Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38].CCN(C(C)C)C(C)C>C1COCC1.CO>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:2]=4[NH2:1])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5F)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 5-[3-amino-2-(2-fluorobenzyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.1 g, 0.22 mmol) in THF (2 mL) was added 2-chloro-N,N-dimethylacetamide (0.024 g, 0.2 mmol) and DIEA (0.11 g, 0.88 mmol). The mixture was stirred at room temperature for 18 h, diluted with methanol, and concentrated. The crude product was purified by HPLC (10 to 90% CH3CN). 1H NMR (400 MHz, CD2Cl2) δ 7.87 (s, 1 H) 7.58 (d, 1 H) 7.11-7.35 (m, 5 H) 7.01 (d, 1 H) 6.55 (s, 1 H) 5.50-5.55 (m, 4 H) 4.25 (s, 2 H) 2.90-3.30 (m, 11 H) 2.30 (dt, 2 H) 2.10 (d, 2 H) 1.83 (dt, 2 H). LC-MS [M+H]+=542.3, RT=0.31 min.
Reaction SMILES: C(N=[N+]=[N-])C1C=CC=CC=1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[N+:12]=[N-:13].[C:25]([C:27]1[S:28][C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:30]([CH3:32])[N:31]=1)#[CH:26]>>[CH3:32][C:30]1[N:31]=[C:27]([C:25]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH:26]=2)[S:28][C:29]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Agent: [N-]=[N+]=NCc1ccccc1
Product: CCOC(=O)c1sc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)nc1C
Yield: 67 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with 1-(azidomethyl)-4-(trifluoromethyl)benzene to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 67% yield: 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.66-7.55 (m, 2H), 7.45-7.39 (m, 2H), 4.29 (q, J=7.1 Hz, 2H), 5.62 (s, 2H), 2.66 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); MS (ES+) m/z 397.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[C:2]3[Cl:1])=[O:23])=[CH:18][CH:19]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Nc1cccc2c(Cl)nccc12
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2c(Cl)nccc12
Temperature: 90 °C
Yield: 63.1 %

Procedure:
The product from Example 64A (520 mg, 2.91 mmol) in toluene (8 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.41 mL, 2.93 mmol) with stirring and then the mixture was heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature, filtered, the filter cake washed with toluene, and air-dried to provide the title compound as an off-white solid (717 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.34-8.37 (m, 2H), 8.00 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.92-7.95 (m, 1H), 7.73 (t, J=8.1, 1H, 7.53-7.56 (m, 2H), 7.30-7.33 (m, 2H), 7.12 (t, J=5.8 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H); MS (ESI+) m/z 390/392 (M+H+, 35Cl/37Cl).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Product: Cc1ccc([N+](=O)[O-])cc1N=C1N[C@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl-5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with methyl iodide according to Method D2a to afford (4R)-2-(2-methyl-5-nitrophenylimino)-4-isobutyl-3-methyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:18])=[CH:5][CH2:6][CH2:7][C:8]([CH3:17])=[CH:9][CH2:10][CH2:11][C:12]([CH3:16])(O)[CH:13]=[CH2:14].O.COCC(C)=CCCC(C)=CCC=C(C)C=C>CCOCC.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][CH2:3][C:4]([CH3:18])=[CH:5][CH2:6][CH2:7][C:8]([CH3:17])=[CH:9][CH2:10][CH2:11][C:12](=[CH2:16])[CH:13]=[CH2:14]
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)COC
Agent: [Cu+2]
Agent: C=CC(C)=CCC=C(C)CCC=C(C)COC
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: C=CC(=C)CCC=C(C)CCC=C(C)COC
Temperature: 180 °C
Yield: 47 %

Procedure:
5 g of copper sulfate pentahydrate are suspended in 20 g of paraffin oil, with vigorous stirring, and the suspension is heated at 180° C under 20 mm Hg. The water of crystallization which is eliminated is removed through a descending condenser. After the reaction has ended, 25 g (0.1 mole) of 12-methoxy-3,7,11-trimethyl-dodeca-1,6,10-trien-3-ol are added dropwise to the suspension and water and reaction product are distilled off simultaneously (reaction time about 30 minutes). After completion, the distillate is taken up in 100 ml of ether, the ether solution is washed with sodium carbonate solution, then washed neutral with water and dried over sodium sulfate, and the drying agent is then filtered off. After distilling off the ether, the product which remains is fractionated, giving 11 g of a 2:1 mixture of 12-methoxy-3,7,11-trimethyl-dodeca-1,3,6,10-tetraene and 12-methoxy-3-methylene-7,11-dimethyl-dodeca-1,6,10- -triene (yield 47%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1>FC(F)(F)CO.[Pd]>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])[N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2cccnc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2cccnc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To tert-butyl (2R,5S)-2-[(2-aminopyridin-3-yl)ethynyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (1 eq.) in 2,2,2,-trifluoroethanol (0.4 M) at rt was added 10% Pd/C (0.2 eq.). The reaction was degassed and then shaken under 1 atm of H2 for 24 hrs. The reaction mixture was filtered on celite and concentrated to afford the desired compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:20]3[C:16](=[CH:15][C:14]([N:13]([CH3:23])[CH3:12])=[CH:22][CH:21]=3)[C:17](=[O:18])[O:8]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1

