Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[OH-].[K+].[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH3:29])([CH3:28])[CH3:27]>CS(C)=O.O>[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][C:2]2[CH:20]=[CH:19][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product from Example 172b (215 mg, 0.655 mmol) was dissolved in DMSO (30 ml) to which KOH (75 mg, 1.31 mmol) and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (137 mg, 0.655 mmol) were added. The reaction mixture was then heated to 80° C. for 2 h reaction mixture was then cooled to room temperature and diluted with water and the title compound collected by filtration (240 mg, 78%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=S.[N:22]#[C:23][NH2:24].[Pb]>>[CH2:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH2:9][NH:8][CH2:7][CH2:6][NH:5][C:3]([NH:24][C:23]#[N:22])=[N:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CN
Reactant: CNC(=S)NCCNCc1ncoc1Cc1ccccc1
Agent: [Pb]
Product: CN=C(NC#N)NCCNCc1ncoc1Cc1ccccc1

Procedure:
Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[O:20][C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([CH:36]([CH3:42])[C:37]([O:39]CC)=[O:38])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[O:22])=[N:18][N:17]=2)=[CH:11][CH:10]=1)#[N:8].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[O:20][C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([CH:36]([CH3:42])[C:37]([OH:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[O:22])=[N:18][N:17]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccc(C#N)cc4)o3)cc2)CC1
Agent: C[Si](C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccc(C#N)cc4)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium trimethylsilanolate (65 mg, 0.51 mmol) was added in one portion to a solution of trans-ethyl 2-(4-{4-[({5-[(4-cyanophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]-phenyl}cyclohexyl)propanoate (Example 583, 25 mg, 0.051 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature for 48 h. A 1M aqueous solution of citric acid (10 mL) was added and the mixture was filtered to leave a solid. The solid was washed with H2O (2 mL) and purified by reverse phase preparative HPLC, eluting with a gradient of CH3CN and H2O containing 0.2% TFA, to give the title compound (11 mg, 47%) as a solid; 1H NMR δ 1.05 (3H, t), 1.1-1.3 (2H, m), 1.38-1.51 (2H, m), 1.52-1.63 (1H, m), 1.7-1.9 (4H, m), 2.13-2.25 (1H, m), 2.4-2.5 (1H, m), 7.22 (2H, d), 7.7 (2H, d), 7.76 (2H, d), 7.85 (2H, d), 11.0 (1H, s); MS m/e MH+ 460.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[C:6]2=[O:15].O.[OH-].[Li+]>C1COCC1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[C:6]2=[O:15]
Reactant: COC(=O)c1ccc(CN2Cc3c(cc(OC)c(OC)c3Br)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)O)cc1)C2=O
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Methyl 4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzoate (500 mg, 1.19 mmol) in the step 2 and lithium hydroxide monohydrate (199 mg, 4.76 mmol, 4 equiv.) were dissolved in a mixture of THF and distilled water (mixture ratio=2:1 (v/v), 10 mL), and stirred at room temperature for 1 night. The reaction proceeded until no starting material is detectable by TLC. The resulting mixture thus obtained was distilled under a reduced pressure to remove THF. The resulting material was dissolved in distilled water and 1N HCl was added thereto to be pH 2. White precipitates thus obtained were filtered and dried under vacuum to obtain the title compound (380 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH:34]1([CH:40]=[CH:41]B(O)O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:41]=[CH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: OB(O)C=CC1CCCCC1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(C=CC3CCCCC3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (137 mg, 0.25 mmol) was coupled with 2-cyclohexylvinylboronic acid (59 mg, 0.38 mmol) according to general procedure G to give {-4-[2-[4-(2-cyclohexyl-vinyl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:16][CH2:17][N:12]([C:18]2[N:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:13][CH2:14]1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)nicotinonitrile (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.75 (m, 4H) 3.68 (m, 4H) 4.07 (s, 2H) 6.94 (m, 1H) 7.56 (m, 1H) 8.08 (dd, J=7.80, 2.03 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.42 (dd, J=4.75, 1.70 Hz, 1H) 8.60 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 337 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH:14]=O)[C:11]([NH:16][CH3:17])=[C:10]2[CH:18]=[CH:19][N:20]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](=[O:35])[CH2:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[C:12]2[C:11]([N:16]([CH3:17])[C:23](=[O:35])[C:24]([C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=3[CH3:34])=[CH:14]2)=[C:10]2[CH:18]=[CH:19][N:20]=[C:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1c(C=O)cn(Cc2ccccc2)c2nccc1-2
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1cc2cn(Cc3ccccc3)c3nccc-3c2n(C)c1=O
Temperature: 120 °C

