Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[S:11][C:12]=1[CH3:13])(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[S:11][C:12]=1[CH3:13])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cc(-c2nc(CCOS(C)(=O)=O)c(C)s2)ccn1
Agent: [Na+]
Product: CCc1cc(-c2nc(CCN=[N+]=[N-])c(C)s2)ccn1

Procedure:
The product was obtained starting from 2-(2-(2-ethylpyridin-4-yl)-5-methylthiazol-4-yl)ethyl methanesulfonate (226 mg, 692 μmol) and sodium azide (63.0 mg, 969 μmol) according to the method described in example 46, step 2 as light yellow oil (138 mg, 505 μmol, 72.9%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:2].[Cl:17][C:18]([Cl:24])([S:22]Cl)[CH:19]([Cl:21])[Cl:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:22][C:18]([Cl:24])([Cl:17])[CH:19]([Cl:21])[Cl:20])[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)c1cccc2ccccc12
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)C(Cl)Cl)C(=O)c1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5.0 g (0.024 N-cyanomethyl-1-naphthamide (the product of Example 11) and 6.2 g (0.026 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride in 125 ml methylene chloride, 3.0 g (0.030 mole) triethylamine in 25 ml methylene chloride were dropped in over 40 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate, and stripped down to a volume of 50 ml. The methylene chloride solution was then chromatographed on a column containing about 125 g silica gel, eluting with methylene chloride. The eluate was stripped to give 4.3 g of the above-identified product as an amber glass which tended to crystallize slowly.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[F-].[Cs+].[CH3:22][N:23]([CH:25]=O)[CH3:24]>O>[C:12]([NH:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH2:9][CH2:25][N:23]([CH3:22])[CH3:24])=[O:19])=[CH:14][CH:15]=3)=[CH:7][N:6]2[N:8]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3nc(NC(=O)c4ccccc4)nn3c2)cc1
Temperature: 95 °C
Yield: 24 %

Procedure:
To a reaction vessel containing N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 mol eq.), N-(2-dimethylamino-ethyl)-4-boronic acid-benzamide (85 mg, 0.36 mmol, 1.2 mol eq.) and cesium fluoride (135 mg, 0.9 mmol, 3 mol eq.) in DMF (0.75 mL) and H2O (0.5 mL) was added bis-triphenylphosphine palladium dichloride (0.009 mmol, 3 mol %) in DMF (0.25 mL). The vessel was purged with nitrogen, capped and heated at 95° C. for approximately 18 hours. The reaction mixture was cooled to room temperature, filtered and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (30.4 mg, 24%). HPLC, Rt: 1.74 min (purity: 99%). LC/MS M+(ESI): 429.3, M−(ESI) 427.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C:11]=3[C:10](=[O:28])[N:9]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[CH2:18][CH:17]([N:12]2[C:11]3[C:10](=[O:28])[N:9]([C:29]4[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=4)[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:15]=3[C:14]([CH3:16])=[N:13]2)[CH2:20]1
Reactant: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(C2CNC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of tert-butyl 3-(4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)azetidine-1-carboxylate (Step 138.1a) (280 mg, 0.534 mmol) in CH2Cl2 (4 mL) was added TFA (0.412 mL, 5.34 mmol). The reaction mixture was stirred for 1 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried on Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (NH3 1%/CH2Cl2/MeOH 1-4%) to afford 200 mg of the title compound as a colorless solid. tR: 0.66 min (LC-MS 2); ESI-MS: 424.1 [M+H]+ (LC-MS 2); Rf=0.09 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3H) 1.94 (s, 3H) 3.35 (s, 3H) 3.70-3.78 (m, 2H) 4.06-4.14 (m, 2H) 5.26-5.37 (m, 1H) 6.07 (br. s, 1H) 7.23-7.29 (m, 2H) 7.34-7.40 (m, 3H) 7.71 (d, J=2.74 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([S:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][C:14]3[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=3)=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:32])=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(OC)c(OC)c2)ccc1Oc1cncc(Cl)c1
Yield: 68 %