Procedure:
In a second synthetic route to CVL, which is also a multi-step synthesis, 4-dimethylaminobenzaldehyde is reacted with 3-dimethylaminobenzoic acid to obtain 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide in the first step. In a second step, the 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide from step one is interacted with N,N-dimethylaniline in the presence of a Friedel-Crafts type catalyst to obtain 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. In a third step, the benzoic acid from step two is oxidized to obtain 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide.
Reaction SMILES: C(=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH3:15])C1C=CC=CC=1.C(=O)C1C=CC=CC=1.[ClH:24]>>[ClH:24].[NH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH3:15]
Reactant: CCc1nccn1N=Cc1ccccc1
Agent: Cl
Solvent: O=Cc1ccccc1
Product: CCc1nccn1N

Procedure:
A solution of 19.9 g (0.1 mol) of 1-benzylideneamino-2-ethyl-imidazole in 200 ml of 1.5N hydrochloric acid is subjected to a steam distillation until benzaldehyde no longer results. The mixture is evaporated and the product obtained is recrystallized from ethanol/ether. There are obtained 14.5 g of 1-amino-2-ethylimidazole hydrochloride of melting point 90°-91°.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[C:7]([Cl:6])[C:12]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting diethylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in ethanol to give the product melting at 35° - 36°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][NH:13][N:14]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][F:25]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:23][CH2:24][F:25])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)NCCc1nn[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nnn(CCF)n1
Reaction time: 0.25 h

Procedure:
To a solution of [2-(2H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester 0.45 g, 2.11 mmol) in dry DMF (14 ml) was suspended Cs2CO3 (0.825 g, 2.53 mmol) and the reaction mixture stirred for 15 minutes. 1-Bromo-2-fluoroethane (0.63 ml, 8.44 mmol) was added and the reaction mixture stirred at ambient temperature for 5 hours. The reaction mixture was filtered and the DMF evaporated to afford the crude product as a brown oil. The crude material was absorbed onto silica and purified by silica chromatography eluting with a gradient of 3:1 to 2:1 Ethylacetate:hexane to afford the titled product as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol), and piperazine (0.043 g, 0.5 mmol) were combined in CH2Cl2 (2 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.0318 g, 0.15 mmol) was added and the mixture stirred for 30 h. Aqueous workup was followed using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 1 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 729.4 (M+H)+, 1.31 min (ret time); mp 135-138° C. Analytical HPLC shows 98.4% purity, (ret time 10.019 min).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][OH:17])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][O:17][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CC=C(C)CCCC(C)CO)C(C)=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
324 mg (1.20 mmol) of a raw product of 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one and 219 μl (202 mg, 2.40 mmol) dihydropyrane was dissolved in 8.5 ml DCM. After addition of 30 mg (0.12 mmol) pyridinium paratoluene sulfonate, the reaction mixture was stirred for 18 hrs at ambient temperature. Then, 25 ml diethylether was added, the resulting organic phase was washed once with 25 ml semiconcentrated NaCl solution, and dried over Na2SO4. After filtration and removal of the solvent in vacuo, the remaining product was purified by flash chromatography (parameters of the chromatography column: 2.0×20.0 cm, ethylacetate/petroleum ether=1:4) on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3cc(Cl)ccc23)CC1
Reaction time: 40 h
Yield: 111.3 %

Procedure:
A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 14 mmol), K2CO3 (2.5 g, 18 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 30 hours. After standing at room temperature for 40 hours, the reaction was filtered and the filter cake was washed well with acetonitrile. The filtrate was concentrated to an oily solid, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 6.9 g of a dark oil, which solidified after 2 days under vacuum. The product was purified by preparative HPLC (Waters Associates Prep LC/system 500 utilizing 2 silica gel columns and 6% methanol/methylene chloride as eluent) to yield 4.2 g. The material was recrystallized from ethanol to yield 3.4 g of glistening, beige, 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-ethanone crystals, m.p.=132°-134° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[PH:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C[O-].[Na+]>CO>[OH:9][CH:8]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: CCO[PH](=O)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.8 %

