Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C@H:9]([CH3:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:4]([C@@H:6]1[CH2:10][C@H:9]([CH3:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1C[C@H](C)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(2S,4S)-tert-butyl 2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-1-carboxylate (5.30 g, 19.5 mmol) was dissolved in 120 mL THF, cooled to −78° C. and treated with lithium aluminum hydride (1M in THF, 19.5 mL, 19.5 mmol) dropwise via addition funnel. After 1 hour, the mixture was brought to 0° C. and kept at that temperature for 2 hours. It was quenched by dropwise addition of a 50 mL solution of 3.0 g KHSO4 in water, removed from the ice bath, and stirred 15 minutes at room temperature. The product was extracted with three 75 mL portions of ethyl acetate and washed with brine. The organic phase was dried over sodium sulphate, filtered, and concentrated to give crude (2S,4S)-tert-butyl 2-formyl-4-methylpyrrolidine-1-carboxylate. (4.89 g)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][NH:9][C:8](=O)[CH2:7]1>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:7][CH2:8][NH:9][CH2:10]1
Reactant: O=C1CC(c2cccs2)CN1
Solvent: C1CCOC1
Product: c1csc(C2CCNC2)c1

Procedure:
To a suspension of LiA1H4 (0.46 g) in THF (25 ml) was added the product of Example 134 (1.0 g) in THF (30 ml). After the addition was complete the reaction was heated at reflux for 4 hrs.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:26][CH2:27][CH:22]([CH2:21][N:20]([CH3:28])[CH3:19])[CH2:23][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)CC1CCNCC1
Product: CN(C)CC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with dimethyl-piperidin-4-ylmethyl-amine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-ylmethyl]-dimethyl-amine as an off white solid (51% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 332 as an off white solid (36% yield). NMR (CDCl3, 400 MHz), 1.29-1.35 (2H, m), 1.46-1.51 (1H, m), 1.77 (2H, d, J=11.8), 2.08-2.15 (4H, m), 2.22 (6H, s), 2.99 (2H, d, J=11.5), 3.82 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=469
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([N:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[O:14][CH:13](O)[C:12]2=[O:20])[CH2:3][CH2:2]1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1)[CH:45]=O>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([N:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[O:14]/[C:13](=[CH:45]\[C:44]3[CH:47]=[CH:48][C:49]([N:50]4[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]4)=[C:42]([F:41])[CH:43]=3)/[C:12]2=[O:20])[CH2:3][CH2:2]1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Reactant: CC1(C)CN([C@H]2CCOc3ccccc32)C(=O)C(O)O1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: Cc1cn(-c2ccc(/C=C3\OC(C)(C)CN([C@H]4CCOc5ccccc54)C3=O)cc2F)cn1

Procedure:
25.4 mg of the title compound was obtained from 4-[(S)-chroman-4-yl]-2-hydroxy-6,6-dimethylmorpholin-3-one, triphenylphosphonium bromide, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 12.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([C:19]([F:21])([F:20])[F:22])=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To the mixture of 9-pentyl-3-(trifluoromethyl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (50 mg, 0.16 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (42 mg, 0.24 mmol). The mixture was stirred at 70° C. for 3 hour. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product. 1HNMR (300 MHz, CD3OD): δ 4.44 (t, J=7.6 Hz, 2H), 1.94 (m, 2H), 1.42 (m, 4H), 0.93 (m, 3H). LCMS calculated for C12H13BrF3N6O(M+H): 393.0, found: 393.0, 395.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccn3)c2n1C1CC1
Temperature: 150 °C
Yield: 24.1 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (70 mg, 0.17 mmol), 2-(tributylstannyl)pyridine (0.06 mL, 0.19 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (6 mg, 20 mol %) in dioxane (1 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor (Biotage). After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford 442 as a pale yellow solid (17 mg, 24%). LCMS (Method K): RT 3.05 min [M+H]+ 415.07. 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (1H, ddd, J=4.87, 1.81, 0.94 Hz), 8.02 (1H, s), 7.94 (1H, td, J=7.71, 1.84 Hz), 7.73-7.66 (3H, m), 7.45 (1H, ddd, J=7.59, 4.87, 1.16 Hz), 7.30 (2H, s), 7.16 (1H, dd, J=10.65, 8.75 Hz), 5.84-5.75 (1H, m), 3.02-2.95 (1H, m), 1.61 (3H, d, J=6.76 Hz), 1.25-1.20 (1H, m), 0.79-0.69 (1H, m), 0.52-0.43 (1H, m), 0.41-0.28 (1H, m)
