Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:31]([CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:32][CH:33]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (49.0 mg, 0.258 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.029 g, 27%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.09 (dd, J=4.6, 1.4 Hz, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.79 (dd, J=8.2, 1.3 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.28-7.24 (m, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.82 (s, 1H), 6.76 (t, J=7.0 Hz, 1H), 3.33 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.87-1.74 (m, 4H). MS=507 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3S[C:21](=[O:23])[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1.[NH:25]1CC(=O)NC1=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3[NH:25][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)S1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)N1

Procedure:
5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was prepared using the same procedure as for the synthesis of 5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione using hydantoin instead of thiazolidine-2,4-dione.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[S:8][CH:9]=1)[CH3:3].[Br:14]Br>CC(O)=O>[Br:14][C:9]1[S:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:6][C:5]=1[CH2:4][N:2]([CH3:1])[CH3:3]
Reactant: BrBr
Reactant: CC(=O)Nc1nc(CN(C)C)cs1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CN(C)C)c(Br)s1
Yield: 65.4 %

Procedure:
To a solution of N-(4-((dimethylamino)methyl)thiazol-2-yl)acetamide (1.1 g, 5.5 mmol) in 10 mL AcOH was added Br2 (0.28 mL, 5.5 mmol) dropwise. The resulting mixture discolored instantly, and a precipitate appeared. The precipitate was filtered and washed with AcOH. The collected precipitate was neutralized with saturated sodium bicarbonate and extracted twice with 100 mL EtOAc. The organic layer was combined, washed once with brine, and dried over sodium sulfate. After removing the solvent, the product was obtained as a white solid (1.0 g, yield=65%). LCMS (API-ES) m/z (%) 278.0 (100%, M++H). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 3H) 2.28 (s, 6H) 3.44 (s, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[BH4-].[Na+]>CC(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][N:19]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2ccncc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Fc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Benzyl bromide (52.4 mL, 441 mmol) was added to a solution of 4-(4-fluorophenyl)pyridine (Description 14, 50.87 g, 294 mmol) in acetone (500 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled to room temperature and the solid was collected, washed with acetone and diethyl ether and dried in vacuo. The solid was dissolved in methanol (400 mL) and water (100 mL), cooled to 0° C. and sodium borohydride (20.6 g, 542 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, then heated to reflux for 18 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Dichloromethane (300 mL) and water (200 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light brown oil (61.5 g, 78%). m/z (ES+) 268 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:14]C(=O)C)=[C:4]([F:18])[CH:3]=1.[OH-].[Na+]>Cl>[NH2:14][C:5]1[C:4]([F:18])=[CH:3][C:2]([Cl:1])=[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])[CH:6]=1
Reactant: CC(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
74.5 g of crude N-[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]acetamide (purity: 90%) was suspended in 355 mL of 6 N hydrochloric acid and heated to 95° C. After 1.5 hours the suspension turned into a solution. The mixture was cooled to room temperature and 90 mL of a NaOH solution (50%) was added (pH 3). The precipitated product was filtered and washed with water to yield, after drying, 62.8 g of the title compound as yellow crystals (purity: 86.4% by HPLC) which could be further purified by recrystallization as described above in Example 5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:47]
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: COC1CCN(c2c(NC(=O)c3nc(-c4cc(C)ccc4F)sc3N)cnn2C)CCC1N
Yield: 40 %

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid gave 325 (70.8 mg, 40% over two steps). 1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.48 (s, 1H), 7.40 (s, 2H), 7.23 (d, J=9.0 Hz, 2H), 3.64 (s, 3H), 3.24 (s, 4H), 3.23-2.86 (m, 8H), 2.37 (s, 3H), 2.11-1.95 (m, 1H), 1.91-1.79 (m, 1H), 1.79-1.53 (m, 2H). LCMS (ES+) m/z 474 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:25][Cr](O[Cr]([O-])(=O)=O)(=O)=O.O>CN(C=O)C>[C:11]([C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:25])=[O:1])[CH:10]=[CH:9][N:8]=1)#[N:12]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: N#Cc1cc(CCCO)ccn1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(CCC(=O)O)ccn1
Reaction time: 16 h

