Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[C:56]([CH:60]([O:62][Si](C(C)(C)C)(C)C)[CH3:61])[NH:57]4)=[CH:53][CH:52]=3)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:72])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[C:56]([CH:60]([OH:62])[CH3:61])[NH:57]4)=[CH:53][CH:52]=3)[CH:46]([O:70][CH3:71])[CH2:45]2)[CH:7]([CH3:73])[CH:6]([OH:74])[CH2:5][C:4]1=[O:75])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(C(C)O[Si](C)(C)C(C)(C)C)[nH]c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(C(C)O)[nH]c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg) in CH2Cl2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.). The reaction mixture was stirred for 2 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 55 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15](Cl)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].Cl.Cl.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:33][CH2:34][CH2:35][NH:36][C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
120 mg (0.23 mmol) of ethyl{4-[5-chloro-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 55A), 54.9 mg (0.28 mmol) of 6-[(2-aminoethyl)amino]-pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine were initially charged in 2.33 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 113 mg (77% of theory) of the product as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCCC1
Reaction time: 16 h
Yield: 13 %

Procedure:
|2-Fluoronitrobenzene (2.82 g, 20 mmol) was mixed with pyrrolidine (1.56 g, 22 mmol), and potassium carbonate (5.5 g, 40 mmol) in DMF (10 mL). After beating for 16 hours, the mixture was filtered and the filtrate evaporated in vacuo to an oil. This oil was treated with water (10 mL) and dichloromethane (100 mL). The organic phase was collected, dried (MgSO4), filtered, and evaporated to give 1-(2-nitrophenyl)pyrrolidine (0.5 g). The crude product was reduced using 5% palladium on carbon (0.1 g) in ethanol (30mL) and hydrogen at 40 psi for 2 hours. The solution was filtered through celite to remove catalyst and the filtrate evaporated in vacuo to give 2-(1-pyrrolidino)aniline (0.33 g). The crude product was coupled with CMI, under conditions described in the general procedure for CM couplings, to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-pyrrolidinyl)aniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Fc1ccccc1I
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 470.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([F:14])=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[C:5]#[N:6].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1>S1(CCCC1)(=O)=O>[F:14][C:3]1[C:2]([F:15])=[CH:9][CH:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:4]=1[C:5]#[N:6]
Reactant: [F-]
Reactant: N#Cc1c(C(F)(F)F)ccc(Cl)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1c(C(F)(F)F)ccc(F)c1F
Temperature: 165 °C
Reaction time: 7 h
Yield: 79.3 %

Procedure:
To a solution of 35.0 g of 3-chloro-2-fluoro-6-trifluoromethylbenzo nitrile in 200 ml of sulfolane was added 36.3 g of spray-dried potassium fluoride and 4.1 g of 18-crown-6-ether, and the mixture was stirred for 7 hours at 160-170° C. under a nitrogen atmosphere. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer obtained was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. Following to the concentration of the extract, the oily product obtained was distilled under reduced pressure to obtain 25.7 g of the title compound (bp. 98-100° C. (25 mmHg) nD 20.0-1.4413).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH2:13]([NH2:19])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1.COC(OC)OC.[BH4-].[Na+]>CO.CC(O)=O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:19][CH2:13][C:14]2[O:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: NCc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: CCCOc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
4-Propoxy benzaldehyde (5 g, 31 mmol) and furfuryl amine (3.9 g, 40 mmol) in a mixture of methanol (50 mL), trimethylorthoformate (10 mL) and AcOH (˜1 mL) were stirred at room temperature, under an atmosphere of nitrogen for 16 hours. Sodium borohydride (1.4 g, 35 mmol) was added in 4 portions, over a period of 30 minutes (exothermic reaction). The reaction was stirred for an additional 2 hours at room temperature. The solvent was removed on the rotovap and the residue taken up in ethyl acetate (150 mL). The organic phase was washed with H2O (200 mL) and aqueous phase was back extracted with ethyl acetate (2×, 100 mL). The combined organic layers were concentrated and the residue was purified on silica gel (70% ethyl acetate in hexanes with ˜2% triethylamine) to afford N-(4-propoxybenzyl)-1-(furan-2-yl)methanamine (5.3 g, 75%) as a yellow oil. NMR (CDCl3, 400 MHz): δ 1.03 (t, J=7.2 Hz, 3H), 1.79 (m, J=6.4 Hz, 2H), 3.71 (s, 2H), 3.76 (s, 2H), 3.90 (t, J=6.8 Hz, 2H), 6.17 (d, J=3.2 Hz, 1H), 6.32 (m, 1H), 6.85 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.37 (m, 1H).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[OH:13])[C:6]([O:24][CH3:25])=[N:5]1)([CH3:3])[CH3:2].N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[Si:35]([O:13][C@@H:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)[C@H:7]1[C:6]([O:24][CH3:25])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Yield: 73.4 %

