Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]4[C@:21]([CH2:23][OH:24])([CH2:22][C:13]=3[CH:12]=[N:11]2)[CH2:20][N:19]([S:25]([C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:18][CH2:17]4)=[CH:6][CH:5]=1.O1CC[CH2:42][CH2:41]1>ICC>[CH2:41]([O:24][CH2:23][C@@:21]12[CH2:20][N:19]([S:25]([C:28]3[CH:29]=[N:30][C:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:32][CH:33]=3)(=[O:26])=[O:27])[CH2:18][CH2:17][C:16]1=[CH:15][C:14]1[N:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[N:11]=[CH:12][C:13]=1[CH2:22]2)[CH3:42]
Reactant: C1CCOC1
Reactant: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (1.5 g) in tetrahydrofuran (20 mL) at room temperature was treated sequentially with a solution of [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triaza-cyclopent-a[b]naphthalen-4a-yl]methanol (8.0 g) in tetrahydrofuran (60 mL) and iodoethane (3.7 mL), and the resulting mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature and partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with aqueous sodium thiosulfate solution, aqueous potassium carbonate solution, water and brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and diethyl ether (1:20 to 1:10 by volume), to afford a cream foam (7.5 g). The cream foam was crystallized from industrial methylated spirits to afford the title compound as a white solid (6.3 g). LCMS (Method A): 552 (M+H)+, Retention time 5.0 minutes. 1H NMR (CDCl3): δ 8.53-8.49 (d, 1H, J=2.4 Hz), 7.79-7.73 (dd, 1H, J=9.2, 2.5 Hz), 7.41-7.33 (m, 3H), 7.15-7.07 (t, 2H, J=8.0 Hz), 6.62-6.55 (d, 1H, J=9.0 Hz), 6.25-6.21 (d, 1H, J=2.3 Hz), 4.15-4.08 (dd, 1H, J=12, 2.3 Hz), 3.89-3.80 (m, 1H), 3.80-3.73 (m, 4H), 3.67-3.59 (m, 4H), 3.52-3.35 (m, 3H), 3.14-3.02 (m, 2H), 2.74-2.61 (m, 1H), 2.41-2.29 (m, 2H), 2.20-2.04 (dd, 2H, J=34, 16 Hz), 1.19-1.11 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C@@:2]1([OH:41])[C@H:6]([O:7]CC2C=CC(Cl)=CC=2Cl)[C@@H:5]([CH2:17][O:18]CC2C=CC(Cl)=CC=2Cl)[O:4][C@H:3]1[N:28]1[CH:40]=[C:32]2[CH2:33][CH2:34][C:35]3[O:36][NH:37][N:38]=[CH:39][C:30]([C:31]=32)=[N:29]1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][C@@:2]1([OH:41])[C@H:6]([OH:7])[C@@H:5]([CH2:17][OH:18])[O:4][C@H:3]1[N:28]1[CH:40]=[C:32]2[CH2:33][CH2:34][C:35]3[O:36][NH:37][N:38]=[CH:39][C:30]([C:31]=32)=[N:29]1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc2c3c(o[nH]ncc-3n1)CC2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c3c(o[nH]ncc-3n1)CC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
To a solution of compound 2.8 (128.0 mg, 0.20 mmol) in CH2Cl2 (25 mL) at −78° C., was added a 1.0M solution of BCl3 in CH2Cl2 (2.0 mL, 2.0 mmol) dropwise via syringe. The mixture was stirred at −78° C. for 1.5 h, then at −35° C. to −40° C. for 2.5 hr. The reaction was quenched with MeOH (8.0 ml) and the solvents were evaporated. The resulting crude product was purified by flash column chromatography over silica gel using 5% MeOH in CH2Cl2 as eluent to give the title compound 2.9 (59.2 mg) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH3:12])([CH2:10][OH:11])[C:6]1=[O:13])=[O:4].[CH3:22][O:23][CH2:24]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:10][O:11][CH2:22][O:23][CH3:24])([CH3:12])[C:6]1=[O:13])=[O:4]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCOCC1(C)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Reaction time: 0.17 h

Procedure:
1-(4-Chlorobenzyl)-3-methyl-3-hydroxymethyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XI), R1=CH3, R2=CH3, Ym=4-Cl) (186 mg, 0.60 mmol) was dissolved in methylene chloride (5.6 ml), and dimethoxymethane (2.8 ml) was added. This was cooled in a water bath, diphosphorus pentoxide (372 mg) was added and vigorous stirring was conducted at room temperature for 10 minutes. After completion of the reaction, saturated brine was combined with the reaction solution, and extraction with diethyl ether was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away and dried under reduced pressure to obtain a crude 1-(4-chlorobenzyl)-3-methoxymethoxymethyl-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (X), R1=CH3, R2=CH3, Ym=4-Cl, G=CH2OCH2OCH3) (195 mg). From this, an aliquot (188.8 mg) was dissolved in isopropanol (0.53 ml), a 2M aqueous solution of sodium hydroxide (0.53 ml, 1.12 mmol) was added, and stirring was conducted at 60 degrees C. for 1 hour. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=7:1) to obtain the desired substance as a mixture of two isomers (Isomer (a):Isomer (b)=36:65).