Procedure:
A mixture of 7-benzyl-4-methylamino-7H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (400 mg, 1.5 mmol), (2-methyl-5-nitro-phenyl)-acetic acid methyl ester (350 mg, 1.67 mmol) and cesium carbonate (1.1 g, 3 mmol) in 5 ml anhydrous DMF is heated to 120° C. for 30 min. The reaction mixture is cooled down to room temperature. The reaction mixture is partitioned in water and ethyl acetate, extracted with ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by silica gel flash chromatography, eluted with 40% to 100% ethyl acetate in hexane to give the title compound as light yellow solid. MS m/z 426.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13](SC)[N:12]=1)=[O:10].O>CCO.[Ni]>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)[OH:10]
Reactant: CSc1nccc(C(=O)c2cccc(C)c2Br)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(O)c2ccncn2)c1Br

Procedure:
To a solution of (2-bromo-3-methylphenyl)(2-(methylthio)pyrimidin-4-yl)methanone (0.10 g, 0.309 mmol) in EtOH (10 mL) was added Raney 2800 nickel, slurry, in water (0.022 mL, 3.41 mmol) and the resulting mixture was reflux until starting material was consumed (2 h). The mixture was brought to RT and decanted. The remaining Ni was extracted with DCM/NH3 (2M in MeOH). The combined organic layers were concentrated and the residue obtained was extracted with DCM and the extracts were combined and concentrated to afford a yellow oil as (2-bromo-3-methylphenyl)(pyrimidin-4-yl)methanol which was used without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Si:7]([CH3:10])([CH3:9])[CH3:8].C([Li])(C)(C)C.CCCCC.[CH3:21][Si:22](C[Li])([CH3:29])[C:23]1C=CC=CN=1.Cl[Si](C)(C)C.Cl>C(OCC)C>[CH3:8][Si:7]([CH3:10])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][Si:22]([CH3:29])([CH3:23])[CH3:21]
Reactant: C[Si](C)(C)c1ccccn1
Reactant: [Li]C[Si](C)(C)c1ccccn1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C[Si](C)(C)c1ccccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
After dissolving 151 mg (1.0 mmol) of (2-pyridyl)trimethylsilane in 2 ml of dry diethyl ether, 0.67 ml (1.1 mmol) of a t-butyllithium/pentane solution (the concentration: 1.64 M) was added dropwise at an inner temperature of −78° C., whereby the reaction solution turned orange indicating the formation of [dimethyl(2-pyridyl)silyl]methyllithium. After that, the mixture was continued to be stirred at an inner temperature of −78° C. for 30 minutes, and then 130 mg (1.2 mmol) of chlorotrimethylsilane was added to the mixture, which was subsequently stirred at an inner temperature of −78° C. overnight. To the resulting reaction solution was added 5 ml of 1N hydrochloric acid, and the mixture was separated to the organic and aqueous layers. The organic layer was extracted with four portions of 5 ml of 1N hydrochloric acid. The resulting aqueous layers were combined together, and neutralized by the addition of sodium hydroxide pellets. The neutralized aqueous layer was extracted with three portions of 10 ml of diethyl ether. The resulting organic layers were combined together and dried over magnesium sulfate. The solvent was evaporated to give 208 mg of dimethyl(2-pyridyl)(trimethylsilylmethyl)silane (yield: 93%; NMR purity: 95% or more).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C.[OH-].[Na+]>OS(O)(=O)=O.CO>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCCCO
Reactant: COC(=O)C(C)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOC(=O)C(C)O
Yield: 180.9 %

