Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C@H:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1)[CH3:22].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:32](=[O:33])[CH2:31][O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][C@H:24]([O:23][CH2:21][CH3:22])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][CH:35]=2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCNCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of N-[4-(benzyloxy)benzyl]-N-butylamine (3.59 g, 12.0 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (2.96 g, 10.0 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (4.00 mL, 23.0 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.85 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.80 g (33%) of a whitish oil.
Reaction SMILES: [F:1][C:2]([F:30])([C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[C:22]([F:23])[C:17]2=[N:16][N:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([OH:13])=[CH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CO.C(Cl)Cl.C1COCC1>[F:30][C:2]([F:1])([C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[C:22]([F:23])[C:17]2=[N:16][N:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([O:13][CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[CH:6]2
Reactant: OCCCN1CCOCC1
Reactant: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(O)cc5c4)n3c2)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(OCCCN6CCOCC6)cc5c4)n3c2)cn1
Temperature: 0 °C
Yield: 33 %

Procedure:
To a flask charged with 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol (17.3 mg, 42 mol), was added triphenylphosphine (55 mg, 211 μmol), THF (1 mL), and 4-(3-hydroxypropyl)-morpholine, 95% (31 μl, 211 μmol). The mixture was placed under N2 and cooled to 0° C. Di-tert-butyl azodicarboxylate (49 mg, 211 μmol) was added as a solid in a single portion and the solution was allowed to warm to rt and was maintained for 48 h. The solution was concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 99:1 CH2Cl2:MeOH to 90:10 CH2Cl2: MeOH gradient to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-(3-morpholinopropoxy)quinoline (7.5 mg, 33% yield) as a colorless solid. LRMS (ESI) m/z calcd for C27H27FN7O2 (M+H) 538.2. found 538.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH2:30]C=C)[C:15](=[O:29])[C@H:16]([NH:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[CH2:17][CH:18]=[CH2:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCOC(C)=O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C@@H:16]2[CH2:17][CH:18]=[CH:19][CH2:30][N:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]3)[C:15]2=[O:29])[CH:26]=[C:25]([F:27])[CH:24]=1
Reactant: C=CC[C@@H](Nc1cc(F)cc(Cl)c1)C(=O)N(CC=C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CC=CC[C@@H](Nc3cc(F)cc(Cl)c3)C2=O)C1
Temperature: 25 °C

Procedure:
A solution of (R)-3-{allyl-[(R)-2-(3-chloro-5-fluoro-phenylamino)-pent-4-enoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.4 mmol) in DCM (50 mL) was degassed and purged with argon. To the solution was added Grubb's 2nd generation catalyst (0.12 g, 0.13 mmol) and the mixture was refluxed for 90 minutes. After the solution was cooled to rt, the solvent was removed under reduced pressure to afford a solid which was dissolved in EtOAc. The organic phase was washed with brine, a solution of NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford a residue which was purified by silica gel chromatography (gradient hexanes:EtOAc 0-70%). LCMS, m/z 381.9 [M-tBu]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C([O:12][CH:13]=[C:14]([C:20]([O-])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[OH:12][C:13]1[C:7]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:9][CH:8]=2)[N:6]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: COc1cccc(N)c1
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1O

Procedure:
Using the procedure of Steps A and B of Example 19, 3-methoxy-aniline and ethyl ethoxymethylenemalonate were reacted to obtain ethyl 4-hydroxy-7-methoxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]3[C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][C@@H:34]([CH2:43][S:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)(=O)=O)[CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[C:29]([S:53]([C:56]([F:59])([F:58])[F:57])(=[O:55])=[O:54])[CH:28]=4)(=[O:26])=[O:25])=[N:21][N:22]=[C:16]3[CH2:15]2)[CH2:10][CH:9]1[CH3:60])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:60][CH:9]1[CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][N:17]3[C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][C@@H:34]([CH2:43][S:44][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:35][CH2:36][N:37]5[CH2:38][CH2:39][O:40][CH2:41][CH2:42]5)=[C:29]([S:53]([C:56]([F:59])([F:57])[F:58])(=[O:55])=[O:54])[CH:28]=4)(=[O:26])=[O:25])=[N:21][N:22]=[C:16]3[CH2:15]2)[CH2:12][CH2:13][NH:8]1
Reactant: CC1CC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CS(=O)(=O)c4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CCN1
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
To a solution of 2-methyl-4-{3-[4-((R)-3-morpholin-4-yl-1-phenylsulfonylmethylpropyl-amino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester (42 mg, 0.048 mmol) in CH2Cl2 (1 mL) under nitrogen was added trifluoroacetic acid (0.093 mL, 1.203 mmol) and the reaction was stirred for 2.5 hours. The reaction mixture was then concentrated and diluted with water and CH2Cl2. It was then basified to pH approximately 8 with saturated Na2CO3. The aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-[7-(2-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide (22 mg, 59% yield). MS [m/z; (M+1)+]: 773.6
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([O:15]C(C)(C)C)=[O:14])[CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O.C(Cl)[Cl:28]>>[ClH:28].[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:8]=2)[NH:3]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)CC(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Yield: 33 %

