Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:3]1.[NH2:19][C:20]1[N:24](C(OC(C)(C)C)=O)[N:23]=[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)[CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([CH2:33][CH2:32][C:22]2[CH:21]=[C:20]([NH:19][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][CH:6]([CH3:8])[NH:7][CH:2]([CH3:1])[CH2:3]4)=[CH:18][CH:17]=3)[NH:24][N:23]=2)[CH:35]=[C:36]([O:42][CH3:43])[CH:37]=1
Reactant: COC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CC(C)NC(C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 10.5 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide was prepared as for Example 94, but starting from methyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol ), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 34-54% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (34 mg, 10%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.04 (6H, d), 2.22 (2H, t), 2.53 (2H, d), 2.82 (2H, t), 2.87 (4H, s), 3.71 (1H, s), 3.73 (7H, s), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.94 (2H, d), 7.89 (2H, d), 10.27 (1H, s), 12.07 (1H,s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:27])=[C:6]([C:23]([F:26])=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)[C:12](=[O:14])[CH:13]=1)[CH3:2].[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH:40][C:16](=[O:18])[CH:15]([N:11]3[C:12](=[O:14])[CH:13]=[C:8]([O:7][C:6]4[C:23]([F:26])=[CH:24][CH:25]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:27])[CH:9]=[N:10]3)[CH2:19][CH:20]([CH3:21])[CH3:22])=[N:36]2)[CH2:31][O:30]1
Reactant: CCOc1ccc(F)c(Oc2cnn(C(CC(C)C)C(=O)O)c(=O)c2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CCOc1ccc(F)c(Oc2cnn(C(CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1F

Procedure:
Using the method described in Example 49, 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 92) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as an off-white solid as a mixture of diastereoisomers (164 mg, 78%).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])[CH2:4][CH:5]=[CH:6][C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].OCC1C=C(C=CC=1)C=O.Cl.C(NC/C=C/C#CC(C)(C)C)C.OCC1OC(C=O)=CC=1.Cl.C(NC/C=C/C#CC(OC)(C)C)C.[OH-].[K+]>>[CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:4][CH:5]=[CH:6][C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc(CN(CC)CC=CC#CC(C)(C)C)c1
Agent: CCNC/C=C/C#CC(C)(C)C
Agent: CCNC/C=C/C#CC(C)(C)OC
Agent: Cl
Product: CCN(CC=CC#CC(C)(C)C)Cc1cccc(/C=C/C(=O)O)c1

Procedure:
When ethyl (E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)cinnamate, prepared by using 3-hydroxymethylbenzaldehyde and (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride instead of the starting 5-hydroxymethyl-2-furaldehyde and (E)-N-ethyl-6-methoxy-6-methyl-2-hepten-4-ynylamine hydrochloride as in Referential Example 46, is hydrolyzed with potassium hydroxide, (E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl) cinnamic acid is obtained.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:28][N:14]3[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@H:13]3[CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO>[OH:10][C@@H:11]1[CH2:28][N:14]2[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:19][C@H:13]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@@H]2C1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
tert-Butyl (8S,9aR)-8-[(4-nitrobenzoyl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (156 mg, 0.372 mmol, 1.0 equivalent, Part E) was dissolved in methanol (3 mL). Potassium carbonate (20 mg, 0.145 mmol, 0.39 equivalent) was added and stirring was continued at room temperature for 30 minutes. The solvent was removed in vacuo, and the crude material was loaded onto a 12-g silica column with dichloromethane and eluted with 0-5% methanol:dichloromethane over 15 minutes, held at 5% methanol:dichloromethane for five minutes, then eluted with 10% methanol:dichloromethane for 10 minutes to afford the titled compound (65 mg, 0.240 mmol, 64.6% yield over two steps) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 4.44 (t, J=3.7 Hz, 1H), 4.39-3.86 (m, J=79.8 Hz, 2H), 4.06 (dt, J=17.5, 8.9 Hz, 1H), 3.83 (dd, J=13.2, 2.3 Hz, 1H), 3.51 (dd, J=13.2, 3.7 Hz, 1H), 3.35-2.96 (br s, 1H), 2.74-2.46 (m, 3H), 2.24 (dd, J=13.2, 6.0 Hz, 1H), 1.74 (ddd, J=12.0, 9.0, 3.0 Hz, 1H), 1.48 (s, 9H); MS (ESI+) m/z 270.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](Br)[N:3]=1.[NH3:11]>>[Br:1][C:2]1[N:3]=[C:4]([NH2:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)nc(Br)c1
Reactant: N
Product: COc1cc(N)nc(Br)c1