Procedure:
The title compound was prepared in a manner similar to Example 3, beginning with 0.1 g of the aniline of Example 1 and 3,4-dimethoxybenzenesulfonyl chloride, and adding 0.2 mL of pyridine to the reaction mixture to yield 0.115 g (68%) of the title sulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([CH2:16][CH2:17][C:18](=O)[C:19]([OH:21])=O)=[CH:5][CH:4]=1.C(O)(=O)C.[NH2:27][NH2:28]>C(O)C>[CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([C:16]2[CH2:17][CH2:18][C:19](=[O:21])[NH:27][N:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(=O)C(=O)O)c2cc(C(F)(F)F)nn12
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)CC2)c2cc(C(F)(F)F)nn12
Reaction time: 8 h
Yield: 20.2 %

Procedure:
The compound of Example 207 (616 mg, crude) was dissolved in ethanol (15.0 mL). To this solution, hydrazine monoacetate (428 mg) was added and the mixture was stirred for 8 hours under reflux. Subsequently, the solvent was evaporated and the residue was purified by amino-silica gel column chromatography (ethyl acetate) to afford the title compound as a yellow powder (123 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.79 (s, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.40-8.44 (m, 1H), 7.94-8.05 (m, 2H), 7.73-7.81 (m, 2H), 7.68 (dd, J=5.0, 1.5 Hz, 1H), 7.36-7.45 (m, 4H), 3.72 (s, 2H); MS (APCI+) M/Z 425 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc2c(c1Br)OCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4Br)OCO5)c3c2s1
Yield: 21 %

Procedure:
Prepared from VII and 2-bromo-3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 21%; yellow solid, mp>260° C.; IR (KBr) νmax/cm−1 2887, 2233, 1632, 1610, 1581, 1501, 1484, 1465, 1379, 1348, 1303, 1267, 1232, 1161, 1116, 1034, 970, 929, 829; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.06 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.25 (s, 1H), 6.83 (s, 1H), 6.06 (s, 2H); HRMS calcd for C17H9N5O2SBr (M+H+): 425.9660, found 425.9646.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=1[O:39][CH3:40]>>[F:38][C:32]1[C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:29]([C:20]2[CH:21]=[CH:22][C:23]([C:25]([F:27])([F:28])[F:26])=[CH:24][C:19]=2[CH2:18][N:8]2[C@@H:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH2:11][O:10][C:9]2=[O:12])=[C:30]([O:39][CH3:40])[CH:31]=1
Reactant: Cc1ccc(C[C@H]2COC(=O)N2)cc1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccc(C)cc1

Procedure:
(4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one (Step B, 14 mg, 0.074 mmol) was treated with sodium hydride (60% in oil, 6.2 mg, 0.154 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 25 mg, 0.062 mmol) as described in Example 305 to afford (4S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as clear gum. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.65-7.60 (m, 1 H), 7.53 (s, 1 H), 7.35-7.32 (m, 1 H), 7.06-7.20 (m, 2 H), 6.82-6.75 (m, 2 H), 6.69 (d, J=11.7 Hz, 1 H), 4.67 (d, J=15.8 Hz, 1 H), 4.06 (d, J=15.8 Hz, 1 H), 4.04-4.00 (m, 1 H), 3.96-3.93 (m, 1 H), 3.73 (s, 3 H), 3.55-3.48 (m, 1 H), 3.23-3.15 (m, 1 H), 2.63 (dd, J=13.5, 3.6 Hz, 1 H), 2.35 (d, J=13.5 Hz, 1 H), 2.29 (s, 3 H), 1.25-1.13 (m, 6 H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C:7]#[N:8])[C:3]#[N:4].[NH3:9]>[Pd]>[CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: CC(C#N)CCC#N
Reactant: N
Agent: [Pd]
Product: Cc1ccc(N)nc1N
Temperature: 200 °C