Procedure:
The title compound was prepared as described in Taylor, W P, et. Al, Bioorg. Med. Chem. 4:1515-1520 (1996). 4-Nitrobenzaldehyde (3.0 g, 19.85 mmol) and diethyl phosphonate (2.74 g, 19.85 mmol) were combined and treated with a 0.5N solution of sodium methoxide in methanol (0.993 mL, 0.496 mmol). The resulting red-orange solution was stirred 12 h at room temperature. The reaction mixture was extracted with dichloromethane (20 mL) followed by half saturated ammonium chloride (20 mL). The organic layer was separated, dried and concentrated under vacuum to provide the title compound as a semi-solid (5.1 g, 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([F:61])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:51]4[CH:60]=[C:59]5[C:54]([CH:55]=[C:56]([F:61])[CH:57]=[N:58]5)=[CH:53][CH:52]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]
Reactant: Fc1cnc2cc(Br)ccc2c1
Reactant: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(-c4ccc5cc(F)cnc5c4)cc3F)CC2)OCC1=O
Temperature: 110 °C

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (266 mg, 0.47 mmol) in dry 1,4-dioxane (3 mL) was treated with bis(pinacolato)diboron (142 mg, 0.56 mmol), potassium acetate (49 mg, 0.5 mmol) and PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol). The reaction mixture was degassed with nitrogen for ˜3 min and the vessel was purged with nitrogen, sealed, and heated to 110° C. for 3 h. Analysis of a reaction mixture aliquot indicated complete conversion of the starting material to the boronate intermediate. To the cooled reaction mixture was added 7-bromo-3-fluoroquinoline (105 mg, 0.47 mmol), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol) and 2M aq K2CO3 (0.7 mL, 1.4 mmol). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase HPLC (5-75% acetonitrile:water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Lux Cell 4, methanol) to afford the title product in 95% ee (29 mg, 12% yield). αD=+26 deg (c=0.14, methanol); MS(ES)+ m/e 495 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.06-1.18 (m, 3 H) 1.63-1.84 (m, 2 H) 1.90-1.97 (m, 2 H) 2.27-2.39 (m, 1 H) 2.53-2.73 (m, 2 H) 2.80 (d, J=11.37 Hz, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.95-4.08 (m, 2 H) 4.53 (s, 1 H) 6.28 (br. s., 1 H) 7.29 (br. s., 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.55 (dd, J=11.24, 1.89 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.83-7.93 (m, 2 H) 7.93-8.00 (m, 1 H) 8.37 (d, J=1.77 Hz, 1 H) 8.88 (d, J=2.53 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC(F)(F)F)c(Cl)c4)n3)cccc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCc1nccc2c(-c3noc(-c4ccc(OCC(F)(F)F)c(Cl)c4)n3)cccc12
Reaction time: 2 h
Yield: 124.6 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{3-chloro-4-[(2,2,2-trifluoroethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D47; 55 mg, 0.103 mmol) was dissolved in 4N HCl in 1,4-dioxane (4 ml) and the solution allowed to stand at room temperature for 2 h. A white precipitate was formed which was filtered off, washed with dry ether and dried to give the title compound as a white solid (33 mg)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:30]([C@H:31](O)[CH3:32])=[CH:29][C:28]2[C:23](=[C:24]([F:34])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.C1(P([N:49]=[N+:50]=[N-:51])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:49]([C@H:31]([C:30]1[C:21]([Cl:20])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[F:34])[CH3:32])=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])c1cc2cccc(F)c2nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphenylphosphine (1.81 g, 6.9 mmol, 1.2 eq) was dissolved in anhydrous THF (30 mL) and cooled to 0° C. To this solution was added diispropylazodicarboxylate (1.36 mL, 6.9 mmol, 1.2 eq). The reaction was stirred for 30 minutes at 0° C. and (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (1.3 g, 5.7 mmol) in 30 mL of THF was added, followed by diphenylphosphoryl azide (1.37 mL, 6.3 mmol, 1.1 eq). The reaction was allowed to warm to rt and stir at rt overnight. The reaction was deposited on silica gel and concentrated. Purification by column chromato-graphy (3% etoac in hexanes) afforded (S)-3-(1-azidoethyl)-2-chloro-8-fluoro-quinoline. 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=1.2 Hz, 1H), 7.67 (br d, J=8.22 Hz, 1H), 7.54 (td, J=7.8, 4.7 Hz, 1H), 7.45 (ddd, J=10.2, 7.8, 1.2 Hz) 5.22 (q, J=6.7 Hz, 1H), 1.68 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/e=250.9 (M+1).