Procedure:
A 250 mL round bottom flask equipped with a spin bar and a distillation column was charged with 100 g (0.96 moles) of methyl lactate, 304.1 g (1.92 moles) of decyl alcohol, and 500 mg of H2SO4. The reaction was heated until methanol formation ceased. The reaction was then neutralized with 0.1N NaOH (100 mL) and extracted with ether. The organic layer was dried over MgSO4, filtered and dried in vacuo to give 400 g of crude mixture. The fractional distillation was carried out three times to give 98.5 g (45% yield, 100% pure by GC) of a clear colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH:16]=[C:17]1[NH:21][C:20](=[O:22])[CH2:19][S:18]1>>[NH:16]=[C:17]1[NH:21][C:20](=[O:22])[C:19](=[CH:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][N:4]=[C:3]3[N:2]([CH3:15])[CH3:1])[S:18]1
Reactant: N=C1NC(=O)CS1
Reactant: CN(C)c1ncnc2ccc(C=O)cc12
Product: CN(C)c1ncnc2ccc(C=C3SC(=N)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-piperidine-quinazoline-6-carbaldehyde (intermediate 14) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]([O:24][CH3:6])=[N:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: C[O+](C)C
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Trimethyloxonium tetrafluoroborate (Meerwein's salt) (141 mg, 0.94 mmol) was added in one portion to a solution of 1-(tert-butoxycarbonyl)hexahydro-(5H)-1,4-diazepin-5-one (200 mg, 0.94 mmol) in 2.0 mL of anhydrous methylene chloride. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between 10 mL of saturated aqueous sodium bicarbonate and 20 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 3×10 mL of ethyl acetate. The combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the organic solution was concentrated in vacuo to give 180 mg (85%) of 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-5-methoxy-(1H)-1,4-diazepine as a yellow liquid.
Reaction SMILES: [C:1]([CH:3]([C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1)[NH:4][S:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:6])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:23][OH:24]>C(O)C>[C:7]([S:5]([NH:4][CH:3]([C:11]1([CH3:15])[CH2:12][O:13][CH2:14]1)[C:1]([NH2:2])=[N:23][OH:24])=[O:6])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC1(C(C#N)NS(=O)C(C)(C)C)COC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C(NS(=O)C(C)(C)C)C(N)=NO)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
To a solution of N-[cyano-(3-methyloxetan-3-yl)methyl]-2-methyl-propane-2-sulfinamide (example 251a, 680 mg, 2.95 mmol) in Ethanol (15 ml) was added potassium carbonate (408 mg, 2.95 mmol) and hydroxylamine hydrochloride (226 mg, 3.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by stirring at 50° C. overnight. The reaction was diluted with ethanol and sonicated a few minutes followed by removal of insolubles by filtration. The filtrate was concentrated in vacuo to dryness to yield a crude yellow gum of the title compound (892 mg) which was used without any purification. MS (ESI, m/z): 264.3 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH3:44][S:45]([CH:48]1[CH2:52][CH2:51][NH:50][CH2:49]1)(=[O:47])=[O:46]>>[CH3:32][O:31][C:28]1[N:27]=[CH:26][C:25]([NH:24][C:17]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:23][C:20]([CH2:21][N:50]3[CH2:51][CH2:52][CH:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49]3)=[CH:19][N:18]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)C1CCNC1
Product: COc1ccc(Nc2ncc(CN3CCC(S(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.23 g, 0.398 mmol) and 3-(methylsulfonyl)pyrrolidine (PharmaBlock, Carrboro, N.C.) (0.089 g, 0.597 mmol). 1H NMR (400 MHz, CDCl3) δ 11.63 (s, 1H); 8.73 (d, J=2.35 Hz, 1H); 8.36 (d, J=2.54 Hz, 1H); 8.21 (d, J=2.15 Hz, 1H); 8.10 (dd, J=8.80, 2.74 Hz, 1H); 6.78 (d, J=8.80 Hz, 1H); 5.55 (br. s., 2H); 3.94 (s, 3H); 3.56-3.68 (m, 3H); 2.99-3.05 (m, 1H); 2.88-2.95 (m, 1H); 2.87 (s, 3H); 2.76-2.84 (m, 1H); 2.61-2.70 (m, 1H); 2.56 (s, 3H); 2.25-2.35 (m, 2H). m/z (ESI, +ve ion) 470.9 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].C([N-]C(C)C)(C)C.[Li+].[C:20](=O)([O:23]C)[O:21][CH3:22]>O1CCCC1>[OH:11][C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[C:20]([O:21][CH3:22])=[O:23]
Reactant: COC(=O)OC
Reactant: O=C1CCc2ccccc2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 2-tetralone (25.0 g, 171 mmol) in dry tetrahydrofuran (250 ml) at 0° C. under argon was added lithium diisopropylamide (111 ml, 2M solution, 222 mmol). After stirring at 0° C. for 1 h, dimethyl carbonate was added (145 ml, 1710 mmol). After stirring at 0° C. for 0.5 h, the reaction mixture was warmed to room temperature, and then heated at reflux for 16 h. The mixture was then cooled to 0° C. and quenched with hydrochloric acid (1M, 450 ml). The resulting mixture was extracted with ethyl acetate (3×1000 ml) and the combined extracts were washed with brine (1000 ml) then dried (Na2SO4) and evaporated in vacuo to afford the title compound as a dark brown oil (36.3 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[C:5]([N+:31]([O-])=O)[CH:4]=1)#[N:2].Cl>CO>[NH2:31][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:30]=[CH:29][C:6]=1[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1
Reactant: N#Cc1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(N)c1
Temperature: 95 °C
Yield: 22.1 %

