Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])#[N:2].[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24]>O1CCCC1.CCOCC>[C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][C:9]1([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)OCCC#N)CC1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC1(CC(=O)OCCC#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The process is performed according to the procedure described in Example 18 (step 18.1.). Starting with 5.00 g (16.99 mmol) of tert-butyl 4-(cyanoethoxycarbonylmethylene)piperidine-1-carboxylate (WO 2006/001 752) in 56 mL of tetrahydrofuran, and 16.99 mL (33.97 mmol) of a 2M solution of isobutylmagnesium bromide in ether, 1.46 g of pure product are obtained in the form of a wax.
Reaction SMILES: [C@H:1]1([C:8]([OH:10])=[O:9])[CH2:4][C@@H:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH2:11]([O:6][C:5]([C@@H:3]1[CH2:4][C@H:1]([C:8]([OH:10])=[O:9])[CH2:2]1)=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Reaction time: 8 h

Procedure:
To a solution of cis-cyclobutane-1,3-dicarboxylic acid (4.00 g, 27.75 mmol), benzyl alcohol (2.87 mL, 27.75 mmol) and DMAP (0.339 g, 2.78 mmol) in DMF (80 mL) was added WSC (5.59 mL, 30.53 mmol) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the pH of the mixture was adjusted to 2 to 3 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude cis-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (5.93 g, 25.3 mmol, 91%) as a colorless oil. This compound was used for the next step without purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
From benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(O)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Nc2ccc3[nH]ccc3c2)c([N+](=O)[O-])c1
Yield: 79 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 4-chloro-3-nitrobenzonitrile (0.444 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in absolute ethanol and the reaction was heated at reflux under nitrogen for 3 hours. After evaporation of the solvent, the residue was chromatographed using ether/hexanes [1:1] to afford the title compound (79%) as a red amorphous solid. Mp, decomposes 134° C.; 13C NMR (DMSO-d6) δ146.9, 137.3, 134.8, 131.9, 131.3, 128.9, 128.3, 126.9, 119.8, 118.2, 117.9, 117.2, 112.5, 101.5, 97.4; LRMS (m/z, relative intensity) 278 (M+, 100), 261 (31), 244 (73), 231 (78). HRMS calculated for C15H10N4O2 : 278.0802. Found: 278.0808. Analytical calculated for C15H10N4O2 : C, 64.74; H, 3.62; N, 20.13. Found: 64.84; H, 3.57; N, 20.13.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:28]=5)[C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].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.O>[CH3:35][N:36]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[C:21]([C:24]6[CH:25]=[N:26][N:27]([CH:29]7[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]7)[CH:28]=6)[C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:38]=[N:37]1
Reactant: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(-c3cnn(C)c3)nn12
Temperature: 100 °C

Procedure:
A suspension of 7-[(S)-1-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)furo[3,2-c]pyridin-6-ylamine (0.289 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.507 mmol, 2.7 eq), Pd(PPh3)4 (66.8 mg, 0.0578 mmol, 20 mol %), and K2CO3 (200 mg, 1.45 mmol, 5.0 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated in a microwave reactor at 100° C. for 0.5 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by chromatography on an SCX column and HPLC giving the title compound as a diformate salt. 1H NMR (400 MHz, CD3OD): δ=2.15 (d, J=6.8 Hz, 3H), 2.25-2.40 (m, 4H), 3.18-3.28 (ddd, J=12.9, 11.6, 3.8 Hz, 2H), 3.59 (dt, J=13.3, 3.3 Hz, 2H), 3.85 (s, 3H), 4.60 (dddd, J=10.0, 4.9, 4.8 Hz, 1H), 6.34 (q, J=6.6 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 7.84 (s, 2H), 8.03 (s, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.34 (br s, 4H). MS (ES+): m/z 526.17 (20) [MH+]. HPLC: tR=1.94 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[C:26]4=[N:27][C:28]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:29][C:30](=[O:31])[N:25]4[CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[C:26]4=[N:27][C:28]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:29][C:30](=[O:31])[N:25]4[CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(CN)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reaction time: 2 h

