Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([O-])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[N:26]1(OC(N(C)C)=[N+](C)C)[C:30]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN>CN(C)C=O>[CH3:30][NH:26][C:16]([C:14]1[CH:13]=[CH:12][C:10]2[O:11][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:9]=2[CH:15]=1)=[O:17]
Reactant: O=C([O-])c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a suspension of 23.0 g of lithium 2,2-diphenyl-1,3-benzodioxole-5-carboxylate in 200 ml of dimethylformamide were added 27.0 g of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium-hexafluorophosphate. The mixture was stirred at 20° C. for 2 hours, then 25 ml of methylamine were added, and stirring was continued for another 2 hours. The mixture was partitioned between ethyl acetate and water, the organic layer was washed successively with 2N potassium hydrogensulfate solution, saturated sodium carbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the solid residue was crystallized from ethanol to give 15.6 g of N-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide, m.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@H:5]1[CH2:10][C@@H:9]([CH:11]=CC2C=CC=CC=2)[O:8][C:7]([CH3:20])([CH3:19])[O:6]1.[O:22]=[O+][O-]>CO>[CH3:20][C:7]1([CH3:19])[O:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[CH2:10][CH:9]([CH:11]=[O:22])[O:8]1
Reactant: COC(=O)C[C@H]1C[C@@H](C=Cc2ccccc2)OC(C)(C)O1
Reactant: O=[O+][O-]
Solvent: CO
Product: COC(=O)CC1CC(C=O)OC(C)(C)O1
Temperature: 25 °C

Procedure:
Cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid methyl ester (prepared in Example 133) was dissolved in methanol (10 mL) and ozone was passed through the solution at -78° C. until the color of the solution turned blue. The reaction mixture was purged with nitrogen to remove excess ozone then dimethyl sulfide was added and the temperature was allowed to warm up to room temperature. The reaction was evaporated in vacuo and the residual oil was purified by chromatography on silica gel using diethyl ether-hexane (3:1) as the eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.FC1C(B(O)O)=CC=CN=1.C([O-])(=O)C.[K+].CN(C=O)C>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.O>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[CH:2][CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: OB(O)c1cccnc1F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 105 °C
Yield: 106.1 %

Procedure:
10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 (0.057 g, 0.15 mmol), 2-fluoropyridin-3-ylboronic acid (0.026 g, 0.183 mmol), potassium acetate (0.059 g, 0.609 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.007 mmol), DMF (6 mL) and water (0.6 mL) were mixed. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir and heat at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 1042-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (47 mg, 80%). MS (ESI(+)): m/z 391.1 (M+H)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:13]=[C:14]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[C:15]4[O:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>CO>[OH:31][N:30]=[C:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:14]2[C:15]3[O:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10]([C:2]([CH3:1])=[N:3][NH:4]4)=[CH:9][CH:8]=3)[N:13]=2)[CH2:22][CH2:23]1)[NH2:28]
Reactant: Cc1n[nH]c2cc(Nc3nc(N4CCC(C#N)CC4)c4occc4n3)ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1n[nH]c2cc(Nc3nc(N4CCC(C(N)=NO)CC4)c4occc4n3)ccc12
Temperature: 70 °C
Reaction time: 120 h
Yield: 22.4 %