Procedure:
To a stirred solution of 4-cyano-2-nitro-1-N-[1-(3,3-diphenylpropyl)-piperidin-4-yl]aniline (300 mg, 0.68 mmol) in methanol (4 ml) was added concentrated HCl (1 ml) followed by stannous chloride dihydrate (620 mg) and the mixture was heated to 95° C. After 3 h the reaction mixture was concentrated and suspended in water (100 ml) and potassium carbonate was added to basify the solution. The solution was extracted with EtOAc (150 ml) and the emulsion left to separate. The mixture was then filtered through Celite™, separated. dried (MgSO4), concentrated and purified by Bond Elut™ chromatography (using 1% to 7.5% EtOH in DCM) to give the title compound as an oil (60 mg, 0.15 mmol); MS: 411.
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N+:15]([O-])=O)[CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[H][H]>O1CCOCC1.[Ni]>[C:1]([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c([N+](=O)[O-])cccc2cn1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: CC(=O)Oc1cc2c(N)cccc2cn1

Procedure:
5-Nitro-3-isoquinolinyl acetate (50 mg, 0.21 mmol) in 1,4-dioxane (20 mL) was treated with Raney-nickel powder (85 mg) and exposed to a hydrogen atmosphere via a balloon for 16 hours. The mixture was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to provide the title compound which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].COCCN(S(F)(F)[F:33])CCOC>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a stirred solution of compound 1.2 (5 g, 16.54 mmol, 1.00 equiv) in dichloromethane (250 mL) under nitrogen at −78° C. was added dropwise Deoxo-Fluor® (4.4 g, 19.89 mmol, 1.20 equiv). The resulting mixture was stirred for 1 h at −78° C. The reaction mixture was then carefully quenched by the addition of 50 mL of sodium bicarbonate (aq.sat.) and extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with 150 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:30) as eluent to yield 2.5 g (35%) of the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([C:12](O)=[O:13])=[N:10][CH:11]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([C:12]([Cl:3])=[O:13])=[N:10][CH:11]=1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cnc1C(=O)Cl
Temperature: 60 °C

Procedure:
Thionyl chloride (71 μl, 962 μmol) is added to a mixture of 5-chloro-3-methyl-pyridine-2-carboxylic acid (150 mg, 874 μmol), toluene (1 ml) and DMF (20 μl). The mixture is heated to 60° C. for 1 hour. The mixture is concentrated in vacuo and the crude product used directly without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:34]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=3)=[O:35])[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nccn3n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg, 0.80 mmol) and triethylamine (0.040 mL, 0.29 mmol) in tetrahydrofuran (10 mL) was added 3-(trifluoromethyl)phenyl isocyanate (0.154 mL, 1.12 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and precipitated from methanol to give the title compound (205 mg, 62%) as a white powder.