Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:6]1=[O:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[O:25]=[C:6]1[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][CH2:3][CH:2]=[O:1]
Reactant: O=C1N(CCCO)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 17 h
Yield: 87.6 %

Procedure:
To a solution of 1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (2.00 g, 5.92 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (3.70 g, 8.46 mmol). The reaction mixture was stirred at 0° C. for 17 h, diluted with ethyl acetate, washed with 10% sodium thiosulfate solution and saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, the residue was subjected to column chromatography with ethyl acetate in hexanes (20% to 50% gradient) to afford 3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal (1.74 g, 87%): MS (ES+) m/z 336.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:55][C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]>>[F:55][C:56]1[CH:57]=[C:58]([C:2]2[C:3](=[O:28])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:5]=3)[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCOCC4)cc3C2=O)cc1F
Yield: 81 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 of Example 124 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: OCCCc1cccc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1c(Cl)cccc1CCCBr
Yield: 87.1 %

Procedure:
Compound 63-2 (2.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.80 g) and N-bromosuccinimide (2.57 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:13]([OH:14])=[CH:12][C:5]2[C:6](=O)[C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:13]([OH:14])=[CH:12][C:5]2[C:6](=[S:24])[C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)Oc2cc(Cl)c(O)cc2C1=O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc(Cl)c(O)cc2C1=S
Temperature: 25 °C

Procedure:
A solution of 20 mmol 6-chloro-5-hydroxy-2,2-dimethyl-benzofuran-3-one in 30 ml toluene is admixed with 10 mmol Lawesson's reagent and heated for 3 hours to boiling under reflux. After cooling to room temperature it is filtered on 50 g silica gel. The red fraction of the filtrate is collected. After removing the toluene by distillation a red oil remains.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[S:26]1(=[O:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[NH:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:29]4[CH2:28][CH2:27][S:26](=[O:25])(=[O:40])[CH2:31][CH2:30]4)=[CH:34][CH:35]=3)=[CH:19][CH:20]=2)[C:12]([CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 118 h
Yield: 82.6 %

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-methyl-biphenyl-4-carboxylic acid (500 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl) -phenylamine (367 mg), triethylamine (0.64 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (869 mg) in dry DMF (20 ml) was stirred at 20 C for 118 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol; 1:1 removed high Rf impurities and further elution with ethyl acetate gave the title compound as a pale yellow solid (693 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].C(OCC)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:10](=[O:12])[CH2:11][C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH:9]=1
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(Cl)cc1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.2 mmol) was added portionwise to a stirred solution of 1-(5-chloro-2-methoxy-phenyl)-ethanone (10.0 g, 54.2 mmol) in THF (100 mL) at 0° C. The mixture was then stirred for 10 minutes before addition of diethyl carbonate (7.68 g, 65.0 mmol) and then for an additional 1 hour. The mixture was warmed to room temperature for 2 hours and then heated to 65° C. for 2 hours. Diethyl ether was added, the organics washed with water and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (50 to 100% dichloromethane in cyclohexane) to yield 3.41 g of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=257.2; NMR (400 MHz, CDCl3): δ 7.59 (d, 1H); 7.38 (dd, 1H); 6.89 (d, 1H); 4.18 (q, 2H); 3.95 (s, 2H); 3.88 (s, 3H); 1.24 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][CH:18]4[CH2:20][CH:19]4[C:21]([O:23][CH3:24])=[O:22])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[Si:25]([O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CC=CC=1.CC1C=CC(S(OCC23CCC(C4SC(C)=NC=4C4C=CC=CC=4)(CC2)OC3)(=O)=O)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Si:25]([O:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][CH:18]4[CH2:20][CH:19]4[C:21]([O:23][CH3:24])=[O:22])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Reactant: COC(=O)C1CC1CCC12CCC(c3cccc(O)c3)(CC1)OC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CC1CCC12CCC(c3cccc(Oc4cccc(O[Si](C)(C)C(C)(C)C)c4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.2 %