Procedure:
To a solution of (S)-((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol (3.5 g, 9.8 mmol), and imidazole (0.8 g, 11.8 mmol) in CH2Cl2 (50 mL) was added tert-butylchlorodimethylsilane (1.6 g, 10.4 mmol) and TEA (1.6 mL, 11.8 mmol) at room temperature. The mixture was stirred over the weekend. The mixture was diluted with DCM and washed with water, saturated NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (40-50% DCM-hexane) to provide the product as a white solid (3.4 g, 74%). LCMS (API-ES) m/z: 473 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[C:19](O)(=[O:29])[C:20]1[CH:28]=[CH:27][CH:26]=[C:22]([C:23](N)=[O:24])[CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:23](=[O:24])[C:22]4=[CH:26][CH:27]=[CH:28][C:20](=[CH:21]4)[C:19]3=[O:29])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: NC(=O)c1cccc(C(=O)O)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(N3C(=O)c4cccc(c4)C3=O)CC2)ccc1Cl
Yield: 48 %

Procedure:
The title compound (20 mg, 48%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with isophthalamic acid (Chem. Ber. 1910, 43, 3474). MS: 416.4 (MH+)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:12]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[S:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:12][S:32]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(CCCC2CO2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCCC2CS2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(3-phenylpropyl)oxirane (Example 35b) (2.0 g, 0.0123 mol) and triphenylphosphine sulphide (3.62 g, 0.0123 mol) in toluene (20 ml), trifluoroacetic acid (1.40 g, 0.0123 mol) was added over 5 min. After stirring for 1 hour at room temperature, the reaction mixture was washed with water, sodium hydrogen carbonate solution and again with water. After drying (MgSO4) and removal of solvent at reduced pressure, the product contaminated with triphenylphosphine oxide was isolated as a crystalline mass. Attempted purification of the thiirane resulted in its extensive decomposition and it was therefore used in its crude state.
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:65]([NH:75][C:76](=[O:94])[CH2:77][N:78]2[C:86]3[C:85]([F:88])([F:87])[CH2:84][CH2:83][C:82]([F:90])([F:89])[C:81]=3[C:80]([CH:91]([F:93])[F:92])=[N:79]2)[CH2:66][C:67]2[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][N:59]2[CH2:63][CH2:62][NH:61][C:60]2=[O:64])=[N:54][CH:55]=1>>[F:93][CH:91]([F:92])[C:80]1[C:81]2[C:82]([F:89])([F:90])[CH2:83][CH2:84][C:85]([F:88])([F:87])[C:86]=2[N:78]([CH2:77][C:76]([NH:75][C@H:65]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][N:59]3[CH2:63][CH2:62][NH:61][C:60]3=[O:64])[N:52]=2)[CH2:66][C:67]2[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=2)=[O:94])[N:79]=1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCN2CCNC2=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCCN3CCNC3=O)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (22B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 22A. 1H NMR (400 MHz, CD3OD) δ 8.88 (m, 1H), 8.07 (s, 1H), 7.47-7.29 (m, 2H), 7.27-7.14 (m, 1H), 6.96-6.59 (m, 2H), 6.45 (d, J=6.4 Hz, 2H), 5.26 (m, 1H), 5.09 (s, 2H), 3.82-3.49 (m, 6H), 3.40 (m, 2H), 3.15-2.95 (m, 2H), 2.51 (m, 4H). MS (m/z) 784.22 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16].NCCC(O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]2[NH:14][C:15](=[O:16])[NH:17][C:18]2=[O:19])[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C1CNC(=O)N1
Agent: NCCC(=O)O
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1O
Yield: 75.7 %

