Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=3)[N:8]=2)=[CH:3][CH:2]=1.[CH:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[CH2:39].C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([C:43]4[CH:44]=[CH:45][C:40]([CH:38]=[CH2:39])=[CH:41][CH:42]=4)=[CH:27][CH:26]=3)[N:8]=2)=[CH:3][CH:2]=1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Reactant: C=Cc1ccc(B(O)O)cc1
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: C1CCOC1
Product: C=Cc1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5ccccc5)cc4)n3)cc2)cc1

Procedure:
1.0 g (0.00185 mol) of 2,4-bisbiphenyl-4-yl-6-(4-bromophenyl)-1,3,5-triazine, 0.4106 g of 4-vinylphenylboronic acid and 0.02368 g of Pd(PPh3)4 are brought to reaction under reflux for 48 h with addition of 15 ml of 1M sodium carbonate solution and 30 ml of THF.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:25])[CH2:4][CH2:3]2.[CH3:26]I>>[CH3:26][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:25]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(S(=O)(=O)c4ccccc4)cc3CC[C@@H]12

Procedure:
A 200 mg portion of (4aR)-(10bR)-10b-methyl-8-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one was methylated with methyl iodide to obtain 144 mg of the desired product. mp 165°-167° FDMS: m/e=369. α[D]589 =+76.2, α[D]365 =+269.7 (chloroform).
Reaction SMILES: CCOCC.C1([Mg]Br)CC1.[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](I)=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C:34]1(=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:34]3([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reactant: O=C1CCCCC1
Agent: Br[Mg]C1CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
Via addition funnel slowly add over 0.5 hours the 2M EtOEt solution of cyclopropyl magnesium bromide (2.16 g, 6.23 ml, 12.46 mmol, 1.1 eq) to the −78° C. THF solution (30 ml) of 4-(3-Iodo-indole-1-sulfonyl)-benzoic acid methyl ester (5 g, 11.33 mmol, 1.00 eq). Stir for 2 hours and then warm to 0° C. Stir for 0.5 hours. Recool to −10° C. and then slowly add a THF solution (3 ml) of cyclohexanone (1.298 g, 13.03 mmol, 1.15 eq). Stir for 15 min and warm to room temperature. Stir for 1.5 days. Quench reaction with saturated aqueous ammonium chloride, remove organics on rotovap, and add EtOAc to crude mix. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as an oil. Purify by silica gel chromatography to give 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (948 mg, 20% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]([NH:23][C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:31])=[N:14][CH2:15][CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:32][CH3:33].[CH3:34][Si](C=[N+]=[N-])(C)C>>[CH3:33][O:32][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH3:34])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]([NH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:31])=[N:14][CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc2c(NC(=NCCC3CCCN3C)Nc3c(C)cccc3C)ncnc2cc1O
Product: COc1cc2ncnc(NC(=NCCC3CCCN3C)Nc3c(C)cccc3C)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 11. N-(7-hydroxy-6-methoxyquinazolin-4-yl)-N′-(2,6-dimethylphenyl)-N″-[2-(N-methylpyrrolidin-2-yl)ethyl]guanidine was reacted with trimethylsilyldiazomethane to give the title compound; NMR Spectrum: (DMSOd6, 100° C.) 1.65 (m, 3H), 1.68 (m, 1H), 1.8–1.96 (m, 2H), 2.07 (q, 1H), 2.15 (s, 3H), 2.32 (s, 6H), 2.32 (s, 6H), 2.79 (br t, 1H), 2.59 (m, 1H), 2.69 (m, 1H), 3.84 (s, 3H), 3.95 (s, 3H), 7.08 (s, 1H), 7.20 (m, 4H), 7.74 (s, 1H), 8.47 (s, 1H), 10.9–11.3 (br s, 1H); Mass Spectrum: M+H+ 463.
Reaction SMILES: CC1C(C[N:8]2[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=3[CH3:27])([CH3:13])[C:11]3[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=3[S:9]2(=[O:33])=[O:32])=C(C)ON=1.C([O-])([O-])=O.[K+].[K+].[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br>CN(C=O)C.CCOC(C)=O>[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45][N:8]1[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=2[CH3:27])([CH3:13])[C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[S:9]1(=[O:33])=[O:32]
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1noc(C)c1CN1C(C)(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2(C)c3ccccc3S(=O)(=O)N2Cc2cccc(F)c2)c2ccccc2n1CC(=O)O
Temperature: 75 °C

