Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[CH:5]=1)[CH3:2].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=2)[CH:11]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOc1ccnc(-c2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a suspension of 3-(4-ethoxypyridin-2-yl)aniline (258 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (399 mg) and diisopropylethyl-amine (0.482 ml) in dichloromethane (12 ml) was added 1-methyl-2-chloropyridinium iodide (400 mg), and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl) -N″-(3-(4-ethoxypyridin-2-yl)phenyl)guanidine (389 mg).
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([NH:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+]>CC#N>[N:10]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:2][CH2:3][C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[NH:9]1
Reactant: COC(=O)[C@H](CCI)NNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.9 %

Procedure:
To a solution of phenylmethyl 2-{(1S)-3-iodo-1-[(methyloxy)carbonyl]propyl}hydrazinecarboxylate (3.38 g, 8.6 mmol) in CH3CN (500 mL) was added K2CO3 (2.38 g, 17.2 mmol), and the mixture was stirred overnight at rt. LC-MS showed that all starting material was consumed. The mixture was filtered, and the filtrate was concentrated to provide the crude 3-methyl 1-(phenylmethyl) (3S)-1,3-pyrazolidinedicarboxylate as an oil (2.77 g, 100%) without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:19]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:11][C@H:9]1[O:8][C@@:7]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:19]=[C:2]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=3)[C:20]#[N:21])[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: CC1Nc2ccc(Br)cc2C(C)(c2ccccc2)O1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
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: COCCOC
Solvent: O
Product: C[C@@H]1Nc2ccc(-c3cc(F)cc(C#N)c3)cc2[C@](C)(c2ccccc2)O1
Temperature: 85 °C
Yield: 13.2 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine (0.6 g, 1.9 mmol), 3-cyano-5-fluorobenzene boronic acid (0.45 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmol), sodium carbonate (0.6 g, 5.7 mmol) in a mixture of DME and water (20/5 mL) was subject to a positive nitrogen flow to remove oxygen and then heated to 85° C. under a blanket of nitrogen for 2 hours. The mixture was allowed to cool to ambient temperature. Brine (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/4:1) to afford the title compound as off-white solid (0.09 g, 13%): mp 128-129° C.; 1H-NMR (DMSO-d6) δ 8.08 (s, 1H), 7.91 (dt, 1H, J=10.7, 1.9 Hz), 7.71 (d, 1H, J=2.0 Hz), 7.65 (m, 1H), 7.57 (dd, 1H, J=8.8, 2.4 Hz), 7.32-7.36 (m, 2H), 7.24-7.29 (m, 3H), 6.71 (d, 1H, J=1.6 Hz), 6.69 (d, 1H, J=8.3 Hz), 4.33 (m, 1H), 1.84 (s, 3H), 1.24 (d, 3H, J=5.5 Hz); MS (ESI) m/z 357 [M−H]−.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCN1CCN(CC(=O)OC)C(=O)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN1CCN(C(Cc2ccccc2)C(=O)OC)C(=O)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)acetate (Intermediate E, 270 mg, 1.1 mmol) in 10 mL THF, cooled to −78° C., was added lithium bis(trimethylsilyl)amide (1M solution in THF, 1.3 mL, 1.3 mmol) dropwise. The reaction was stirred at −78° C. for 30 min and benzyl bromide (0.33 mL, 2.75 mmol) was added. The mixture was allowed to warm to rt over 2.5 h, quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. Flash chromatography (silica gel, 50-100% EtOAc/hexanes) gave methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)-3-phenylpropanoate. 1H NMR (CDCl3) δ 7.26 (m, 5H), 5.35 (X of ABX, 1H, J=11 Hz, J=5.6 Hz), 3.76 (s, 3H), 3.47-3.34 (m, 6H), 3.12 (m, 2H), 1.49 (m, 2H), 1.27 (m, 2H), 0.90 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:21]=1)(=[O:3])[CH3:2].C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: CC(=O)c1ccc2c(c1)CCc1ccc(CO)cc1S2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([NH2:38])[CH:40]=2)=[O:15])[CH:3]=1
Reactant: NCc1cccc(N)c1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2cccc(N)c2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 3-aminobenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.27-1.39 (m, 3H) 4.18-4.75 (m, 4H) 6.31-7.50 (m, 5H). MS (ESI) positive ion 312 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([OH:32])[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29].[OH-].[Na+].I[CH3:36]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([O:32][CH3:36])[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29]
Reactant: CCC(C)(C)C(O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(C)(C)C(OC)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2,2-dimethylbutan-1-ol (53.8 mg) in DMF (1227 μL) were added 60% sodium hydroxide (9.8 mg) and iodomethane (15.3 μL) at 0° C., and the mixture was stirred for 5 hr. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (42.1 mg) as a transparent gummy substance.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CCCCCC.O1CCCC1>[CH2:17]([C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:22][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC1(c2ccccc2)CC=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 10 mmol of methyl acetoacetate, 11 mmol of NaH 60% dispersion in oil, 10.5 mmol of 1.6M n-butyl lithium in hexane, 10 mmol of hexanophenone and 28 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 123°-124° C.). 1H NMR (CDCl3) δ0.83 (t, 3H), 1.1-1.4 (m, 6H), 1.9-2.0 (m, 2H), 2.90 (d, 1H), 2.92 (d, 1H), 3.25 (d, 1H), 3.35 (d, 1H), 7.2-7.5 (m, 5H).
Reaction SMILES: [C:1]([O:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:25](C(OCC4C=CC=CC=4)=O)[CH2:24][CH2:23][C@@:20]4([C:21]=2[CH:22]=1)[C@H:15]3[CH2:16][CH2:17][CH2:18][CH2:19]4)(=[O:5])[CH:2]([CH3:4])[CH3:3]>CCO.[Pd]>[C:1]([O:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[NH:25][CH2:24][CH2:23][C@@:20]4([C:21]=2[CH:22]=1)[C@H:15]3[CH2:16][CH2:17][CH2:18][CH2:19]4)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Yield: 37.4 %