Procedure:
To a nitrogen filled vessel containing a stirring solution of 9-{2-[2-(3-azidomethyl-phenyl)-1-methyl -ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (190 mg, 0.39 mmol) in methanol (25 mL) was added 10% palladium on carbon (20 mg). Mixture stirred over an atmosphere of hydrogen. After 2 h, reaction filtered through a bed of Celite and solvent removed under vacuum. Residue purified on silica and isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.CCCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]=[O:30])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (1.14 g, 5 mmol) in dry THF (20 mL) was cooled to −70° C. under an inert atmosphere and 1.7 M t-butyl lithium/pentane (8 mL, 13.5 mmol) was slowly added. The reaction was stirred for two hours and then dry DMF (1.2 mL, 15.5 mmol) was added. The reaction was allowed to slowly warm to room temperature over a three hour period. The reaction mixture was quenched with 3 N HCl (12 mL) and diluted with diethyl ether. The ether layer was washed with aqueous NaHCO3, dried (over Na2SO4), filtered and evaporated. The residue was triturated with cold diethyl ether to give pure t-butyl (2-chloro-3-formylpyridin-4-yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 15-20% ethyl acetate/hexane to give additional product. 1H-NMR (500 MHz, CDCl3): δ 11.0 (1H, br s), 10.52 (1H, s), 8.38 (1H, d, J. 6 Hz), 8.31 (1H, d, J. 6 Hz), 1.54 (9H, s); m/e (m+1): 257.2.
Reaction SMILES: [F:1][C:2]1([CH2:18][OH:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1([CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in CH2Cl2 (10 mL) at RT was added methanesulfonyl chloride (0.29 mL, 3.7 mmol) and triethylamine (1.04 mL, 7.5 mmol). The reaction mixture was stirred at rt for 5 min, and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate. M.S. (M+1): 346
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>O1CCCC1.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.[Cu](I)I>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])=[CH:25][C:24]=2[F:30])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][OH:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NOCCO)c1cc(C=NOCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCCO)c(F)c2F)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyimino)-methyl]-benzamide (334 mg, 0.620 mmol) prepared in Example 1 was dissolved in anhydrous tetrahydrofuran (10 mL). (PPh3)2PdCl2 (20,867-1, Sigma-Aldrich Inc.) (21 mg, 0.031 mmol), copper iodide (11 mg, 0.0062 mmol), N,N-diisopropylethylamine (130 μL, 0.774 mmol), and trimethylsilylacetylene (1 mL) were then added thereto at room temperature. The mixture was stirred at 50° C. for two hours.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN1C(=O)CCC1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:24]5[CH2:28][CH2:27][CH2:26][CH:25]5[C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: c1cc(C2CCCN2)ccn1
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3c3ccncc3)cc1OCC2
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (150 mg, 0.450 mmol), TEA (0.5 mL), and 4-(pyrrolidin-2-yl)pyridine (134 mg, 0.900 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. The resulting mixture was purified by reverse phase combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 136, which was further purified by chiral HPLC (AD column, 30% EtOH (0.1% DEA) in n-Hexane isocratic) to separate the (R) and (S) enantiomers, 23 mg of one enantiomer and 28 mg of the other (26% total yield).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20]N1C(=O)CCC1=O.O[C:29]1[C:30]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:20][C:29]1[C:30]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2C1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ncnc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of PPh3 (81.4 g, 310 mmol) and N-chlorosuccinimide (41.4 g, 310 mmol) in dioxane (850 mL) was stirred at ambient temperature for 30 minutes. To this suspension was added tert-butyl 4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and the mixture stirred at 50° C. for 18 hours. The mixture was subsequently treated with triethylamine (25 mL, 183 mmol) and the resulting brown solution concentrated. The black oil was dry packed onto silica gel and purified by chromatography eluting with 15-20% EtOAc/Hexanes to give the title compound as a yellow gum.
Reaction SMILES: C(O[C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[CH2:8][N:9]1[C:18]2[C:13](=[C:14]([CH2:23][CH:24]=[CH2:25])[C:15]([OH:22])=[C:16]([CH2:19][CH:20]=[CH2:21])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:26])C=C.C1(CN2C3C(=C(CC=C)[C:43]([OH:50])=C(CC=C)C=3)CCC2=O)CCCCC1>>[CH2:19]([C:16]1[C:15]([OH:22])=[C:14]([CH2:23][CH:24]=[CH2:25])[CH:13]=[C:18]2[C:17]=1[CH2:12][CH2:11][C:10](=[O:26])[N:9]2[CH2:8][C:7]1[CH:27]=[CH:28][C:29]([O:50][CH3:43])=[CH:5][CH:6]=1)[CH:20]=[CH2:21]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC1CCCCC1
Reactant: C=CCOc1cccc(CN2C(=O)CCc3c2cc(CC=C)c(O)c3CC=C)c1
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2Cc1ccc(OC)cc1