Reaction SMILES: O=S(Cl)Cl.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH3:15]O>>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)cc1

Procedure:
2.95 ml of SOCl2 were added to a suspension of 10 g of 4-iodobenzoic acid in 100 ml of methanol and the reaction mixture was refluxed for 24 hours and then evaporated under reduced pressure until 10.49 g of a dry extract were obtained corresponding to the expected product with a Rf=0.55 (cyclohexane/ethyl acetate 80/20).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([CH2:16][N:25]3[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:26]3)=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)NC1CCNC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)NC1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)C1
Yield: 46.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), ethanesulfonic acid pyrrolidin-3-yl amide hydrochloride (41 mg, 0.19 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 35 mg (47%) of the desired product after purification.
Reaction SMILES: [Cl-].[NH2:2][P+:3]([N:10]([CH3:12])[CH3:11])([N:7]([CH3:9])[CH3:8])[N:4]([CH3:6])[CH3:5].[OH-]>>[NH:2]=[P:3]([N:4]([CH3:6])[CH3:5])([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8]
Reactant: CN(C)[P+](N)(N(C)C)N(C)C
Agent: [Cl-]
Agent: [OH-]
Product: CN(C)P(=N)(N(C)C)N(C)C

Procedure:
A process is provided for preparing iminotris(dimethylamino)phosphorane at high purity and high yield from aminotris(dimethylamino)phosphonium chloride. Aminotris(dimethylamino)phosphonium chloride is first reacted with an aqueous solution of the hydroxide of an alkali metal or alkaline earth metal in the presence of a solvent in which the chloride and hydroxide of the alkali metal or alkaline earth metal are sparingly soluble, whereby iminotris(dimethylamino)phosphorane is formed. After water is dissolved off at a temperature of 70° C. or lower from the reaction mixture, solids are removed from the thus-concentrated reaction mixture by solid-liquid separation. The resultant mother liquor is then distilled to obtain iminotris(dimethylamino)phosphorane.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.OCCCCCCCCCC(O)=O.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51]CC2)CCCCC1>O1CCCC1>[CH3:1][N:45]([C:46]1[CH:51]=[CH:52][CH:53]=[CH:48][N:47]=1)[CH3:39]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)CCCCCCCCCO
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 471 mg of 10-hydroxydecanoic acid, 25 ml of dry tetrahydrofuran, 516 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 332 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH:12]CC3C=CC=CC=3)[CH2:11][C:5]=2[CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CC(N)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
A mixture of N-[(2R)-3-(3-methylsulfonylamino-4-benzyloxy)phenyl-2-hydroxypropyl]-N-[(6RS)-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)benzylamine (34 mg), 50% wet palladium (10%) on charcoal (10 mg) and methanol (1 ml) was stirred under hydrogen (1 atm) at room temperature for 1.5 hours. The reaction mixture was filtered and evaporated. The residue was purified by preparative TLC (eluent; 25% methanol-dichloromethane) to give N-[(2R)-3-(3-methylsulfonylamino-4-hydroxy)phenyl-2-hydroxypropyl]-[(6RS)-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine (6.9 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])=[CH2:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 2-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 29) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethylbenzo[f][1,7]naphthyridin-5-amine as a solid. 1H NMR (methanol-d4): δ 8.78-8.81 (m, 2H), 8.45 (d, 1H), 7.55-7.63 (m, 2H), 7.35-7.40 (m, 1H), 2.97 (q, 2H), 1.43 (t, 2H). LRMS [M+H]=224.1.