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:13]1([C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.C([O-])(=O)C.[Na+]>CCOCC.O.C(O)(=O)C>[C:1]([NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][S:9][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N[C@@H](CS)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
This compound was synthesized by adapting, to N-isobutyryl-L-cysteine, the tritylation method described by K.-Y. Zee-Cheng and C. C. Cheng, J. Med. Chem., 1970, 13, 414-418. A suspension comprising 4.1 g (21.5 mmol) of N-isobutyryl-L-cysteine [(prepared according to H. Brückner et al., J. Chromatogr., 1989, 476, 73-82), ([α]D20=+84° (c 1, CHCl3))], 5.6 g (21.5 mmol) of triphenylmethanol and 16 ml of glacial acetic acid is stirred at ambient temperature. 4.1 ml (32.2 mmol) of BF3 etherate are added dropwise to the mixture while maintaining the temperature at 20-25° C. After stirring for 3 h, the brown solution obtained is subsequently cooled to 0° C. and then 70 ml of an aqueous sodium acetate solution and 140 ml of water are added. At the end of the additions, the reaction mixture sets solid in the form of a gel. This mixture is left overnight at 0° C. and then 150 ml of ice-cold water and 120 ml of ether are subsequently added with vigorous stirring. The ethereal phase is separated by settling and the aqueous waste liquors are washed with 4×80 ml of ether. The organic phases are combined, washed with 4×60 ml of ice-cold water, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The crude product obtained is purified by washing successively with hexane (5×50 ml) to provide 13 in the form of a gum which is homogeneous by TLC with a yield of 81%. Rf (CH2Cl2/MeOH/AcOH, 9.4/0.6/0.07): 0.53. [α]D20=+21.4° (c 1.12, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][C:9](=[O:20])[C:8]=3[CH2:7][CH2:6][N:5]2[C:21]=1[CH3:22].O1CCCC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][C:9](=[O:20])[C:8]=3[CH:7]=[CH:6][N:5]2[C:21]=1[CH3:22]
Reactant: Cc1nc2n(c1C)CCC1=C2N[C@H](c2ccccc2)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc2c3c(ccn2c1C)C(=O)C[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
63.5 g (0.22 mol) of (9S)-2,3-dimethyl-9-phenyl-5,6,7,8,9,10-hexahydroimidazo[1,2-h][1,7]naphthyridin-7-one are dissolved in 250 ml of toluene and 250 ml of tetrahydrofuran and cooled to 0° C. 59 g (0.26 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are introduced in portions of 10 g over a period of 1 h with mechanical stirring. The reaction mixture is stirred at room temperature for 16 h. 1.2 l of 0.5 N sodium hydroxide solution and 1 l of ethyl acetate are then added dropwise. The organic phase is separated off and washed with water. The aqueous phase is reextracted with ethyl acetate and the combined organic phases are dried over sodium sulfate and evaporated. The residue is crystallized in 300 ml of methanol at 0° C. The solid is filtered off with suction, washed with cold methanol and dried. 20 g (32%) of the title compound are isolated as a slightly yellow solid (m.p. 103-105° C.).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:16]([OH:18])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O1CCCCC1[N:58]1[C:66]2[C:61](=[CH:62][C:63]([CH:67]([NH2:69])[CH3:68])=[CH:64][CH:65]=2)[CH:60]=[N:59]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:58]1[C:66]2[C:61](=[CH:62][C:63]([CH:67]([NH:69][C:16]([CH:4]3[CH2:3][N:2]([CH3:1])[C:7]4[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=4[O:5]3)=[O:18])[CH3:68])=[CH:64][CH:65]=2)[CH:60]=[N:59]1
Reactant: CC(N)c1ccc2c(cnn2C2CCCCO2)c1