Procedure:
A solution of K2CO3 (1.67 g, 12.1 mmol) in H2O (30 ml) was added to a stirred solution of 3-(2-cyanopyridin-4-yl)propyl acetate (4.94 g, 24.2 mmol) in MeOH (130 ml). After 25 min, the MeOH was removed under reduced pressure, then the aqueous phase was extracted three times with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish 4-(3-hydroxypropyl)pyridine-2-carbonitrile: m/z (ES+)=163.1 [M+H]+. A solution of this alcohol (500 mg, 3.1 mmol) in DMF (20 ml) was treated with PDC (7 g, 18.6 mmol) and H2O (0.5 ml). The reaction was stirred for 16 h, before being partitioned between H2O and EtOAc. The aqueous phase was extracted twice with EtOAc, then the combined organic extracts were washed with brine, before being dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES−)=177.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:13]=[O:14])[N:8]2[CH2:11][CH3:12])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:13][OH:14])[N:8]2[CH2:11][CH3:12])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CCn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(CO)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
A solution of 2-chloro-9-ethyl-6-morpholino-9H-purine-8-carbaldehyde (2.4 g) in MeOH (200 mL) at 0° C. was treated portion wise with sodium borohydride (0.84 g). The reaction was warmed to room temperature and stirred 15 minutes. The reaction mixture was quenched with saturated solution of sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to yield crude (2-chloro-9-ethyl-6-morpholino-9H-purin-8-yl)methanol (2.3 g) as a white solid.
Reaction SMILES: C(O[C:9]([C:11]1[N:12]=[C:13]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[NH:14][C:15]=1[CH2:16][O:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:10])C1C=CC=CC=1.[CH2:34]([O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH2:49])[CH:44]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][C:9]([C:11]2[N:12]=[C:13]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[NH:14][C:15]=2[CH2:16][O:17][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:10])[CH:44]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=C(OCc1ccccc1)c1nc(C2CCCCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Yield: 65.3 %

Procedure:
The product of step d (0.76 g, 2.122 mmol) was reacted with 3-amino-benzoic acid benzyl ester (0.48 g, 2.12 mmol) according to the procedure of Example 20, step d. The crude material was purified by flash chromatography (silica, DCM/ethyl acetate 98:2, then 95:5) to afford colourless foam (786 mg, 65.5%). 1H NMR (300 MHz, CDCl3) 9.50 and 8.90 (1H, 2× br s), 8.15 (2H, m), 7.81 (1H, d), 7.40 (6H, m), 5.38 (2H, s), 4.98 (2H, br s), 2.71 (1H, m), 2.16 (3H, br s), 2.00 (2H, m), 1.85-1.24 (20H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1C=CC=CC=1.O.[NH2:22][NH2:23]>O>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:2]1[NH:23][N:22]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: NN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: c1ccccc1
Solvent: O
Product: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Yield: 83 %

Procedure:
A mixture of 20.8 g (0.1 mole) of 4-chloro-3-nitroquinoline, 40 ml of benzene and 40 ml of hydrazine hydrate is refluxed for 2 hours, then cooled. The separated phase containing hydrazine hydrate is diluted with 150 ml of water. Yellow-white crystals separate. Thus, 16.8 g (83%) of 5-(o-aminophenyl)-4-nitropyrazole are obtained. M.p.: 175°-176° C. (ethanol).
Reaction SMILES: [CH2:1]([SH:5])[C:2]([OH:4])=[O:3].CS(O[CH2:11][CH2:12][C:13]#[CH:14])(=O)=O>>[CH2:14]([S:5][CH2:1][C:2]([OH:4])=[O:3])[CH2:13][C:12]#[CH:11]
Reactant: C#CCCOS(C)(=O)=O
Reactant: O=C(O)CS
Product: C#CCCSCC(=O)O