Procedure:
Prepared according to the procedure described in Example 90 using 3,5-dimethoxy-4-hydroxybenzaldehyde (5.6 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), and β-alanine (1.4 g, 16 mmoles), to afford the pure product (6.0 g), mp 296°-297° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:36]([NH2:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:41][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NCC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (2.150 g, 10 mmol) and HATU (3.80 g, 10.00 mmol) in DMF (20 mL) was stirred for 10 min at RT. Neopentylamine (1.170 mL, 10.00 mmol) was slowly added and the reaction mixture was allowed to stir at RT overnight. The reaction was quenched with 1N HCl and the solution was partitioned between brine and EtOAc. The aqueous phase was extracted with EtOAc. The organic phases were combined and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (6-50% EtOAc/hexanes). 2-Bromo-3-methyl-N-neopentylbenzamide was isolated as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18](O)[CH2:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@H:18]([O:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:15])[C:4]=3[CH:3]=1)[CH2:17]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2ccc(O[C@@H]3CN4CCC3CC4)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a 0° C. mixture of 2-hydroxyfluoren-9-one (196 mg, 1.00 mmol; Aldrich), (3R)-quinuclidin-3-ol (151 mg, 1.20 mmol; Acros), and polymer-bound triphenylphosphine (500 mg, 3 mmol/g; Aldrich) in THF (5 mL) was added diethylazodicarboxylate (200 μL, 1.27 mmol; Aldrich). After 1 h, the reaction mixture was allowed to warm to room temperature and was stirred overnight (16 h). The mixture was filtered through diatomaceous earth, the filter pad rinsed with dichloromethane, and the organic extracts purified twice by flash chromatography (80 g silica gel, eluting with 1-5% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound (104 mg, 0.340 mmol, 34% yield). MS (DCl/NH3): m/z 306 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:40]=[CH:39][CH:38]=[CH:37][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17](Br)=[C:18]2[C:23]=1[CH2:22][C@:21]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:41]#[N:42].[K+]>CN(C)C(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[CH2:1]([O:8][C:9]([C:11]1[CH:40]=[CH:39][CH:38]=[CH:37][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:41]#[N:42])=[C:18]2[C:23]=1[CH2:22][C@:21]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@]1(NC(=O)OC(C)(C)C)CCc2c(Br)ccc(Oc3ccccc3C(=O)OCc3ccccc3)c2C1
Reactant: [C-]#N
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@]1(NC(=O)OC(C)(C)C)CCc2c(C#N)ccc(Oc3ccccc3C(=O)OCc3ccccc3)c2C1
Reaction time: 15 h
Yield: 8.6 %