Procedure:
The product of example 65, step a) (50 mg, 0.12 mmol) was dissolved in 2 mL DMF and treated with K2CO3 (32 mg, 0.23 mmol) and 3-fluoro-benzylbromide (43 mg, 0.23 mmol). After heating to 75° C. for 2 h, the reaction was cooled, diluted with EtOAc, and washed 3× H2O. The organic solution was concentrated and treated with 3 mL TFA for 2 h at rt. The reaction was concentrated and the title compound was isolated by preparative LCMS to give the title compound. MS: ESI (negative): 477.5 (M−H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[N+:22]([C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][OH:25])[CH2:29][CH2:30]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: OCCN1CCNCC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=NCc1nnc(N3CCN(CCO)CC3)n1-2

Procedure:
In the manner given in Example 1, 1-bromo-8-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-nitro-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>CN(C=O)C.O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil, 0.54 g, 14 mmol) in DMF (15 mL) was added commercially available 2,2,2-trifluoroethanol (0.97 mL, 14 mmol) at room temperature. After stirring for 15 minutes, a solution of 3,5-dibromopyridine (3.2 g, 14 mmol) in 5 mL of DMF was added dropwise. The reaction mixture was heated overnight at 70° C. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (5% ethyl acetate/hexanes) to give the title compound (1.6 g, 46% yield) as clear oil. 1H NMR (CDCl3) δ 8.42 (d, 1H, J=1.7 Hz), 8.32 (d, 1H, J=2.5 Hz), 7.46 (m, 1H), 4.42 (m, 2H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(N2CCCCC2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCCCC4)cc3)(CC1)CC2
Yield: 19.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and N-(4-aminophenyl)piperidine (61.4 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-piperidinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.6 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ccc(Br)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: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-6-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (342 mg, 66%) as a brown solid.
Reaction SMILES: [CH2:1]1[C:11]2[C:4](=[CH:5][C:6]([C:8]([CH:10]=2)=[O:9])=[O:7])[NH:3][CH:2]1C(O)=O.OC1C=C2C(=CC=1O)NC(C(O)=O)=C2>>[OH:9][C:8]1[CH:10]=[C:11]2[C:4](=[CH:5][C:6]=1[OH:7])[NH:3][CH:2]=[CH:1]2
Reactant: O=C1C=C2CC(C(=O)O)NC2=CC1=O
Agent: O=C(O)c1cc2cc(O)c(O)cc2[nH]1
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
TRP-2 catalyzes the tautomerization of DOPAchrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). In the absence of TRP-2, the DOPAchrome undergoes a spontaneous decarboxylation to form 5,6-dihydroxyindole (DHI).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:21])[CH:10](C([O-])=O)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][C:11](=[O:21])[CH2:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C1C(=O)CC(Cc2ccccc2)N(Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1CC(=O)N(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 106.1 g (0.301 mol of methyl (6R(-1,6-dibenzyl-2,4-dioxo3-piperidine carboxylate in 298 ml of toluene and 445 ml of 10% strength (vol/vol) acetic acid is heated at 80° for 21/2 hours. The reaction mixture is cooled to room temperature, neutralised by adding 48 g of solid sodium carbonate while cooling in ice-water, the phases are separated, and the aqueous phase is extracted once more with 300 ml of ethyl acetate. The combined organic phases are washed with water, then with brine dried over sodium sulfate and evaporated to dryness. The resulting oil is crystallised from ether, resulting in the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)C(C)C)(C)C.Cl[C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][NH:31][C:27]=2[N:28]=[CH:29][N:30]=1>C(O)(C)C>[CH3:1][C@H:2]1[CH2:7][N:6]([C:25]2[C:26]3[C:33]([CH3:34])=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c12
Temperature: 120 °C
Yield: 37.5 %

Procedure:
(S)-tert-butyl 2-methylpiperazine-1-carboxylate (3 g, 15 mmol), N,N-diisopropylethylamine (3 ml), and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 12 mmol) were added to isopropanol (10 ml). The solution was heated at 120° C. in a sealed pressure tube for 12 hours. The reaction was concentrated under vacuum, and the residue was purified by flash chromatography (80 g SiO2, 0-5% MeOH: CH2Cl2, 50 min) to give clean (S)-tert-butyl 2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 4.5 mmol, 38%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCCCC1
Product: Cc1ccccc1N1C(C)N(CCN2CCCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=610.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:4].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([N:5]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:13](=[O:15])[CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2)=[O:4]
Reactant: COC(=O)N(c1ccccc1)c1ccccc1CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A mixture of [2-(methoxycarbonyl-phenyl-amino)-phenyl]-acetic acid (16 g, 55.5 mmol) and polyphosphoric acid (29 g, 167 mmol in terms of P2O5) is heated to 100° C. for 4 hours. To the reaction mixture, water (41 ml) is added dropwise at 85–100° C. with stirring and cooling. At 65° C. toluene (41 ml) is added and the mixture is stirred for 30 min. The two phases are separated and washed. The organic phases are concentrated and allowed to crystallize at 0° C. to yield 12 g of pure title compound (80%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(OC2CCNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 30.4 %