Reactant: CN1CC(C(=O)O)Oc2ccc(C(F)(F)F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C1CN(C)c2cc(C(F)(F)F)ccc2O1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A stirred solution of 4-methyl-6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (50 mg, 0.2 mmol), HBTU (73 mg, 0.2 mmol) and DIPEA (67 μL, 1.5 mmol) in anhydrous DMF (2 mL) was added to a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (43 mg, 0.17 mmol) in anhydrous DMF (0.5 mL). The reaction was stirred overnight at room temperature, then poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. The resulting product was redissolved in MeOH (10 mL), and 2N HCl (1 mL) was added. After stirring overnight at 50° C., the methanol was removed by evaporation, and the aqueous residue poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 3.5% MeOH in DCM) gave the title compound (22 mg, 31%) as a solid, containing a mixture of diastereomers. m/z=405.5 (M+1), r.t.=3.36, 3.42 mins. 1H NMR (400 MHz; d6-DMSO) δ 13.00 (1H, s), 12.98 (1H, s), 8.51 (1H, d), 8.44 (1H, d), 8.04 (1H, s), 7.95 (1H, s), 7.68 (1H, s), 7.54-7.51 (2H, m), 7.42 (1H, d), 7.36 (1H, d), 7.25 (1H, d), 7.03-6.89 (6H, m), 5.12-5.04 (2H, m), 4.87-4.81 (2H, m), 3.48-3.43 (2H, m), 3.34-3.30 (2H, m), 2.88 (6H, d), 1.47-1.43 (6H, m).
Reaction SMILES: C(OC(=O)N([C@H](C(=O)N[C@@H](C1CCCCC1)C(N1C[C@@H](N)C[C@H]1C(=O)NCC1C=CC=CC=1)=O)C)C)(C)(C)C.C1C2C(COC(=O)[NH:56][C@H:57]3[CH2:61][C@@H:60]([C:62](=[O:74])[NH:63][C@H:64]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66][CH2:65]4)[N:59]([C:75](=[O:97])[C@@H:76]([NH:83][C:84](=[O:96])[C@@H:85]([N:87]([C:89]([O:91][C:92]([CH3:95])([CH3:94])[CH3:93])=[O:90])[CH3:88])[CH3:86])[CH:77]4[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]4)[CH2:58]3)C3C(=CC=CC=3)C=2C=CC=1>>[C:92]([O:91][C:89](=[O:90])[N:87]([C@H:85]([C:84](=[O:96])[NH:83][C@@H:76]([CH:77]1[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82]1)[C:75]([N:59]1[CH2:58][C@@H:57]([NH2:56])[CH2:61][C@H:60]1[C:62](=[O:74])[NH:63][C@H:64]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH2:67][CH2:66][CH2:65]1)=[O:97])[CH3:86])[CH3:88])([CH3:93])([CH3:94])[CH3:95]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
In a similar manner to that described for {(S)-1-[(S)-2-((2S,4S)-4-amino-2-benzylcarbamoyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 28, Step 2), {(3S,5S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester (Intermediate 25) (500 mg, 0.62 mmol) was converted to the title compound (360 mg, foam).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]([C:16]1[C:17]([CH3:39])=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CN(C=O)C>O>[CH3:38][C:19]1[CH:18]=[C:17]([CH3:39])[C:16]([C:14]2[NH:12][C:9]3[CH:10]=[N:11][C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:7][C:8]=3[N:13]=2)=[CH:37][C:20]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1cc(C)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Reactant: Nc1cnc(N2CCCC2)cc1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3cc(N4CCCC4)ncc3[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Yield: 13.3 %

Procedure:
To a 100 mL round bottom flask was added 6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 20.2, 641 mg, 3.60 mmol, 1.0 equiv), 4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 16.4, 1.25 g, 3.60 mmol, 1.0 equiv), sodium metabisulfite (890 mg, 4.68 mmol, 1.3 equiv) and DMF (36 mL). The mixture was heated at 100° C. under air for 22 hours then allowed to cool to room temperature. Water (80 mL) was added slowly to the stirred solution until no further product precipitated. The solids were filtered and washed with water (2×15 mL) and dried to a brown solid (1.42 g). Additional product precipitated from the filtrate upon standing which was filtered and washed with water (2×10 mL) to obtain an off white solid (241 mg). The above reaction was repeated a second time in the exact manner and quantities as described to yield additional product (1.26 g of brown solid upon initial precipitation, plus 288 mg of off white solid from additional precipitation). The aqueous filtrates from the two reactions were combined and aqueous NaHCO3 was added to adjust the pH to 7. The aqueous was extracted with DCM/2% MeOH (300 mL), dried (Na2SO4), filtered and evaporated to obtain a brown solid (547 mg). All products obtained were combined and purified by silica gel chromatography (DCM/MeOH) to obtain the title compound as a yellow solid (2.37 g, 65% based on the theoretical yield for the two reactions). m/z (ES+) 505.