Procedure:
2-Methylglutaronitrile was combined with Pd.C (5 mol % of 10 wt % Pd on carbon) in a 10 mL Hastelloy shaker autoclave to which liquid NH3 was added. The mixture was heated at 200° C. for 45 h. The mixture was cooled to ambient temperature and the excess NH3 removed by N2 purge. The crude mixture was suspended in 10 mL anhydrous methanol, the catalyst was removed by syringe filtration, and the crude reaction mixture was concentrated in vacuo. 2-Methylglutaronitrile conversion was 100% to give 0.02 mmol of 3-methylpyridine-2,6-diamine in 2.3% net yield.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[CH3:6])[CH:3]1[O:5][CH2:4]1
Reactant: BrCC1CO1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (1.0 g, 7.6 mmole) was added to a stirred solution of 2-methylbenzimidazole (1.0 g, 7.6 mmole) and sodium hydride (0.3 g, 7.6 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for 0.5 hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.4 g). This was purified by flash silica gel chromatography (10% methanol in CH2Cl2) to afford the titled product as a light oil (0.64 g, 45% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(C(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (2.73 g), (1-bromoethyl)benzene (1.15 mL) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 19%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[CH:7][CH:6]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:35][CH3:36])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:14]=3[C:15]=2[C:16](=[O:25])[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:33]
Reactant: COc1ccc2oc(-c3ccc(OCCCl)cc3)c(C(=O)c3cc(C)cc(C)c3)c2c1
Reactant: CCNCC
Product: CCN(CC)CCOc1ccc(-c2oc3ccc(OC)cc3c2C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
Reaction of 2-[4'-(2-chloroethoxy)phenyl]-5-methoxy-3-(3',5'-dimethylbenzoyl)benzofuran with diethylamine by the procedure of Example 25 gives the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Br:17]P(Br)Br>C(Cl)(Cl)Cl>[Br:17][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[N:14][CH:13]=1
Reactant: CCN1CCN(c2ccc(CO)cn2)CC1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(CBr)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of [6-(4-ethylpiperazin-1-yl)pyridin-3-yl]methanol (3.0 g, 13.55 mmol) in anhydrous chloroform was added at 0° C. tribromophosphane (4.03 g, 14.91 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours. The solvent was evaporated to provide 1-[5-(bromomethyl)pyridin-2-yl]-4-ethylpiperazine (3.85 g), which was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:10]=[C:9]([C:21]2[N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[C:24]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[N:23][CH:22]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)c(F)c4)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (82 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mmol) and Pd(PPh3)4 (45 mg, 0.038 mmol) in dioxane (2.2 mL) and 1.5M Na2CO3 (0.83 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The residue is triturated with Et2O to afford the title compound as a solid. HPLC (254 nm): Rt 1.94 min (93.5%); m/z (APCI) 446 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:15]3[CH2:16][CH:12]([CH2:13][NH:14]3)[CH2:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1.[CH2:17]=O>C(O)=O>[CH3:17][N:14]1[CH2:13][CH:12]2[CH2:16][CH:15]1[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:10][CH2:11]2
Reactant: C=O
Reactant: COc1cncc(C2=CCC3CNC2C3)c1
Solvent: O=CO
Product: COc1cncc(C2=CCC3CC2N(C)C3)c1
Yield: 56 %

