]([CH:9]=O)[CH:7]=O)([O-:5])=[O:4].[NH2:11][C:12]1[N:16]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:15]=[C:14]([OH:27])[CH:13]=1.FC1(F)C[C@H]1C1C2C(=NC=C(NC(=O)C3C(F)=CC=C(NS(CCC)(=O)=O)C=3F)C=2)NN=1>C(O)(=O)C.O>[N+:3]([C:6]1[CH:7]=[C:13]2[C:14]([OH:27])=[N:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:12]2=[N:11][CH:9]=1)([O-:5])=[O:4]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2nc(O)cc2N)cc1
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc([C@@H]4CC4(F)F)c3c2)c1F
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2nc(O)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 50 °C
Yield: 63.8 %

Procedure:
Nitromalonaldehyde sodium salt monohydrate (3.57 g, 22.7 mmol) was added to suspension of 5-amino-1-tosyl-1H-pyrazol-3-ol (5.00 g, 19.7 mmol; see Elgemeie, Galal H., et al. “Novel Synthesis of 5-Amino-1-arylsulfonyl-4-pyrazolin-3-ones as a New Class of N-Sulfonylated Pyrazoles.” J. Chem. Res. (S). Issue 6 (1999): pp. 384-385) in acetic acid (30 mL). The mixture was heated at 50° C. for 4 hours. The partial suspension was allowed to cool and diluted with water. The resulting solid was collected by vacuum filtration and dried under high vacuum to afford 5-nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-ol (4.21 g, 12.6 mmol, 63.8% yield) as a solid.