Procedure:
To a stirred solution of tert-butyl (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylate (0.80 g, 3.1 mmole) in CH2Cl2 (50 mL) at RT was added trifluoroacetic acid (20 mL). After 1 hr the reaction solution was concentrated and the residue was dried under vacuum. An HCl solution (20 mL, 4 M in dioxane) was added and the mixture was concentrated under vacuum. The remaining solid was triturated with diethyl ether and filtered giving the title compound (0.74 g, 33%) as a white solid: MS (ES) m/e 205 (M+H−HCl)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:22]([C:25]2[C:26](Cl)=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:22]([C:25]2[CH:26]=[N:27][C:28]([O:11][CH:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]3)=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1cccnc1Cl
Reactant: CS(=O)(=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a solution of 1-methanesulfonyl-piperidin-4-ol (86 mg, 482 μmol) in anhydrous THF (5 mL) at room temperature was added NaH (60% dispersion in mineral oil, 21 mg, 526 μmol) and the reaction was stirred at room temperature for 15 minutes. Chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (150 mg, 439 μmol) was added and the reaction stirred at room temperature for 45 minutes then heated at 80° C. for 2 hours. Water and saturated NaHCO3 were added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-25% EtOAc in cyclohexane) to give the title compound (137 mg). 1H NMR (400 MHz, DMSO): δ 8.30 (dd, J=2.6, 0.67 Hz, 1H), 7.75 (dd, J=8.8, 2.60 Hz, 1H), 7.19-7.20 (m, 4H), 6.97 (dd, J=8.8, 0.7 Hz, 1H), 5.23-5.25 (m, 1H), 3.39 (d, J=8.8 Hz, 4H), 3.13 (ddd, J=12.2, 8.56, 3.46 Hz, 2H), 2.91 (s, 3H), 2.04-2.09 (m, 2H), 1.78-1.80 (m, 2H), 1.44 (dd, J=13.6, 6.9 Hz, 1H), 0.85 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 485.9 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11]N1C(=O)CCC1=O>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=C1Cc2cc(I)ccc2N1
Temperature: 10 °C
Yield: 58 %

Procedure:
2-Oxindole (82.9 g) was suspended in 630 mL of acetic acid with mechanical stirring and the mixture cooled to 10° C. in an ice water bath. Solid N-iodosuccinimide (175 g) was added in portions over 10 minutes. After the addition was complete the mixture was stirred for 1.0 hour at 10° C. The suspended solid which had always present became very thick at this time. The solid was collected by vacuum filtration, washed with 100 mL of 50% acetic acid in water and then with 200 mL of water and sucked dry for 20 minutes in the funnel. The product was dried under vacuum to give 93.5 g (36%) of 5-iodo-2-oxindole containing about 5% 2-oxindole by proton NMR.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 145, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.05 mmol) was reacted with phenyl isocyanate to provide 0.45 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}-N′-phenylurea as a white powder, m.p. 125.0-130.0° C. Analysis: Calculated for C25H30N6O2.0.40 H2O: % C, 66.18; % H, 6.84; % N, 18.52. Found: % C, 66.05; % H, 6.61; % N, 18.64. % H2O calculated: 1.59. found: 1.53 (Karl Fisher);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][C@@H:13]([OH:22])[C@@:12]2([OH:23])[C:11]2[C:24]([O:31][CH2:32][CH3:33])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[CH:27][C:10]=2[O:9]3)=[CH:4][CH:3]=1.[NH2:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.CS(C)=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>[NH2:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]([C@:8]34[C@H:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH2:14][C@@H:13]([OH:22])[C@@:12]3([OH:23])[C:11]3[C:24]([O:31][CH2:32][CH3:33])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[CH:27][C:10]=3[O:9]4)=[CH:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Br)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(-c4cccc(N)c4)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O

Procedure:
51.1 mg (0.10 mmol) of (1R*,3S*,3aR*,8bS*)-3a-(4-bromophenyl)-6,8-diethoxy-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 8A), 15.5 mg (0.10 mmol) of 3-aminophenyl boronic acid, 10.6 mg (0.10 mmol) of sodium carbonate and 5.8 mg (0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) are heated in a mixture of 0.1 ml of water and 0.5 ml of dioxane at 80° C. under argon overnight. The mixture is then diluted with DMSO and filtered, and the filtrate is purified by preparative HPLC. 17.4 mg (25% of theory) of the product are obtained.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([N:27]2[CH2:32][CH2:31][C@:30]([CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:29][C:28]2=[O:44])[CH3:26])=[CH:21][CH:20]=1)#[CH:18].CN(C)C=O>[Cu]I.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.O>[OH:43][C:40]([CH3:41])([CH3:42])[CH2:39][C@@:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:29][C:28](=[O:44])[N:27]([C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([C:17]#[C:18][C:9]3[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=3)=[CH:24][CH:23]=2)[CH3:26])[CH2:32][CH2:31]1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Reactant: Cn1ccc(Br)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C#Cc2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
CuI (68 mg), Pd(PPh3)2Cl2 (125 mg), and NEt3 (0.82 mL) were added successively to a flask charged with a stir bar, 4-bromo-1-methyl-1H-pyridin-2-one (0.38 g), 3-[(S)-1-(4-ethynyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.61 g), and N,N-dimethylformamide (3 mL) and kept at room temperature under argon atmosphere. The resulting mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling the mixture to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel twice (first chromatography: ethyl acetate/methanol 1:0->4:1; second chromatography: dichloromethane/methanol 19:1->9:1) to afford the title compound as an oil which crystallized from ethyl acetate. Yield: 0.27 g (34% of theory); LC-MS (Method 1): tR=3.41 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.O.[NH2:12][NH2:13].O.C(OCC)(=O)C>C(O)CCC>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:13][N:12]=[CH:7]2
Reactant: O=Cc1cc(Br)ccc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]ncc2c1
Temperature: 65 °C
Yield: 29.5 %