Procedure:
(+)-[N-(Benzyloxycarbonyl)morphinan-3-yloxy]methyl isobutyrate (4.12 g, 8.63 mmol) from Example 44 was subjected to hydrogenation (balloon) on 10% Pd/C (600 mg) in EtOH (100 mL) at room temperature. After the reaction was completed, the reaction mixture was filtered through a Celite, and washed with EtOH (300 mL). The combined EtOH solution was evaporated under vacuum. The residue was further purified by reverse-phase prep HPLC to provide the title compound (1.11 g, 37%) as a light yellow gum.
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=[O:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.Cl>C(O)C>[OH:9][C:8]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[C:13]([Br:12])[CH:14]=3)[NH:18][CH:17]=2)[C:6](=[O:7])[NH:5][C:3](=[O:4])[NH:2][C:10]1=[O:11]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(O)(c2c[nH]c3ccc(Br)cc23)C(=O)N1
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
Alloxan hydrate (1.6 g., 0.01 mole) was dissolved in 40 ml. of ethanol by heating. 5-Bromoindole (1.96 g., 0.01 mole) was added and heating near reflux continued for 15 minutes. Tlc did not indicate that reaction had occured. 1N Hydrochloric acid (10 ml.) was then added while maintaining the reaction near reflux. After 10 minutes, the reaction was concentrated to wet solids. Trituration of these wet solids with water gave the title product [3.17 g., m.p. >250° C.; Rf 0.45 (1:1 ethyl acetate:hexane/5% acetic acid); Rf 0.3 (1:5 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2]1.N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2]1)(=[O:37])[CH2:35][CH3:36]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)N1CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.150 g, 0.38 mmol) was dissolved in 2 mL of DCM and pyridine was added (0.120 mL/1.54 mmol). Propionyl chloride (0.05 mL, 5.4 mmol) was added dropwise to the solution and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and was quenched by addition of saturated solution of NaHCO3. The aqueous layer was extracted once with DCM and the combined organics were dried (MgSO4), filtered and, concentrated. The crude was purified by SiO2 chromatography using DCM/(DCM:MeOH:NH4OH; 60:10:1) 75% DCM) to give 0.130 g of 1-(1-propionyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (76% yield).
Reaction SMILES: [N:1]1[CH2:2][CH:3]=[CH:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C.CS(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>CC(C)=O>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: C1=CCN=c2ccccc2=C1
Reactant: CS(=O)(=O)OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: FC(F)(F)CN1C=CC=Cc2ccccc21
Temperature: 25 °C
Yield: 119.5 %