Procedure:
A mixture of 1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidine-4-carbonitrile (0.082 g, 0.22 mmol), hydroxylamine hydrochloride (0.061 g, 0.88 mmol) and NaHCO3 (0.15 g, 1.7 mmol) in MeOH (20 mL) was stirred at about 70° C. for about 120 h. The solvent was removed and the residue was purified by preparative HPLC (Table 2, Method p) to give N′-hydroxy-1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidine-4-carboximidamide (0.020 g, 22%): LC/MS (Table 2, Method h) Rt=1.66 min; MS m/z: 407 (M+H)+. Syk IC50=B
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:14])[C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:14])[C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[CH2:5][NH2:6]
Reactant: CCCNc1c(Cl)cc(C#N)cc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1c(Cl)cc(CN)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
Step AR3. To crude 3-chloro-5-bromo-4-(propylamino)-benzonitrile (450 mg, 1.65 mg) in dry THF (15 mL) was added lithium aluminum hydride (200 mg, 5.3 mmol) in portion. After stirred at RT for 3 hours, sodium sulfate decahydrate (1.7 g, 5.3 mmol) was added in portion and the mixture was stirred for 30 minutes. The solid was filtered off and the filtration was added to a silicon gel column and trapped there for 24 hours. Flash chromatography with DCM, then 20% MeOH in DCM, then 50% MeOH in DCM gave 3-chloro-5-bromo-4-(propylamino)-benzylamine (121 mg, 26.4%). 1H NMR (CD3OD): δ 1.04 (t, 3H), 1.66 (m, 2H), 3.34 (t, 2H), 3.80 (s, 3H), 7.43 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH2:8])([O-:4])=[O:3].[OH-].[Na+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].Cl.NC(C)C(O)=O>O.C(O)C>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:8][CH2:17][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])([O-:4])=[O:3]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: C=CC(=O)OCC
Agent: CC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCNCc1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
o-Nitrobenzylamine hydrochloride (20.4 g., 0.114 mole) was dissolved in a minimum volume of water and the solution was made strongly basic by addition of 10% sodium hydroxide. The clear oil which formed was extracted into two 120-ml. portions of ether. The ether was dried with 10 g. of anhydrous sodium sulfate, filtered, and finally dried over Drierite. The dried solution was filtered and evaporated, leaving a yellow oil. The oil was dissolved in 100 ml. of absolute ethanol and 11.4 g (0.114 mole) of freshly distilled ethyl acrylate was added. This solution was allowed to stand overnight and the solvent removed by distillation from a steam-cone. The oily residue was dissolved in 200 ml. of dry ether, the solution was cooled in an ice bath, and treated with dry hydrogen chloride. When precipitation was complete, the solid was filtered and dissolved in 120 ml. of boiling absolute ethanol. The hydrochloride crystallized from this solution on cooling yielding 20.7 g. of the aminopropionate hydrochloride, m.p. 137.5°-139.0°. By concentrating and cooling the mother liquor, an additional 5 g. was obtained, m.p. 136.5°-138.5°, and by repeating this operation 1.1 g., m.p. 136°-139°, was obtained, raising the total yield to 26.8 g. (81.4%). The analytical sample was prepared by repeated crystallization from absolute ethanol to give a melting point of 138.5°-139.0°.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]3[C@@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:21]4[C@@H:20]([CH2:28][OH:29])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN(CC)CC.Cl[S:38]([NH2:41])(=[O:40])=[O:39].C(#N)C>C(Cl)Cl>[S:38](=[O:40])(=[O:39])([O:29][CH2:28][C@@H:20]1[C@@H:21]2[C@@H:22]([O:23][C:24]([CH3:26])([CH3:27])[O:25]2)[C@H:18]([NH:17][C:13]2[CH:12]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[N:16]=[CH:15][N:14]=2)[CH2:19]1)[NH2:41]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](COS(N)(=O)=O)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methanol (100. mg, 0.252 mmol) and Et3N (0.0527 mL, 0.378 mmol) in DCM (2.50 mL) was added dropwise a 2.00 M solution of chlorosulfonamide in ACN (0.190 mL, 0.380 mmol) at 0° C. and the mixture was stirred for 2 h. The reaction was diluted with DCM, quenched with H2O and the organic layer was separated, then concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (65.0 mg, 54%). LC/MS: Rt=1.58 min, ES+ 476 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:20]=[CH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:5][C:4]=2[N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1cnc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c21
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(CCS(C)(=O)=O)ccc3c21
Temperature: 50 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.1 g), methanol (50 mL) and 1-{4-amino-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (380 mg, 1.05 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 18 hours. The reaction was cooled to ambient temperature, filtered, and then concentrated under reduced pressure. The resulting crude product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-35% gradient of CMA in chloroform) followed by recrystallization from acetonitrile to provide 176 mg of 1-{4-amino-7-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as an off-white solid, mp 269-271° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8](C(O)=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)CCC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([NH2:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCCO
Product: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (12.5 g, 38.3 mmol) in tent-butanol (250 mL) were added triethylamine (5.5 mL, 40 mmol) and diphenylphosphoryl-azide (8.6 mL, 40 mmol). The reaction mixture was stirred at 95° C. for 16 hours, then allowed to cool down to RT, and concentrated in vacuo. The resultant residue was dissolved in EtOAc, washed successively with water, aqueous saturated sodium bicarbonate solution followed by brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (150 mL) and treated with TFA (50 mL). The reaction mixture was stirred at RT for 3 hours then concentrated in vacuo. The resulting residue was triturated with 20% EtOAc/cyclohexane and filtered to afford 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine as an off-white solid (7.94 g, 70%). LCMS: RT=3.13 min, [M+H]+=297/299
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC1CCNCC1

Procedure:
1.5 g 10% Pd/C were added to a solution of 13.9 g (56.0 mmol) (1-benzyl-piperidin-4-yl)-tert-butyl-amine in 140 mL MeOH and the reaction mixture was hydrogenated at RT until the theoretical uptake of H2 had been achieved (2 h). After the catalyst had been removed by suction filtering and the solvent was eliminated, the desired product was obtained, which was farther reacted without being purified.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.Br[CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:14][C:13]([O:15][CH2:26][CH2:27][N:28]3[C:29](=[O:38])[C:30]4[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:33])=[C:12]([CH:11]=2)[C:16]#[N:17])=[CH:23][CH:22]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 70 °C

Procedure:
To the product of Step B Example 19 (600 mg, 1.597 mmol) was added N-(2-bromoethyl)-phthalimide (690 mg, 2.715 mmol), K2CO3 (331 mg, 2.396 mmol) and DMF (8 mL). The mixture was heated to 70° C. for 20 hours. The mixture was filtered, concentrated and passed through a short plug of silica gel eluting with 33% ethyl acetate/hexane. The partially purified material was carried on without further purification. MS (electrospray) m/e 547.8 MH+ (retention time=4.4 min LC/MS).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:54]1[N:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][CH:55]=1)CCC>CN(C=O)C.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>[C:42]([O:41][C:40]([NH:39][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH2:10][C@@H:11]([NH:20][C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:54]2[CH:55]=[CH:56][CH:57]=[C:58]([O:60][CH3:61])[N:59]=2)=[CH:17][CH:18]=1)=[O:46])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc(C[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1