Procedure:
To 1.3 gm of 3-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-pyridine was added 10 mL of solution containing 5 mL of TFA and 5 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1: 0.05, CHCl3: MeOH:conc. NH4OH) to obtain 120 mg (30.4% yield in two steps) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.21 (1H, d, J=2.6 Hz), 8.11 (1H, d, J=4.7 Hz), 7.38 (2H, m), 5.00 (1H, m), 3.13-2.88 (4H, m), 220-1.95 (2H, m); Mass spectrum (ESI) m/z 165.6 (M+H+).
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC(C)=C.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH2:32][C@@H:31]1[C@@H:45]([OH:60])[C@@H:46]([NH:56][C:57](=[O:59])[CH3:58])[CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl.CC(C)=O>[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH2:32][C@@H:31]1[C@H:45]1[O:60][C:3]([CH3:4])([CH3:2])[N:56]([C:57](=[O:59])[CH3:58])[C@H:46]1[CH2:47][C:48]1[CH:49]=[C:50]([F:55])[CH:51]=[C:52]([F:54])[CH:53]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: c1ccncc1
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1 h
Yield: 607.3 %

Procedure:
Add p-toluene sulfonic acid pyridine salt (0.245 g, 1 mmol) and 2-methoxypropene (4.6 mL, 49 mmol) to a solution of (2R,4R)-2-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.64 g, 10.55 mmol) in dichloromethane (25 mL) and acetone (25 mL). Stir 60 min and concentrate under reduced pressure. Dissolve residue in ethyl acetate and wash with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry magnesium sulfate and purify on silica gel with hexanes/ethyl acetate mixtures to give the desired compound as a foam (3.49 g, 61%).
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[N:36]1([C:42]2[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:46]3[CH:45]=[CH:44][CH:43]=[C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:47]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10.5 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 256 mg, 1.50 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (400 mg, 1.24 mmol; prepared in Example 52, Step 2), 3-(4-morpholinyl)phenol (441 mg, 1.23 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated. The residue was purified by repeated chromatography on silica gel using toluene and toluene/EtOAc (8:2) as eluents. Solvents were evaporated and the residue was treated with CH2Cl2/TFA/H2O (1:0.9:0.1; 5 mL) at room temperature for 0.5 h. After concentration, 5 M NaOH was added followed by extraction with CH2Cl2. The organic phase was dried (K2CO3), filtered, and concentrated. The residue was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 50 mg (10%) of the title product as on oil. HRMS m/z calcd for C20H27N5O3 (M)+ 385.2114, found 385.2100.
Reaction SMILES: C(OC(OCC)C1C=C(C2C(C3C=CC=CC=3)C(=O)C3C(C(OC)=O)=CC=CC=3N2)C=CC=1)C.[CH2:35]([O:37][CH:38]([O:67][CH2:68][CH3:69])[C:39]1[CH:40]=[C:41]([CH:45]2[CH:54]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:53](=O)[C:52]3[C:51]([C:62]([O:64]CC)=O)=[CH:50][CH:49]=[CH:48][C:47]=3[NH:46]2)[CH:42]=[CH:43][CH:44]=1)[CH3:36].O.[NH2:71][NH2:72]>CO>[CH2:68]([O:67][CH:38]([O:37][CH2:35][CH3:36])[C:39]1[CH:40]=[C:41]([CH:45]2[NH:46][C:47]3[C:52]4[C:53](=[N:71][NH:72][C:62](=[O:64])[C:51]=4[CH:50]=[CH:49][CH:48]=3)[CH:54]2[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:42]=[CH:43][CH:44]=1)[CH3:69]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1cccc(C(OCC)OCC)c1)N2
Reactant: NN
Agent: CCOC(OCC)c1cccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccccc2)c1
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of methyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (160 mg, 0.36 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3 mL) was stirred at 25° C. for overnight. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the 8-(3-(diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, yield 58%) as a yellow solid. LC-MS (ESI) m/z: 442 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:40][CH2:41]2)(=[O:34])=[O:35])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)CC1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)carbamate. MS (ESI): mass calcd. for C28H30FN5O4S, 551.20; m/z found, 552.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.81 (d, J=2.4, 1H), 8.18-8.04 (m, 2H), 7.69-7.59 (m, 2H), 7.60-7.48 (m, 1H), 7.48-7.30 (m, 4H), 6.85 (dd, J=3.7, 1.9, 1H), 4.44 (d, J=8.2, 1H), 3.79 (d, J=13.2, 1H), 3.49-3.27 (m, 3H), 2.91 (t, J=11.7, 1H), 2.47 (t, J=12.2, 2H), 1.98 (d, J=13.4, 1H), 1.79 (d, J=11.8, 2H), 1.42 (d, J=9.5, 12H), 1.31-1.10 (m, 3H).