Procedure:
A mixture of methyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropane-carboxylate (65B; 360 mg, 1.09 mmol), (3-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (340 mg, 1.348 mmol), Cu(OAc)2 (237 mg, 1.31 mmol), TEA (1.52 mL, 10.9 mmol), pyridine (0.88 mL, 10.9 mmol), and 4A molecular sieves (5 g) in DCM (10 mL) was stirred under air at rt for 3 days. The reaction was then filtered, and the filtrate was concentrated in vacuo. The residual crude oil was dissolved in EtOAc (15 mL) and washed with 1N aq. HCl and water, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 30% over 10 min EtOAc/hexane) to give the title compound (570 mg, 1.06 mmol, 97% yield) as a clear oil. LCMS [M+H]+=537.3; 1H NMR (CDCl3) δ: 7.26 (t, J=7.9 Hz, 1H), 7.18-7.11 (m, 2H), 7.09 (dd, J=2.5, 1.7 Hz, 1H), 6.85 (ddd, J=8.1, 2.5, 1.0 Hz, 1H), 6.58 (dd, J=8.2, 2.3 Hz, 2H), 6.49 (t, J=2.3 Hz, 1H), 3.78 (d, J=1.1 Hz, 2H), 3.68 (s, 3H), 2.00 (dt, J=11.4, 4.1 Hz, 4H), 1.62 (dtd, J=8.1, 4.1, 3.5, 2.0 Hz, 4H), 1.41-1.14 (m, 7H), 0.97 (s, 9H), 0.71 (ddd, J=8.1, 6.3, 4.1 Hz, 1H), 0.18 (s, 6H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH:10][N:11]=[C:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[N:9]=[C:8]([N:10]([CH3:26])[N:11]=[C:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=NNc2cccc(Br)n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(N=C1CCCN(C(=O)OC(C)(C)C)CC1)c1cccc(Br)n1
Reaction time: 0.33 h
Yield: 103.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.83 g, 21 mmol) was added to a solution of tert-butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate (6.4 g, 17 mmol) in DMF (54 mL) at room temperature under N2 and stirred for 20 min. Methyl iodide (1.1 mL, 18 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (100 mL). The solution was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (4×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a dark orange oil. The oil was diluted with EtOAc (100 mL) and washed with brine (6×50 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to provide the title compound (7.00 g, quant.) as an amber oil: 1H NMR (300 MHz, DMSO-d6) δ 7.44-7.36 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.49-6.38 (m, 1H), 3.56-3.35 (m, 4H), 3.06-3.04 (m, 3H), 2.75-2.50 (m, 4H, overlaps with H2O), 1.72-1.51 (m, 2H), 1.43-1.15 (m, 9H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18]([CH2:19][CH:20]=[CH:21][CH:22]=3)=[CH:17][NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.O.[H][H]>[Pd].CO>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][C:15]1=[O:24]
Reactant: O=C1NC=C2CC=CC=C2N1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NCc2ccccc2N1C1CCNCC1
Temperature: 40 °C
Yield: 44.3 %

Procedure:
In this reference example, 16.0 g of 1-benzyl-4-[3,5-dihydro-2(1H)-quinazolinon-1-yl]-piperidine, 4.0 g of 10% Pd-C, 50 ml of 1 N hydrochloric acid, 150 ml of water and 300 ml of methanol are mixed and stirred at 40° C. Hydrogen gas is introduced to the mixture for 5 hours with stirring. Then, the Pd-C is removed by filtration and the filtrate is concentrated. The white crystalline residue is dissolved in 50 ml of water. The solution is adjusted to pH 10 with aqueous 5 N sodium hydroxide and extracted with chloroform. The extract is washed with water, dried and thereafter concentrated. Then, 50 ml of a mixture of ethyl acetate and n-hexane (1:1 by volume) is added to the residue. After trituration, the solid is separated by filtration, washed with the same mixed solvent to obtain 9.9 g of a crude product. The crude product is recrystallized from water-ethanol to obtain 5.1 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.O.[C:31]([OH:35])(=[O:34])[CH:32]=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]2[C:7]=1[CH:32]([C:31]([OH:35])=[O:34])[N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH2:9][CH2:8]2
Reactant: COc1ccc(Br)cc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Br)c2c1CCN(S(=O)(=O)c1ccc(Oc3ccc(F)cc3)cc1)C2C(=O)O
Reaction time: 12 h
Yield: 92.1 %