Procedure:
A mixture of 90.0 mg (0.147 mmol) of methyl (S)-8-(2-benzyloxycarbonyl-phenoxy)-5-bromo-2-(tert.butoxycarbonylamino)-1,2,3,4-tetrahydro-naphthalene-2-carboxylate, 19.2 mg (0.295 mmol) of potassium cyanide, 6.5 mg (11.8 μmol) of 1,1'-bis-(diphenylphosphino)-ferrocene and 3,0 mg (2.9 μmol) of bis-(dibenzylideneacetone)-di-palladium (Pd2 dba3) in 0.2 ml of N,N-dimethylacetamide was stirred at 800 under argon for 15 hours, cooled and filtered over Celite, whereupon the filtrate was evaporated. The residue was chromatographed on 30 g of silica gel with hexane/ethyl acetate (9:1→1:1), whereby firstly 71 mg (78.9%) of starting material were recovered; subsequently there were obtained about 7.0 mg (8.6%) of crude methyl (S)-8-(2-benzyloxycarbonyl-phenoxy)-2-(tert.butoxycarbonylamino)-5-cyano-1,2,3,4-tetrahydro-naphthalene-2-carboxylate which was purified by means of preparative HPLC chromatography (column: Vydac 250-10 RP-18; programme: 60% acetonitrile→100% acetonitrile in 20 minutes). 5.5 mg (6.7% based on starting material used; 31.6% based on reacted starting product) of pure product were obtained. MS: 556 (M+., <1), 439 (10), 397 (20), 91 (100), 57 (24).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[NH2:6][O:5][CH2:4][C:3]([NH:21][CH2:18][CH2:19][CH3:20])=[O:2]
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Reactant: CCCN
Product: CCCNC(=O)CON

Procedure:
Using (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained in Step A of Example 19 and n-propylamine as an amine, synthesis was performed according to the procedure described in Step A of Example 20 to give 2-aminooxy-N-propyl-acetamide.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:58]([CH3:60])[CH3:59])[C:10]([O:12][CH2:13][CH:14]1[N:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[CH:26]=[C:18]2[C:17]2[N:28]=[C:29]([C:32]3[C:33]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:55])=[O:54])=[CH:34][C:35]4[O:39][C:38]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)=[C:37]([C:47](=[O:50])[NH:48][CH3:49])[C:36]=4[CH:51]=3)[CH:30]=[CH:31][C:16]=2[O:15]1)=[O:11])=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C@@H:9]([CH:58]([CH3:60])[CH3:59])[C:10]([O:12][CH2:13][C@H:14]1[N:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[CH:26]=[C:18]2[C:17]2[N:28]=[C:29]([C:32]3[C:33]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:54])=[O:55])=[CH:34][C:35]4[O:39][C:38]([C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[C:37]([C:47](=[O:50])[NH:48][CH3:49])[C:36]=4[CH:51]=3)[CH:30]=[CH:31][C:16]=2[O:15]1)=[O:11]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)O4)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3[C@H](COC(=O)[C@@H](N)C(C)C)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (2S)-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (30 mg, 0.04 mmol) in dichloromethane (2 mL), TFA (0.5 mL) was added. The mixture was stirred at room temperature overnight. The mixture was poured into sat NaHCO3 solution (20 mL) and extracted with dichloromethane. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using prep-TLC (dichloromethane:MeOH=40:1) to provide the product Compound 102 (25 mg, yield: 94%). 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.95˜7.99 (m, 2H), 7.66 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.19˜7.25 (m, 5H), 6.84˜6.89 (m, 1H), 6.63˜6.66 (m, 1H), 5.95 (br s, 1H), 4.41˜4.47 (m, 1H), 4.32˜4.37 (m, 1H), 3.39 (s, 3H), 3.23 (d, J=5.2 Hz, 1H), 3.01 (d, J=4.8 Hz, 3H), 2.74 (s, 3H), 1.82˜1.91 (m, 1H), 0.91 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H). MS (M+H)+: 744.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:14]1[C:18]2[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]Cl)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(C1C=CC=CC=1N(C(C)C)CC)(C)C>C(#N)C>[CH2:7]([N:14]1[C:18]2[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(-c2nc3ccc(OCCCCl)cc3n2Cc2ccccc2)c1
Reactant: C1COCCN1
Agent: CCN(c1ccccc1C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2nc3ccc(OCCCN4CCOCC4)cc3n2Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
The title compound was prepared by first adding morpholine (1.02 g, 11.77 mmol) and the compound of Example 97, supra, (0.39 g, 1.00 mmol) to 125 ml of acetonitrile while stirring under nitrogen purge. To this mixture is then added diisopropylethyl aniline (1.51 ml, 8.67 mmol) dropwise. This reaction mixture is then allowed to stir overnight.