Procedure:
1-(3-allyloxybenzyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and 1-(cyclohexylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.
Reaction SMILES: [C:1]([S:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:29](=O)([O:35]C(C)(C)C)[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:29]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][S:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:35]
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of S-trityl cysteine (see Hiskey and Adams, J. Org. Chem., 30:1340, (1965)) (36.3 g, 0.10 mol) in dioxane (200 ml) and 1M aqueous NaOH (100 ml, 0.10 mol) was added di-t-butyl carbonate (25.36 g, 0.12 mol). The resulting opaque solution became warm and effervesced and the pH fell from 12 to 8 over one hour. After stirring for 90 min, 50% aqueous citric acid (40 ml) was added and the resulting mixture (pH 4) was extracted with ether. The ether was washed with water, then saturated brine, dried (MgSO4), filtered and evaporated to give N-BOC-S-(triphenylmethyl)-cysteine as an oil. Half of this material was dissolved in ether (200 ml) and treated with dicyclohexylamine (10 ml, 50 mmol) to give compound (XX) as a white precipitate which was filtered off, washed with ether and dried (25.1 g, 78%), mp 205°-207°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[NH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[NH:2][CH3:1])[C:7]#[N:8]
Reactant: [H][H]
Reactant: CNc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1ccc(C#N)cc1N
Yield: 95.1 %

Procedure:
4-Methylamino-3-nitrobenzonitrile (0.18 g, 1.0 mmol) was dissolved in EtOAc (10 mL) and placed in a closed vessel. 10% Pd/C (50 mg, 5 mol %) was added and the mixture was hydrogenated via a hydrogen-filled balloon that was affixed to the vessel. After 2 h the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the title product (0.14 g, 93%) as an off-white solid, which was used without further purification. 1H-NMR (CDCl3): δ 7.19 (1H, dd), 6.92 (1H, d), 6.57 (1H, d), 4.04 (1H, br s), 3.30 (2H, br s), 2.91 (3H, br s); TLC (5:95 MeOH/DCM Rf 0.33).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10]Br.[NH2:12][CH2:13][CH2:14][OH:15]>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][NH:12][CH2:13][CH2:14][OH:15]
Reactant: NCCO
Reactant: BrCCOc1ccccc1Br
Solvent: CC(C)O
Product: OCCNCCOc1ccccc1Br
Temperature: 25 °C

Procedure:
A solution of 1-bromo-2-(2-bromoethoxy)benzene (C21) (5.66 g, 20.22 mmol) and 2-aminoethanol (12.30 g, 202 mmol) in 2-propanol (50 mL) was heated to 80° C. After heating overnight, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was taken up in dichloroethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a clear yellow oil. Yield: 5.12 g, 20.18 mmol, 97%. LCMS m/z 259.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.88 (dd, J=5.3, 5.1 Hz, 2H), 3.08 (dd, J=5.1, 5.1 Hz, 2H), 3.67 (dd, J=5.3, 5.3 Hz, 2H), 4.14 (dd, J=5.1, 5.1 Hz, 2H), 6.85 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 6.91 (dd, J=8.2, 1.2 Hz, 1H), 7.26 (ddd, J=8.2, 7.6, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]([CH3:15])=[CH2:14])[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.O[C:17]1C=C(C(CC=C)CC(OC)=O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]([CH3:15])=[CH2:14])[CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(CC(=O)O)c1cccc(O)c1
Reactant: C=CCC(CC(=O)OC)c1cccc(O)c1
Product: C=C(C)C(CC(=O)OC)c1cccc(O)c1
Yield: 83 %

Procedure:
Compound 48.2 (0.63 g, 3.1 mmol) was esterified according to the method described for preparation of 43.3 to afford 48.3 (0.56 g, 83%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[S:39][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:38]3[S:39][CH:40]=[C:36]([F:35])[CH:37]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(F)cs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
To a 30 mL sealed cap glass vessel containing tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol) and 2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.599 mmol) dissolved in DME and water (4:1) was added tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.399 mmol) and potassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, and the reaction mixture was heated at 85° C. for 1 hour and then cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and solvent removed via rotary evaporation to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the resulting mixture was stirred at room temperature for 1 hour to give crude product, which was purified via preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to minimal volume, and lyophilized to give a TFA salt of the title compound (86 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (d, J=9.60 Hz, 1H), 2.03-2.18 (m, 1H), 3.53-3.68 (m, 1H), 3.75 (d, J=11.62 Hz, 1H), 3.85 (br s, 1H), 4.01 (d, J=12.38 Hz, 2H), 4.32 (td, J=8.53, 4.17 Hz, 1H), 4.45 (s, 2H), 7.32 (t, J=1.64 Hz, 1H), 7.40 (d, J=5.31 Hz, 1H), 7.95 (br s, 3H), 8.65 (s, 1H), 8.98 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C16H16F2N4O2S, 367. found, 367.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[S:39]([C:32]2[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[CH3:43])(=[O:41])=[O:40])=[CH:7][CH:8]=1
Reactant: COc1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(Cc2ccc(OC3CCCCO3)cc2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-methoxy-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.100 g, 0.319 mmol) and triethylamine (0.133 mL, 0.957 mmol) in 2 mL methylene chloride was added 2-mesitylenesulfonyl chloride (0.139 g, 0.638 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with 2 mL methylene chloride and the combined organic layers were evaporated to afford the title compound of Step A which was used in the next step without further purification.