Procedure:
A solution containing the product from Example 92D (0.20 g, 0.28 mmol) in DMF (3 mL) was treated with LiCl (0.119 g, 2.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and the product from Example 113A (0.336 g, 0.84 mmol), heated at 100° C. for 16 hours, cooled, filtered through celite®, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:50][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:22])([CH2:16][CH2:17]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCCCCCCN
Product: CCCCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and heptylamine (20.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-heptylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (42.9 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34](C(C)C)[CH:35]([CH3:37])[CH3:36])C.CC(N)C>CN(C=O)C>[CH:35]([NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:37])[CH3:36]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and propan-2-amine (11.5 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 64.8 mg (65%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 9.93 (br. s., 1H), 8.64 (d, J=2.0 Hz, 1H), 8.02-8.11 (m, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.43-4.63 (m, 3H), 4.25 (s, 2H), 4.07 (dd, J=14.1, 6.6 Hz, 1H), 3.93-4.02 (m, 1H), 3.37-3.55 (m, 1H), 2.96-3.25 (m, 4H), 2.68 (td, J=12.9, 2.5 Hz, 1H), 2.02-2.11 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.72 (m, 4H), 1.14 (d, J=6.8 Hz, 6H). [M+H] calc'd for C25H33N7O2, 464. found, 464.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc(Br)c1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12c and 3-bromoanisole
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C@H:7]2[NH:14]C(=O)OC(C)(C)C.CO.Cl>O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C@H:7]2[NH2:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2c1ccc(F)c2Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1(C)C[C@@H](N)c2ccc(F)c(Cl)c2O1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
The crude (R)-tert-butyl 8-chloro-7-fluoro-2,2-dimethylchroman-4-ylcarbamate (4.47 g, 13.5 mmol), MeOH (36 mL), and concentrated HCl (4 mL) were heated to 50° C. After 2 h, complete deprotection observed by LCMS. The reaction mixture was cooled, stirred for 8 h, then diluted with methyl tert-buthy ether (60 mL) and water (40 mL). The mixture was partitioned and the organic layer was extracted with water (50 mL). The aqueous layer was basified with 2N NaOH (40 mL) and extracted with dichloromethane (2×40 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated to give the title compound (2.87 g, 12.50 mmol, 92% yield). MS (ESI+) m/z 230 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si]([O:29][C:30]1[CH:63]=[CH:62][C:33]([C:34]([NH:36][NH:37][C:38](=O)[C@H:39]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=2[CH3:60])[C@H:40]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH3:41])=[O:35])=[CH:32][C:31]=1[Cl:64])(C(C)(C)C)(C)C>C(Cl)Cl>[Si:43]([O:42][C@H:40]([CH3:41])[C@@H:39]([NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=1[CH3:60])[C:38]1[O:35][C:34]([C:33]2[CH:62]=[CH:63][C:30]([OH:29])=[C:31]([Cl:64])[CH:32]=2)=[N:36][N:37]=1)([C:46]([CH3:48])([CH3:47])[CH3:49])([CH3:44])[CH3:45]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 106.6 %

Procedure:
To a 25 mL round bottom flask was added polymer supported triphenylphosphine (687 mg, 2.06 mmol, 2.0 equiv., approx. 3 mmol/g) and 10.3 mL of methylene chloride. The reaction was cooled to 0° C. using an ice-water bath and then iodine (523 mg, 2.06 mmol, 2.0 equiv.) was added followed by TEA (0.57 mL, 4.12 mmol, 4.0 equiv.). After stirring for 5 min, 4-(tert-butyldimethylsilyloxy)-N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-3-chloro benzohydrazide (688 mg, 1.03 mmol, 1.0 equiv.) was added. The reaction was allowed to stir at room temperature for 2 h. The mixture was filtered over Celite® in a ground glass fitted funnel and the solids rinsed with methylene chloride several times. The organics were washed with 10% Na2S2O3 (3×10 mL) followed by a wash with brine (1×10 mL). The solution was dried over Na2SO4 and was concentrated in vacuo to yield a brown oil. The product was purified via automated flash chromatography (0→30% EtOAc/hexanes 100% EtOAc, 40 g of silica gel) to provide the desired product as a yellow oil (586 mg, 88% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.92 (d, J=2.14 Hz, 1H), 7.80 (dd, J=1.95, 8.4 Hz, 1H), 7.50 (d, J=8.79 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.79 Hz, 1H), 5.79 (d, J=9.18 Hz, 1H), 5.02 (dd, J=6.65, 9.19 Hz, 1H), 4.65 (m, 1H), 2.34 (s, 3H), 1.41 (d, J=6.05 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H); LRMS (ESI−) exact mass calcd for C25H30Cl2N4O3Si [M]+ 533.5, found 534.2.