Procedure:
To an orange solution of 5-bromo-2-fluorobenzaldehyde (3.0 g, 14.78 mmol) in n-butanol (6 mL) was added hydrazine hydrate (11.1 g, 10.78 mL, 221.66 mmol) and the thick orange slurry was heated to 125° C. (became clear at 65° C.) in an oil bath for 21 h and cooled to rt. The mixture was poured into water (100 mL) and ethyl acetate (300 mL). The aqueous layer was isolated and extracted with ethyl acetate (100 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated. The product was isolated by column chromatography (33% ethyl acetate in hexanes) as a cream colored solid (0.86 g, 30%). LC-MS [M+H]+=197.1, RT=2.64 min.
Reaction SMILES: [CH2:1]([S:3][CH:4](SCC)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].O.C(S)C>P(=O)(O)(O)O.CCOCC>[CH2:1]([S:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCC(SCC)SCC
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCS
Solvent: CCOCC
Product: CCCCCC=CSCC
Yield: 1.8 %

Procedure:
A mixture of 1,1-di(ethylthio)-heptane (54.5 g., 10.25 mole) and 10 drops of 89% phosphoric acid is heated in a Claisen flask at a pressure of 200-250 mm. Care is taken that the vapor temperature does not exceed 165°. The receiver is cooled with water so that ethanethiol does not condense. The distillate is diluted with ether and washed with 2 N sodium hydroxide and water and dried. Distillation (87°-90°/12 mm.) afforded 1-ethylthio-1-heptene (30 g., 78%), nD20 1.4760.
Reaction SMILES: FC1C=CC=C(F)C=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]23)[CH:17]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O.[OH-].[Ba+2].[OH-]>COCCOC.C(OCC)(=O)C.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>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C@H:13]3[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]23)[CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCNC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCNC3)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-butyl (±)-cis-bromo-4-oxo-1,2,3,4,7b,10,11,11a-octahydro[1,4]diazepino[6,7,1-hi]pyrido[4,3-b]indol-9(8H)-carboxylate from EXAMPLE 70, Part E (150 mg, 0.356 mmol), 2,4-dichlorophenylboronic acid (82 mg, 0.430 mmol) and barium hydroxide (170 mg, 0.540 mmol) were dissolved in DME (7 mL) and water (4 mL), and degassed for 10 minutes under nitrogen. Tetrakis (triphenylphosphine)palladium (O) (10 mg, 0.007 mmol) was added and the reaction was heated to 90° C. for 13 h. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (13% ethyl acetate, hexanes). Fractions were collected, concentrated to a solid, then dissolved in 20% TFA/CHCl3 and stirred for 1 hour. The reaction solution was cooled to 0° C. in an ice bath, and basified to pH=10 with concentrated NH4OH. This was extracted with CHCl3 (3×15 ml), organics collected, dried over MgSO4 and concentrated under reduced pressure to give to give the title compound. 1H NMR(CDCl3, 300 MHz): δ 7.52 (d, 1H, J=1.8 Hz), 7.44 (d, 1H, J=1.8 Hz), 7.26-7.20 (m, 2H), 6.45 (s, 1H), 4.34 (t, 2H, J=9.2 Hz), 4.14-4.06 (m, 2H), 3.18-2.95 (m, 3H), 2.88-2.75 (m, 3H), 2.14 (s-br, 1H), 1.96-1.79 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: Brc1cccc2[nH]ncc12
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2cc(-c3cccc4[nH]ncc34)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
4-bromo-1H-indazole (37.9 mg, 0.192 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (145.7 mg, 0.384 mmol), Fibercat palladium catalyst (Johnson-Matthey, 64.7 mg), and K2CO3 (2 M in water, 0.75 ml, 1.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (2.3 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, washed with water (3×5 ml), dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->75% EtOAc/hexanes). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (7.4 mg, 10%). MS (ESI pos. ion) m/z: 370 (M+H). Calc'd Exact Mass for C22H15N3OS: 369.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:12][CH2:13]1
Reactant: Cc1nc(N)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(N2CCC(N)CC2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
3.2 g (7.6 mmol) of {1-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester are dissolved in DCM (50 mL) and 26 mL TFA are added. The reaction mixture is stirred over night at RT. The reaction mixture is adjusted to neutral pH using concentrated aqueous Na2CO3 solution and the DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried. The crude product is used without further purification in the next step.