Procedure:
2-(But-3-ynylthio)acetic acid was prepared from thioglycollic acid and but-3-ynyl methanesulphonate using the methodology described in stage (i) of Example XIII.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[C:19]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: c1cncc(-c2cccnc2N2CCNCC2)c1
Reactant: COc1cccc(OCCCl)c1
Product: COc1cccc(OCCN2CCN(c3ncccc3-c3cccnc3)CC2)c1

Procedure:
The title compound was prepared starting from 1-(2-chloroethoxy)-3-methoxybenzene and 1-[3-(3-pyridyl)-2-pyridyl]piperazine following the procedure outlined for Example 15. 1H NMR (CDCl3): δ 2.48 (br s, 4H), 2.77 (t, 2H, J=6.0 Hz), 2.88 (app t, 4H), 3.78 (s, 3H), 4.06 (t, 2H, J=6.0 Hz), 6.45-6.52 (m, 3H), 7.04-7.10 (m, 2H) 7.33-7.37 (m, 1H), 7.46 (dd, 1H, J=1.9, 7.4 Hz), 7.97 (dt, 1H, J=1.9, 7.7 Hz), 8.28 (dd, 1H, J=1.9, 4.9 Hz), 8.56 (dd, 1H, J=1.7, 4.9 Hz), 8.82 (d, 1H, J=1.7 Hz). GC-MS m/z 391 (M+1, 3), 390 (M+, 3), 267 (35), 253 (100), 198 (29), 184 (63).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:12][CH3:13])[C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:16](N)[CH2:17][NH2:18]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:10]2[NH:18][CH2:17][CH2:16][N:11]=2)[CH2:12][CH3:13])=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: CCC(C#N)c1ccc(C(F)(F)F)cc1
Product: CCC(C1=NCCN1)c1ccc(C(F)(F)F)cc1

Procedure:
rac-2-[1-(4-Trifluoromethyl-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(4-trifluoromethyl-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 257.0 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:51])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:51])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCCBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 59.3 %

Procedure:
Starting with 0.128 g (0.62 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.349 g (0.62 mmol) of 2-[(8-bromooctyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.232 g; 76.3% overall yield) was obtained as a white solid, mp 112°-117° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:13])[CH2:14][C:15]([N:17]([CH3:25])[C:18]2[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CC(CCO)c1ccc(F)c(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
3,4-Difluoro-β-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (4.3 g) in EtOAc (100 mL) was treated with carbonyldiimidazole (3.24 g) and N,N-dimethylaminopyridine (195 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (3.02 g) in H2O (50 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (1×100 mL), sat. NaHCO3 (1×100 mL) and water (1×100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (3.64 g). Mass spectrum (CI): 320.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([C:12]2[C:13]([CH3:18])=[N:14][NH:15][C:16]=2[NH2:17])[CH:3]=1.[Cl:19][C:20]1[C:21]([OH:29])=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[CH:25]=O>C(O)(C(F)(F)F)=O>[Cl:19][C:20]1[CH:27]=[C:24]([C:25]2[C:3]3[C:2]([F:1])=[C:7]4[O:8][CH2:9][CH2:10][O:11][C:6]4=[CH:5][C:4]=3[C:12]3[C:13]([CH3:18])=[N:14][NH:15][C:16]=3[N:17]=2)[C:23]([F:28])=[CH:22][C:21]=1[OH:29]
Reactant: O=Cc1cc(Cl)c(O)cc1F
Reactant: Cc1n[nH]c(N)c1-c1cc(F)c2c(c1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nc(-c3cc(Cl)c(O)cc3F)c3c(F)c4c(cc3c12)OCCO4
Yield: 11.1 %