Reaction SMILES: [C:1]1([CH2:11]P(=O)(OCC)OCC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH:26]([C:28]1[N:29]=[C:30]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[S:31][CH:32]=1)=O.[Cl-].[NH4+]>O1CCCC1>[C:1]1(/[CH:11]=[CH:26]/[C:28]2[N:29]=[C:30]([CH:33]3[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]3)[S:31][CH:32]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: CCOP(=O)(Cc1cccc2ccccc12)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C/c3cccc4ccccc34)cs2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under argon, diethyl 1-naphthylmethylphosphonate (1.88 g) is dissolved in tetrahydrofuran (20 ml) and cooled to 0° C. 757 mg of potassium tert-butoxide are added, whereupon the colour of the solution changes to dark-red. After a further 10 min of stirring, tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.00 g) is added. The mixture is stirred at 0° C. for 30 min and then warmed to room temperature. After a further 20 min, conc. ammonium chloride solution is added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated, and the residue is purified chromatographically. This gives tert-butyl 4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.16 g) as the E isomer.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC([C:49]3[N:50]([CH2:65][CH2:66][N:67]([CH:69](C)C)[CH3:68])[CH:51]=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:49][N:50]([CH2:65][CH2:66][N:67]([CH3:69])[CH3:68])[CH3:51])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CN(C)CCN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: C([Mg]Br)(C)C.C([Li])CCC.[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH:22]2[CH2:24][CH2:23]2)/[C:17](=[N:25]/[C:26](=[O:38])[C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2F)/[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CN([CH:42]=[O:43])C>C1COCC1.C(N(CC)CC)C.CO.C(OCC)(=O)C>[C:11]([C:15]1[N:19]([CH3:20])[N:18]([CH2:21][CH:22]2[CH2:24][CH2:23]2)/[C:17](=[N:25]/[C:26](=[O:38])[C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:28]=2[CH:42]=[O:43])/[CH:16]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1CC1CC1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2C=O)n1CC1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To the solution of isopropylmagnesium bromide (3 mL, 2.97 mmol, 1.0 M solution in THF) was added n-butyllithium (2.4 ml, 5.93 mmol, 2.5 M solution in hexane). The mixture was cooled to −78° C., and then a solution of Example 9G (0.680 g, 1.48 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. then DMF (0.460 mL, 5.93 mmol) was added, and the mixture was allowed to warm to room temperature. The mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, eluted with a gradient of 5-50% hexanes in solvent B, solvent B: 10:1:0.5 ethyl acetate:methanol:triethylamine) afforded the title compound (560 mg, 1.374 mmol, 93% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42-0.52 (m, 4H), 1.24-1.36 (m, 1H), 1.42 (s, 9H), 3.98 (s, 3H), 4.30 (d, J=7.14 Hz, 2H), 6.92 (s, 1H), 7.33-7.43 (m, 1H), 7.70-7.78 (m, 1H), 8.7 (dd, J=6.74, 2.38 Hz, 1H), 10.58 (s, 1 H); MS (ESI) m/z 408 [M+H]+, 406[M−H]−.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]2=[O:18])=[N:7][CH:8]=1.Cl.N1C=CC=CC=1>ClCCl>[OH:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14]2=[O:15])=[N:7][CH:8]=1
Reactant: COc1cnc(N2C(=O)CC(C)(C)CC2=O)nc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(=O)N(c2ncc(O)cn2)C(=O)C1
Temperature: 190 °C
Yield: 64.2 %

Procedure:
A mixture of 1-(5-methoxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione (0.99 g, 3.97 mmol) and pyridine hydrochloride (1.50 g, 7.99 mmol) was heated at 190° C. for 2.5 hours. After cooling to room temperature the reaction mixture was dissolved in a small amount of dichloromethane and filtered over a short pad of silicagel and washed with ethyl acetate. Evaporation of the solvent in vacuo yielded the title compound (0.60 g, 64% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[I].[K]>CN(C=O)C.C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)cc1