Procedure:
0.81 g (1.7 mmol) of N-[2-(5-bromo-2-methoxyphenyl)ethyl]-4-(4-fluorophenoxy)-benzenesulfonamide (crude product, 21A) is stirred with 0.32 g (3.4 mmol) of glyoxylic acid monohydrate in 10 ml of trifluoroacetic acid at room temperature. After 12 hours, the mixture is poured onto ice and extracted with dichloromethane. Drying with MgSO4 and concentration result in 0.84 g of the title compound which can be reacted further without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 14, 1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester, according to the procedure of Example 1 as an off-white solid; mp 52-58° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.10-1.20 (m, 6H), 1.20-1.35 (m, 2H), 1.50-2.00 (m, 6H), 2.91 (s, 3H), 2.50-3.00 (m, 7H), 3.70-3.90 (m, 2H), 4.00 (m, 1H), 4.40-4.50 (m, 1H), 4.85-5.00 (m, 1H), 6.77 (d, 1H), 6.98 (d, 1H), 7.03 (d, 2H), 7.18 (d, 1H), 7.57 (d, 2H); MS (ES) m/z: 625.1 (MH+); HRMS Calcd. for C28H40N4O8S2 (MH+): 625.2360. Found: 625.2366.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=4)=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.Cl[C:38](=[O:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[C:38]([N:25]1[CH2:24][CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[O:12][C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)=[N:15][CH:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1)=[O:44])[CH3:43]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Clc1cccc(Nc2ncc(-c3ccc(C4=CCNCC4)cc3)o2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of (3-chlorophenyl)-{5-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-oxazol-2-yl}-amine bis HCl salt (50 mg, 0.12 mmol) in DCM (1 mL) at 0° C. is added DIEA (0.052 mL, 0.3 mmol) and after stirring for 5 min, ethyl chlorooxoacetate (0.016 mL, 0.14 mmol) is added dropwise. The mixture is stirred for 2 h and the mixture is purified by RP-HPLC to give the title compound: 1H NMR (400 MHz, DMSO-D6) δ 1.30 (q, J=7.07 Hz, 3H) 2.58 (m, 2H) 3.55-3.90 (m, 2H) 4.07-4.20 (m, 1H) 4.32 (m, 2H) 6.21-6.29 (m, 1H) 7.00 (dd, J=7.45, 1.64 Hz, 1H) 7.34 (t, J=8.08 Hz, 1H) 7.47-7.60 (m, 6H) 7.86 (t, J=2.02 Hz, 1H); (M+H)+452.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[CH2:37](O)[C:38]#[C:39][CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([CH2:23][N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:37][C:38]#[C:39][CH3:40])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH3:12])=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)cc(CN2CCN(C)CC2)c1N(C)S(=O)(=O)c1ccc(O)cc1
Reactant: CC#CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of 0.810 g (1.59 mmol) of the product of Example 73 and 0.594 mL (7.95 mmol) of 2-butyn-1-ol in 8 mL of THF, was added 2.08 g (7.95 mmol) of triphenylphosphine and then 1.25 mL (7.95 mmol) of diethyl azodicarboxylate. The mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 2% methanol/dichloromethane to provide 0.830 g (93%) of the desired product as a beige solid. Electrospray Mass Spec 562.1 (M+H)+
Reaction SMILES: COC[CH2:4][O:5][CH2:6][CH2:7][NH2:8].[CH3:9][C@@H:10]1[CH2:12][C@H:11]1[C:13](O)=O>>[CH3:4][O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH3:13]
Reactant: C[C@@H]1C[C@H]1C(=O)O
Reactant: COCCOCCN
Product: COCCNCC1CC1C