Procedure:
A mixture of 4-(5-methoxy-3-pyridinyl)-6-azabicyclo[3.2.1]oct-3-ene (15 mg, 0.07 mmol), aqueous formaldehyde (37%, 0.25 mL) and 90% formic acid (1 mL) was heated at reflux for 1½ h. The mixture was concentrated under reduced pressure, and the remaining volatiles were removed by azeotropic evaporation with methanol (three times). The residue was made basic with dilute aqueous sodium hydroxide and extracted into dichloromethane. The extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column, eluting with 90:10:1 dichloromethane/methanol/concentrated ammonium hydroxide. Concentration of selected fractions gave the product as an oil (9.0 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[C:19]([Cl:24])[N:18]=1.Cl>O.CC(O)C>[Cl:24][C:19]1[N:18]=[C:17]([NH2:16])[N:22]=[C:21]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: Cc1cc(Oc2ccc(N)cc2)ccn1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Oc2ccc(Nc3cc(Cl)nc(N)n3)cc2)ccn1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
{4-[(2-Methylpyridin-4-yl) oxy] phenyl} amine (47.5 g, 237 mmol) and 2-amino-4,6-dichloropyrimidine (40.8 g, 249 mmol) were suspended in water (900 mL) and 2-propanol (300 mL). 2M aqueous hydrochloric acid solution (23.7 mL) was then added and the mixture was then heated at 95° C. for 17 h. The mixture was then allowed to come to rt and solids were collected by suction filtration and washed with small amount of isopropanol. The solids were then resuspended in DMF and heated at 90° C. Triethylamine (20 mL) was then added and the mixture was stir for additional 10 min at 90° C. Water was then added in excess until cloudiness persisted at temperature. This was cooled to about 5° C. and precipitate formed were collected by suction filtration, washed with water and dried in vacuum oven at 40° C. to afford desired product (50 g, 64%) as light tan solid. 1H NMR (DMSO-d6) δ 9.40 (s, 1H), 8.27 (d, 1H), 7.76 (d, 2H), 7.06 (d, 2H), 6.75 (brs, 2H), 6.72 (d, 1H), 6.66 (s, 1H), 5.98 (s, 1H); MS ES 328 (M+H)+, calcd 328, RT=1.45 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=O)[CH:7]=[CH:6][NH:5][C:4]=1[CH3:10].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)[nH]ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Product: COc1c(Cl)ccnc1C

Procedure:
3-Methoxy-2-methyl-4(1H)-pyridone (5.6 g) was suspended in phosphorus oxychloride (50 ml), refluxed for 10 hours, and concentrated. To the resultant residue was added toluene and the residual phosphorus oxychloride was evaporated under reduced pressure. To the resultant oily substance were added chloroform and water and the chloroform layer was separated. The aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform solutions thus obtained were combined, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, to give 4-chloro-3-methoxy-2-methylpyridine (4.8 g) as a light brown oil.
Reaction SMILES: [H-].[Na+:2].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([O-:16])(=[O:15])=[O:14].[Na+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([O-:16])(=[O:15])=[O:14].[Na+:2]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]

Procedure:
To a solution of sodium 2-methoxy-ethylate prepared by adding 7.3 g of sodium hydride (14.6 g as a state of 50% liquid paraffin dispersion) to 300 ml of methyl cellosolve, 55 g of sodium 2-chloro-5-nitrobenzenesulfonate was added with stirring. The reaction mixture was heated to a temperature from about 80° to 85° C. in a hot water bath with stirring for 30 minutes. After carried out filtration with heating, 1.5 liters of isopropyl alcohol were added to the filtrate. The crystals thus-formed were separated by filtration and washed with 100 ml of isopropyl alcohol. Yield: 59 g. m.p.: 238°-239° C.
Reaction SMILES: CO[C:3](OC)([N:5]([CH3:7])[CH3:6])[CH3:4].[NH2:10][C:11]([NH2:13])=[S:12]>C(Cl)Cl>[NH2:10][C:11](/[N:13]=[C:3](/[N:5]([CH3:7])[CH3:6])\[CH3:4])=[S:12]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(N)=S
Solvent: ClCCl
Product: C/C(=N\C(N)=S)N(C)C
Yield: 76.5 %

Procedure:
N,N-Dimethyl acetamide dimethyl acetal (75 g, 0.56 mole) was added to a suspension of thiourea (33.0 g, 0.43 mole) in methylene chloride. The mixture was heated under reflux for 4 h. The solvent was removed and the residue was crystallized from 5% MeOH and diethyl ether affording (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 76% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@H:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26](O)=[O:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:58]([NH:65][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C@H:14]1[CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: O=C(O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]indol-5-yl acetic acid (1g, 2.76 mmol) in DMF (5 ml) was added TBTU (0.97 g 3.04 mmol), Et3N (0.42 ml 3.04 mmol) and benzylamine (0.33 ml 3.04 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum and the residue chromatographed on Silica 5% MeOH/94% CHCl3 /1% 88O NH3 to give a pale yellow oil. yield: 0.81 g (80%) MS 468 (M+1), 392, 333.