Procedure:
A solution of 2.00 g 2,6-dibromo-4-methoxy-pyridine in 80 g liquid ammonia under was heated in an autoclave to 140° C. for 4 h. The reaction was cooled to room, evaporated and the residue was purified by silica column chromatography to yield 0.457 g of the title compound as white solid. MS (ISP) M+H+=203.2 205.5
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([CH2:23][NH:24]C(=O)OCC3C=CC=CC=3)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:35])=[CH:13][CH:14]=2)[N:9]=1>[Pd].CO>[NH2:24][CH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:35])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Yield: 19.7 %

Procedure:
A solution of benzyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.19 g, 0.41 mmol) and MeOH (5 mL) was stirred with Pd/C (20 mg, 10% weight of Pd on carbon) under an H2 atmosphere at ambient pressure at ambient pressure overnight. Purification via silica gel chromatography using MeOH in CH2Cl2 (0-10%) gave 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (27 mg, 19%). LC/MS: m/z 335.5 (M+H)+ at 1.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]1([NH:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:10]([OH:13])([OH:12])[OH:11].P(Cl)(Cl)Cl.CC(C)=O>O>[CH:1]1([NH:7][CH:8]([P:10]([OH:13])(=[O:11])[OH:12])[P:10]([OH:13])(=[O:12])[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OP(O)O
Reactant: O=CNC1CCCCC1
Solvent: CC(C)=O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(NC1CCCCC1)P(=O)(O)O
Yield: 25 %

Procedure:
127.2 parts of N-cyclohexylformamide and 81 parts of phosphorous acid were reacted with 137.3 parts of phosphorus trichloride at 70°C, and maintained for 5 hours at this temperature. The reaction product was dissolved in water, treated with acetone and the precipitate separated. A 25% yield of N-cyclohexyl-1-aminomethane-1,1-diphosphonic acid, based on PCl3, was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:23].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:23]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccn1
Yield: 77.4 %