Procedure:
Prepared from 2-(2-methoxyethoxy)ethanamine and trans-2-methylcyclopropanecarboxylic acid using steps A and B in the procedure described for the synthesis of Intermediate 3.6.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:11]=[CH:10][C:15]4[C:14]([CH:13]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH2:33][N:35]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: OC1CCNC1
Reactant: Nc1ncnn2c(-c3cccc(CBr)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(-c3cccc(CN4CCC(O)C4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 55 °C
Yield: 22.1 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-[3-(bromomethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (125 mg, 025 mmol) in DMF (1 mL) was added 3-pyrrolidinol (26 μL, 0.27 mmol), triethylamine (103 μl, 0.74 mmol), and sodium iodide (0.4 mg, 0.002 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.92-8.00 (m, 3 H), 7.83 (d, 1 H), 7.69 (d, 1 H), 7.25-7.44 (m, 7 H), 7.22 (dd, 1 H), 7.14 (s, 1 H), 5.67 (s, 2 H), 4.68 (d, 1 H), 4.09-4.21 (m, 1 H), 3.60 (q, 2 H), 2.65-2.72 (m, 1 H), 2.58 (q, 1 H), 2.37-2.46 (m, 1 H), 2.32 (dd, 1 H), 1.93-2.03 (m, 1 H), 1.48-1.59 (m, 1 H); ES-MS m/z 516.20 [M+H]+, HPLC RT (min) 2.53.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[NH:20][CH2:19][CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)=[CH:5][CH:4]=1.Br[CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([NH:25][CH3:26])=[O:24].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[N:20]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([NH:25][CH3:26])=[O:24])[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC2NCCc3ncccc32)cc1
Reactant: CNC(=O)C(Br)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(c1ccccc1)N1CCc2ncccc2C1CCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34.7 %

Procedure:
To a solution of 615 mg (2.29 mmol) 5-[2-(4-methoxy-phenyl)-ethyl]-5,6,7,8-tetrahydro-[1,6]naphthyridine in 25 mL acetonitrile, were added 682 mg (2.98 mmol) 2-bromo-N-methyl -2-phenyl-acetamide, 1.2 mL (6.87 mmol) N-ethyldiisopropylamine and 343 mg (2.29 mmol) sodium iodide. The solution was stirred at 60° C. for 6 h. The solvent was removed in vacuo and the residue was taken in ethyl acetate. The mixture was washed once with water and once with a 2M Na2CO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 330 mg (35%) of 2-{5-[2-(4-methoxy-phenyl)-ethyl]-7,8-dihydro-5H-[1,6]naphthyridin-6-yl}-N-methyl-2-phenyl-acetamide (diastereoisomer 1, first eluting diastereoisomer) as yellow foam
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:7]=1N.[ClH:17]>O.[Cu]Cl>[Cl:17][C:7]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([CH3:13])=[CH:12][C:6]=1[F:5]
Reactant: Cl
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of sodium nitrite (7.6 g, 110 mmol) in water (20 mL) was added dropwise over 30 min at 0° C. to a stirred suspension of 2-fluoro-4-methyl-5-nitroaniline (17 g, 100 mmol) in concentrated hydrochloric acid (200 mL). The mixture was stirred at 0° C. for 20 min then transferred to a dropping funnel and added dropwise over 30 min to a stirred suspension of copper(I)chloride (16 g) in concentrated hydrochloric acid (150 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 h then poured onto ice-water (1.5 L) and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; heptane] to give the product (14.2 g, 75%) as a yellow solid. An analytical sample was recrystallised (heptane) to give a white solid: mp 57-58° C.; NMR δH (400 MHz, CDCl3) 8.03 (1H, d, J 7.2 Hz), 7.13 (1H, d, J 9.1 Hz), 2.6 (3H, s).