Procedure:
A solution of 4-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-1H-pyrazol-5-amine (100 mg, 0.40 mmol) and 5-chloro-2-fluoro-4-hydroxybenzaldehyde (70 mg, 0.40 mmol) in TFA (2 mL) was stirred at 90° C. for 16 h. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-chloro-5-fluoro-4-(6-fluoro-1-methyl-8,9-dihydro-3H-[1,4]dioxino[2,3-g]pyrazolo[3,4-c]isoquinolin-5-yl)phenol (18 mg, 11% yield) as a yellow solid after lyophillization of the pure fractions. 1H NMR (400 MHz, d6-DMSO) δ 10.98 (s, 1H), 7.55 (m, 2H), 6.86 (dd, 1H), 4.44 (m, 4H), 2.74 (s, 3H); MS (EI) for C19H12ClF2N3O3: 404 (MH+).
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4]C1C=CC(Cl)=C2C=1C=C([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)N=C2.[C:34]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2)#[N:35]>>[ClH:4].[ClH:1].[ClH:4].[NH2:33][C:17]1[C:16]([C:42]2[N:43]=[CH:44][C:45]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][C:36]=3[C:34]#[N:35])=[CH:21][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)=[CH:19][N:18]=1
Reactant: N#Cc1cccc2cc(OS(=O)(=O)C(F)(F)F)ncc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: N#Cc1cccc2cc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)ncc12

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 8-cyanoisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.30-2.42 (m, 4H), 3.21-3.27 (m, 2H), 3.59 (d, J=13.4 Hz, 2H), 4.59-4.71 (m, 1H), 7.97-8.04 (m, 1H), 8.08 (s, 1H), 8.25-8.30 (m, 2H), 8.42-8.49 (m, 2H), 8.86 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 9.70 (s, 1H). MS (ES+): m/z=396.19 [MH+]. HPLC: tR=1.67 min (ZQ2, polar—5 min).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=2)[N:33]([CH3:41])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=4)[N:33]([CH3:41])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc2c(c1)c(C(=O)CCCCCBr)cn2C
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(C)c3ccc(C)cc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1,5-dimethyl-1 H-indol-3-yl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1,5-dimethyl-1H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.I[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CC#N>[CH:14]1([C:8]2[C:7]3[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: IC1CCCC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: Nc1ccc2c(C3CCCC3)c[nH]c2c1

Procedure:
3-Cyclopentyl-1H-indol-6-ylamine (B-15) was synthesized following the general scheme above starting from 6-nitroindole and iodo-cyclopentane. Overall yield (16%). HPLC ret. time 2.39 min, 10-99% CH3CN, 5 min run; ESI-MS 201.5 m/z (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[N:18][C:13]3[O:14][CH2:15][CH2:16][NH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Br:34])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].C(N(CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]([C:26]([N:17]2[CH2:16][CH2:15][O:14][C:13]3[N:18]=[CH:19][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)=[CH:11][C:12]2=3)=[O:27])[CH:29]=[C:30]([Br:34])[C:31]=1[O:32][CH3:33]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: FC(F)(F)Oc1ccc(-c2cnc3c(c2)NCCO3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1Br
Yield: 69.8 %

Procedure:
By the same method as in the step c) of Example 45, 7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (83 mg, 0.28 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (138 mg, 0.42 mmol) and triethylamine (78 μl, 0.56 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (115 mg, 69.8%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:12]=[C:13]([CH3:22])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[CH2:26]([C:23]1[N:11]2[N:12]=[C:13]([CH3:22])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:21])=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:10]2=[CH:25][CH:24]=1)[CH3:27]
Reactant: C1COCCN1
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)O)c(C)nn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)N3CCOCC3)c(C)nn12
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (50 mg) in N,N-dimethylformamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg) and 1-hydroxybenzotriazole (28 mg) at ambient temperature. After 30 minutes, to the mixture was added morpholine (24 mg). After 5 hours, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel column chromatography (silica gel, 40 mL) eluted with hexane-ethyl acetate=3-1, 2-1, 1-1, 1-3, and 0-1 to give 3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile as an yellow gum (53 mg)