Procedure:
A mixture of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole (216 mg, 0.68 mmol) and Cs2CO3 (550 mg; 1.69 mmol) in 5 mL DMF was treated with methyl bromoacetate (0.08 mL; 0.85 mmol). The reaction was stirred until tlc analysis indicated complete consumption of starting material (2 hours). The mixture was concentrated and the residue taken up in H2O (50 mL). The aqueous layer was saturated with solid NaCl and was extracted five times with THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The solid was triturated with EtOAc to afford 205 mg (77%) of the {9-[(2-pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as an off white solid. 1H NMR (DMSO-d6) δ 8.47 (d, 1H, J=4.9 Hz), 7.66-7.57 (m, 2H), 7.48 (br s, 1H), 7.38-7.27 (m, 2H), 7.24-7.19 (m, 2H), 7.19 (br s, 1H), 7.04 (d, 1H, J=7.3 Hz), 6.87 (d, 1H, J=7.8 Hz), 6.56 (d, 1H, J=7.8 Hz), 5.71 (s, 2H), 4.89 (s, 2H), and 3.69 (s, 3H). IR (CHCl3, cm−1) 3380, 3140, 1737, 1675, 1500, 1457, 1354, 1340, 1242, 1158, 772, and 715. MS (ES) m/e 390 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]#[N:45])[CH:39]=2)[CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:34])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:44]([C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][N:15]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:18][CH2:17]1)[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:46])=[O:5])=[CH:10][CH:11]=1)#[N:45]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OCC(=O)OC(C)(C)C)cc2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a solution of COMPOUND 143 in CH2Cl2 (2 mL) was added anisole (0.1 mL, 0.92 mmol) followed by TFA (2 mL) and the solution was stirred at room temperature for 90 minutes to afford COMPOUND 149 as a white solid (200 mg, 52%) after a basic work-up and purification. 1H NMR (CD3OD) δ 1.29 (d, 3H, J=6.3 Hz), 1.76-1.89 (m, 5H), 2.07-2.28 (m, 1H), 2.28 (s, 6H), 2.86-3.03 (m, 2H), 3.19-3.27 (m, 3H), 3.37-3.51 (m, 2H), 3.67-3.75 (m, 1H), 4.19 (s, 2H), 4.24 (s, 2H), 6.76 (s, 4H), 7.02 (d, 2H, J=7.5 Hz), 7.11-7.16 (m, 1H), 7.36-7.41 (m, 1H), 7.48-7.55 (m, 3H). 13C NMR (CD3OD) δ 12.82, 18.45, 27.43, 31.16, 36.74, 46.73, 49.61, 50.48, 56.06, 59.61, 67.86, 112.19, 115.51, 118.98, 119.18, 127.52, 128.96, 129.51, 130.55, 130.77, 132.17, 134.23, 137.73, 142.53, 142.92, 152.96, 172.43, 176.24. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.6CH2Cl2: C, 67.06; H, 6.70; N, 9.04. Found. C, 66.95; H, 6.64; N, 8.91.
Reaction SMILES: [C:1](NC(=O)CCCCC)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.C1C=C2C(OC3(C4C(=CC(O)=C(CN(CC(O)=O)CC(O)=O)C=4)OC4C3=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=4)C2=CC=1)=[O:31]>>[OH:31][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)=[O:15]
Reactant: O=C(O)CN(CC(=O)O)Cc1cc2c(cc1O)Oc1cc(O)c(CN(CC(=O)O)CC(=O)O)cc1C21OC(=O)c2ccccc21
Reactant: CCCCCC(=O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Liposomes were bound to adherent ECV304 cells via a biotin-streptavidin linkage. To this end DODAP/MeO-suc-AAPV-DOPE (1:1 mol:mol) liposomes were prepared with 0.3 mol % N-biotinyl caproylamine-PE (N-biotinyl-cap-PE) as well as fluorescent lipid probes or with encapsulated calcein. ECV304 cells that had been plated on glass coverslips in tissue culture plates were washed with HBSS buffer and then incubated sequentially at room temperature with biotin-wheat germ agglutinin (WGA) (20 ug/ml, obtained from Pierce, Rockford, Ill.) and streptavidin (40 ug/ml, obtained from Molecular Probes, Eugene, Oreg.) prepared in HBSS, 30 min/treatment. Cells were washed after each treatment. Liposomes were treated with or without elastase as described above. Certain aliquots of pretreated DODAP/MeO-suc-AAPV-DOPE (1:1 mol/mol) liposomes were freeze/thawed after dialysis and prior to addition to cells to release the liposomal contents. Such freeze/thawed liposomes were exposed to liquid nitrogen/37° C. water bath for 5 cycles. Self-quenching of calcein was reduced by approximately 85% (maximal FDQ determined by detergent solubilization) after freeze/thawing, indicating release of encapsulated calcein. In all cases, 50-100 nmol of liposomes were added to confluent ECV304 cell monolayers (1×105 cells/well of 24 well plate) and incubated in HBSS for 30 min at room temperature to promote N-biotinyl cap-PE binding to streptavidin. Unbound liposomes were removed by repeated washes. After the final wash, fresh HBSS buffer was added to all wells and cells were incubated at 37° C. for given times. Fluorescence was quantitated as described above. Calcein fluorescence was excited with the 488 nm line of a krypton/argon laser and observed at 522 nm emission
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]2([C:31]#[N:32])[CH2:30][CH2:29]2)=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[F:23])=[O:5].[Cl-].[Ca+2].[Cl-].O.[OH-].[Na+]>C(O)C.[Fe].C(OCC)(=O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][C:8]([F:23])=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]4([C:31]#[N:32])[CH2:29][CH2:30]4)[C:2]=3[Cl:1])[CH:12]=2)=[N:15][CH:16]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3F)c2Cl)CC1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)ccc3F)c2Cl)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A suspension of 2-chloro-3-(1-cyanocyclopropyl)-N-{2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (6.60 g, 14.6 mmol), iron powder (1.68 g, 30 mmol) and calcium chloride (3.33 g, 30 mmol) in ethanol (80 mL)-water (20 mL) was stirred at 80° C. overnight. The reaction mixture was poured into 0.5N aqueous sodium hydroxide solution (500 mL), ethyl acetate (300 mL) was added, the mixture was stirred, and the insoluble material was filtered through celite. The ethyl acetate layer was separated from the filtrate, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (4.23 g, 69%) as a pale-yellow amorphous.
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2([CH2:12][C:13]1([CH3:16])[CH2:15][O:14]1)[OH:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C>[OH:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:3]1([OH:11])[CH2:4][CH:5]2[C:8]([CH3:9])([CH3:10])[C:2]1([CH3:1])[CH2:7][CH2:6]2
Reactant: CC1(CC2(O)CC3CCC2(C)C3(C)C)CO1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(O)CC1(O)CC2CCC1(C)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A solution of 30.9 g (~0.14 mol) of crude (1RS,2SR,4RS)-1,7,7-trimethyl-2-(2-methyl-oxiranylmethyl)bicyclo[2.2.1]heptan-2-ol in 100 ml of anhydrous diethyl ether was added dropwise to 11.0 g (0.29 mol) of lithium aluminum hydride suspended in 300 ml of the same solvent under reflux, and under nitrogen. The reaction mixture was stirred overnight at room temperature and treated with 60 ml of 2M sodium hydroxide solution. The white precipitate was filtered out, washed with diethyl ether and the combined organic phases were washed with 2×200 ml of water and 200 ml of brine. After drying (MgSO4) and evaporation of solvent the crude (1RS,2SR,4RS)-2-(2-hydroxy-2-methylpropyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (29.0 g of white waxy solid; two step yield 92%) was used in the next steps without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:4]=1>O1CCCC1>[CH:2]([C:3]1[N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCCn1nc(-c2ccccc2)cc1CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCn1nc(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
The compound prepared in Example 122 (0.25 g) was suspended in tetrahydrofuran (20 mL) manganese (II) oxide (2.05 g) was added and the suspension stirred at room temperature overnight. The reaction mixture was then filtered through a pad of silica and celite (trade mark), eluting with ethyl acetate. The organics were concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 20% ethyl acetate/hexane) to afford the title compound (0.10 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][N:12]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]1B(O)O.[F-].[K+].[Br-]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[N:12]([CH3:11])[C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc(N)cc1C#N
Yield: 92.8 %