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.41 (br s, 1H), 8.52 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.66 & 7.56 (2 br singlets, amide rotamers, ArH, 1H), 7.49 (s, J=8.2 Hz, 2H), 7.29 (s, 1H), 6.31 (br s, 1H), 4.79-4.67 (m, 1H), 3.54-3.34 (m, 5H), 3.17 (app t, J=11.8, 1H), 2.99-2.82 (m, 2H), 2.63 (s, 3H), 2.33 & 2.24 (2 singlets, amide rotamers, ArCH3, 3H), 2.03-1.87 (m, 5H), 1.82-1.38 (m, 3H). Elemental analysis (C31H32N6O.1.3H2O, 528.04), found (calcd), C, 70.66 (70.51); H, 6.54 (6.60); N, 15.78 (15.92).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)[O:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]2)=[CH:35][CH:34]=1>O1CCCC1>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]([C:50]2[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=2)[O:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][C:46](=[CH:2][O:3][CH3:4])[CH2:45][CH2:44]2)=[CH:37][CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Meanwhile, 1.066 g of methoxymethyltriphenylphosphonium chloride was added to 7 ml of tetrahydrofuran, and the mixture was cooled at -10° C. The lithium diisopropylamide solution previously prepared was then added to this mixture, which was then stirred for 30 minutes at -10° C. At the end of this time, 5 ml of a tetrahydrofuran solution containing 1.01 g of 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidone (prepared as described in preparation 6) were dropped into the reaction mixture, at -10° C. The mixture was stirred for 30 minutes, allowed to stand overnight at room temperature, and then condensed by evaporation under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The oily substance obtained was purified by silica gel column chromatography. Elution with a 2:1 by volume mixture of ethyl acetate and hexane afforded 718 mg (yield 66%) of a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][C:8]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:7][CH:6]=2.NC1C=NC2C(C=1NCCCCNC(=O)OC(C)(C)C)=CC=[C:39]([O:57][CH2:58][C:59]1C=CC=CC=1)[CH:38]=2.C(OCC(Cl)=O)C.COCCC(Cl)=O>>[CH2:26]([O:25][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:38]([CH2:39][O:57][CH2:58][CH3:59])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[C:10]=2[CH:9]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CCCCNC(=O)OC(C)(C)C

Procedure:
For Example 73, a modification of the general method described for Part C of Example 50 was followed using tert-butyl {4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (9.25 g, 21.2 mmol) in lieu of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate and ethoxyacetyl chloride (2.86 g, 23.3 mmol) in lieu of methoxypropionyl chloride. After the cyclization reaction, the solvent was removed under reduced pressure, and the residue was dissolved in chloroform (400 mL). The resulting solution was washed with water (2×200 mL) and brine (1×200 mL), concentrated under reduced pressure, and dried under high vacuum to provide a brown oil. The crude product was purified by column chromatography on silica gel (400 g, eluting with 95:5 dichloromethane:methanol). The resulting solid was triturated with diethyl ether and isolated by filtration to provide 5.37 g of tert-butyl {4-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:13][Mg]I.S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: CC(=O)CCc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
4-(4-Fluorophenyl)-2-butanone (10.0 g) in ether (30 ml) was added over 20 min. to a stirred solution of methyl magnesium iodide (0.086 mole) in ether (80 ml). The mixture was stirred at room temperature over 5 hr, then cooled and 2 M sulphuric acid (30 ml) added. The mixture was extracted with ether (5×50 ml), washed with saturated sodium bicarbonate solution, saturated brine and dried (MgSO4). The solvent was removed and the residue was distilled. The alcohol (9.4 g) b.p. 83°-85°/0.1 mm was obtained as a colourless liquid.