Temperature: 40 °C

Procedure:
A mixture of 3-(8-chloro-3-phenylcinnolin-4-yl)phenol (0.05 g, 0.15 mmol), 4-bromomethylphenyl acetic acid (0.10 g, 0.44 mmol), sodium carbonate (0.50 g, 4.7 mmol), and potassium iodine (0.50 g, 3.0 mmol) in DMF (5 mL)/water (1 mL) was heated to 40° C. for 2 hours. The mixture was then poured into water, acidified with acetic acid and extracted with ethyl acetate. The organic residue was purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a colored solid. MS (ESI) m/z 481; HRMS (ESI, [M+H]+) 481.1329.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:39][CH2:40][O:41][CH3:42])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCC(n2cc(-c3ccc4nnc(C(C)C)n4n3)c(-c3ccc(F)cc3F)n2)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
The 6-(3-(2,4-difluorophenyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.15 g, 0.35 mmol; Example #Q.1.2) was dissolved in DMF (4 mL) and then the K2CO3 (0.10 g, 0.71 mmol) and 1-bromo-2-methoxyethane (0.075 g, 0.53 mmol) were added. The mixture was heated at about 65° C. in an oil bath for about 1 h then another portion of 1-bromo-2-methoxyethane (0.075 g, 0.53 mmol) was added. After about 1 h, a third portion of 1-bromo-2-methoxyethane (0.075 g, 0.53 mmol) was added. The mixture was heated for about 1 h longer then cooled and concentrated under reduced pressure. The material was purified by RP-HPLC (Table 1, Method d). The appropriate fractions were concentrated and then basified with 2N NaOH and then extracted with EtOAc. Drying over MgSO4 and evaporating gave an oil which was purified further by flash chromatography on silica with DCM/MeOH (9:1) as an eluent. Concentration of the appropriate fractions followed by trituration with Et2O/heptane resulted in a solid which was collected by filtration to provide the title compound (0.086 g, 50%): LC/MS (Table 1, Method a) Rt=1.90 min; MS m/z: 482.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[S:11]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][C:20]#[N:21])(=[O:18])=[O:17])=[CH:12]1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:19](/[S:16]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)(=[O:18])=[O:17])\[C:20]#[N:21])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccsc1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccsc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and thien-3-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-(thien-3-ylsulfonyl)acrylonitrile
Reaction SMILES: COC1C=CC(CC=O)=CC=1.C[C:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(C)[CH:14]=[C:15]([Br:17])[Br:16]>>[Br:16][C:15]([Br:17])=[CH:14][CH2:13][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Agent: COc1ccc(CC=O)cc1
Product: COc1ccc(CC=C(Br)Br)cc1

Procedure:
This compound was prepared from Compound 74 in the same manner of Compound 53.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:31])=[CH:19][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:42]=[N+:43]=[N-:44])(C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:31])=[CH:19][C:10]=1[C:11]1[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[N:44]=[N:43][N:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
2,4-Bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (3.3 g, 6.8 mmole) was dissolved in anhydrous dichloromethane (20 ml), then PCl5 (1.77 g, 8.2 mmol) was added and the resulting solution was stirred at r.t. for 3 h under nitrogen. The reaction mixture was then cooled to 0° C., and TMSN3 (6 ml, neat) was added at 0° C. and the resulting mixture was stirred at r.t. for 3 hr. After quenching the reaction with NaHCO3 solution, and the reaction mixture was extracted with dichloromethane (30 ml×3). The combined organic was dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (2.8 g, 82%). M.p.: 92-93° C.; 400 MHz 1H NMR (CDCl3) δ: 7.68 (s, 1H), 7.44-7.31 (m, 8H), 7.19-7.15 (m, 2H), 6.64 (s, 1H), 5.17 (s, 2H), 4.99 (s, 2H), 4.28 (t, J=7.2 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.03 (pent, J=6.4 Hz, 2H); LCMS: 509, 511 [M+H].