Procedure:
A mixture of 5-amino-2-chlorobenzonitrile (1.3 g, 8.58 mmol), tris(dibenzylideneacetone)dipalladium (0.192 g, 0.209 mmol), N-methyl-5-cyanopyrroleboronic acid (2.55 g, 17.16 mmol), and potassium fluoride (1.81 g, 31.25 mmol) in tetrahydrofuran (20 mL) was stirred under nitrogen. Tri-tert-butylphosphine (10% solution in hexane, 1.23 mL, 0.414 mmol) was added to the mixture and allowed to stir 3 hours at 50° C. until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/tetrahydrofuran and filtered through a plug of silica gel. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethylacetate, 90/10 to 50/50) to afford the title compound (1.77 g, 92%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][S:27]([NH:30][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:4]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)(=[O:29])=[O:28]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 ml scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methanesulfonamide (9.00 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06-1.20 (m, 2 H), 1.43-1.57 (m, 2 H), 1.74-1.91 (m, 5 H), 2.17-2.26 (m, 2 H), 2.41-2.46 (m, 1 H), 6.95-7.22 (m, 1 H), 7.23-7.44 (m, 2 H), 7.64-7.82 (m, 2 H), 11.68 (s, 1 H), 13.98 (s, 1 H); MS (ESI) m/z 430 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirring solution of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.5 g, 7.5 mmol) in 25 mL CH2Cl2 was added triethylamine (2.1 mL, 15 mmol) at 0° C., followed by the dropwise addition of benzyl chloroformate (1.58 mL, 11.2 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3% MeOH in CH2Cl2 gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.5 g, 60%). LC/MS: m/z: 335.5 (M+H)+ at 3.01 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([N+:10]([O-:12])=[O:11])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A solution of 30.0 g (162 mmol) of 4-bromobenzaldehyde, 116 mL (1.6 mole) of nitroethane, and 37.5 g (486 mmol) of ammonium acetate in 200 mL of toluene was heated under a Dean and Stark trap for 18 hours. The mixture was then cooled to 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was stirred at 80° C. for 2 hours. The mixture was then cooled to ambient temperature and washed with 200 mL of brine. The organic layer was separated and the aqueous layer was extracted three times with 60 mL of diethyl ether. The combined organics were dried (MgSO4), filtered and coincentrated in vacuo. The residue was recrystallised from methanol to afford 18.7 g (47%) of the title compound.