Procedure:
To a solution of the 2H-benzazepine (80 mg, 0.26 mmol) from step J above in acetone (5 mL) were added triethylamine (0.06 mL, 0.43 mmol), N,N-diisopropylethylamine (0.025 mL, 0.26 mmol) and 2,2,2-trifluoroethyl methanesulfonate (60 mg, 0.26 mmol). The reaction solution was heated under reflux for 1 hour and then cooled to room temperature and concentrated in vacuo. The residue obtained was purified by flash column chromatography (90:10 to 80:20 hexanes/ethyl acetate) to give the N-trifluoroethyl benzazepine (70 mg, 69%) as a white foam: 1H NMR (CDCl3, 500 MHz) δ 7.34 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 2H), 6.72 (s, 1H), 6.67-6.50 (br, 2H), 4.29 (d, J=8.0 Hz, 1H), 4.19-4.07 (br, 1H), 3.90 (d, J=15.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.32-3.26 (br, 2H), 3.16-3.12 (m, 4H), 3.03-2.89 (m, 2H), 2.26-2.19 (m, 1H), 2.09-2.00 (m, 1H). To a solution of the N-trifluoroethyl benzazepine (65 mg, 0.17 mmol) in methanol (2 mL) were added maleic acid (19 mg, 0.17 mmol) and water (10 mL). The resultant solution was lyophilized overnight to give 4-(5-phenyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]-azepin-8-yl)morpholine, maleate salt (84 mg, >99.0% AUC HPLC) as a light pink solid: 1H NMR (CD3OD, 500 MHz) δ 7.32 (t, J=7.5 Hz, 2H), 7.23 (t, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 2H), 6.84 (d, J=2.5 Hz, 1H), 6.75 (d, J=6.5 Hz, 1H), 6.71-6.54 (br, 1H), 6.30 (s, 2H), 4.35 (d, J=7.5 Hz, 1H), 4.21-4.04 (br, 1H), 3.92 (d, J=15.0 Hz, 1H), 3.84 (t, J=5.0 Hz, 4H), 3.29-3.25 (m, 2H), 3.22-3.07 (m, 6H), 2.34-2.27 (m, 1H), 2.06 (d, J=13.5 Hz, 1H); ESI MS m/z 391 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][N:37]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:11]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)/C=C/c1ccncc1N=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1cccc(N2CCNCC2)c1
Product: COC(=O)CC1c2ccncc2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17A and 69 mg (0.36 mmol) of 3-methoxyphenylpiperazine, general procedure [C] and purification by preparative HPLC result in 90 mg (46% of theory) of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=CC3C(=[N:54][N:55]([CH3:57])[CH:56]=3)C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[C:22](=[N:54][N:55]([CH3:57])[CH:56]=5)[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: Cn1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Product: Cn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 92 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-2-methyl-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a gummy solid (24 mg, 92%). LCMS (Method B): RT=4.69 min, [M+H]+=522.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:11][C@@H:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[C:20]([CH3:29])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:9][C@H:8]1[C:30]([N:32]1[CH2:36][CH2:35][S:34][CH2:33]1)=[O:31])=O)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C:20]1[CH:19]=[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C@@H:10]3[CH2:11][NH:7][C@H:8]([C:30]([N:32]4[CH2:36][CH2:35][S:34][CH2:33]4)=[O:31])[CH2:9]3)[CH2:13][CH2:14]2)[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=1
Reactant: Cc1cc(N2CCN([C@H]3C[C@@H](C(=O)N4CCSC4)N(C(=O)OC(C)(C)C)C3)CC2)n(-c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)n(-c2ccccc2)n1
Reaction time: 19 h
Yield: 93 %

Procedure:
3-{(2S,4S)-1-(1,1-Dimethylethyloxycarbonyl)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (25.45 g, synthesized according to the compound described in Example 222 of WO02/14271) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (50 mL) was added at room temperature, and the mixture was stirred for 19 hrs. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a solid (19.28 g, yield 93%).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH3:24][OH:25]>O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:3][C:2]1[CH:4]=[C:5]([CH2:24][OH:25])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: CO
Reactant: Cc1ccc2ccccc2n1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1cc(CO)c2ccccc2n1
Yield: 27 %

Procedure:
To a solution of quinaldine (75 g, 0.523 mol) in methanol (1100 mL) and water (550 mL) at room temperature was added sulfuric acid (28 mL, 0.523 mol) followed by iron(II) sulfate heptahydrate. Nitrogen was bubbled into the solution for 20 min and ammonium sulfate (177 g, 1.56 mol) was added. The resultant mixture was stirred in a water bath (20° C.) under nitrogen for 4 hours and quenched with 10% sodium hydroxide (pH=9-10). Methanol was removed by concentration in vacuo and the resulting aqueous solution was extracted with ethyl acetate three times. The combined organic phase was filtered through silica gel and washed with water and brine, dried (MgSO4) and concentrated. Crystallization from ethyl acetate gave 2-methyl-4-hydroxymethylquinoline (24.6 g, 27%) as a solid. MS(NH3-CI): (M+H)+=174.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](O)=[O:24])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][NH:72][CH2:73][CH2:74][N:75]([CH3:77])[CH3:76]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:24])[N:72]([CH2:73][CH2:74][N:75]([CH3:77])[CH3:76])[CH3:71])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CNCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCN(C)C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Intermediate 17 (48 mg, 0.09 mmol) was dissolved in DMF (1 mL), and then diisopropylethylamine (48 μL, 0.28 mmol) and HATU (39 mg, 0.10 mmol) were added. The reaction mixture was stirred at RT for 30 minutes and then N,N,N-trimethylethylenediamine (36 μL, 0.28 mmol) was added. After 3 hours of stirring at RT, another portion of HATU was added (10 mg, 0.03 mmol), and stirring was continued for 1 hour. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% (2M NH3 in MeOH) in DCM to give the title compound as a white solid (40 mg).