Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]#[N:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CCOCC>[CH2:23]([O:24][C:25](=[O:26])[CH2:27][C:13]1([C:15]#[N:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:22]
Reactant: N#CC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)CC1(C#N)c2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
9H-Xanthene-9-carbonitrile [27] (1.0 g, 4.825 mmol) was dissolved in anhydrous Et2O and cooled in an icebath. n-Butyl lithium (1.93 mL, 6.75 mmol. 2.5M soln. in hexanes) was added dropwise over 10 min. with continuos stirring. Stirring was continued for 30 min. at the same temperature and then brought to room temperature. The reaction mixture was heated at reflux (1 hr), cooled in an icebath and ethyl bromo acetate (0.75 mL, 6.755 mmol) was added dropwise via syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 0.9 g (64%) of the product as a colorless oil. 1H NMR (CDCl3)d: 1.04-1.08 (t, J=7.5 Hz, CH3), 3.01 (s, 2H, CH2), 3.90-3.99 (q, 2H, CH2), 7.14-7.69 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 13.54, 39.06, 48.47, 60.85, 116.88, 118.90, 119.75, 123.81, 127.34, 129.83, 150.30, 166.98.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13]Cl)=[CH:7][N:6]=1>C(O)C>[Cl:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][S:2][CH3:1])=[CH:7][N:6]=1
Reactant: COc1cc(CCl)cnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CSC)cnc1Cl
Reaction time: 8 h

Procedure:
To a suspension of sodium thiomethoxide (0.24 g, 3.5 mmol) in ethanol (10 mL) at 25° C. was added solution of 2-chloro-5-chloromethyl-3-methoxypyridine (0.55 mg, 2.9 mmol) in EtOH (4 mL). The solution was stirred overnight, after which the reaction was concentrated under vacuum. The crude reaction mixture was partitioned between H2O and Et2O and the layers separated. The aqueous phase was further extracted with Et2O (3×) and the combined organic phases dried over MgSO4 and concentrated to furnish 2-chloro-3-methoxy-5-methylthiomethylpyridine as a yellow oil (0.42 g, 71% over two steps). GC-MS: Exact mass calcd for C8H10ClNOS [M]+, 203. Found 203.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][OH:39])[CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][OH:39])[CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: OCC1CCCNC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCC(CO)C5)c4)cc23)CC1
Yield: 16.9 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 3-piperidinylmethanol (98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (10.2 mg, 17%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]/[CH:11]=[CH:12]/[C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:5][CH2:4]1.Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:29]1([CH2:28][CH2:27][CH2:26][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][S:10]/[CH:11]=[CH:12]/[C:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH2:5][CH2:4]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1=C(/C=C/SCC2CCNCC2)Sc2cccc3ncc1n23
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C1=C(/C=C/SCC2CCN(CCCc3ccccc3)CC2)Sc2cccc3ncc1n23

Procedure:
A solution of 0.314 g (0.780 mM) of (E)-4-[2-(piperidin-4-ylmethylthio)vinyl]-5-thia-1,8b-diazaacenaphthylene dihydrochloride, 0.19 g (0.94 mM) of 1-bromo-3-phenylpropane, and 0.38 ml (2.73 mM) of triethylamine in 20 ml of ethanol was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 4/1) to provide the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>O1CCCC1>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][C@H:11]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
5.0 g (13.9 mmol) of di-tert-butyl Boc-glutamate (Journal of Peptide Research (2001), 58, 338) were dissolved in 30 mL of tetrahydrofuran and cooled to −70° C. 30.6 mL (30.6 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise over a period of 85 min at this temperature and the mixture was stirred at −70° C. for another 2 hours. 9.0 g (41.7 mmol) of 4-nitrobenzyl bromide in 30 mL of tetrahydrofuran were than added dropwise, and after 1.5 h at this temperature, the cooling bath was removed and 100 mL of 2N aqueous hydrochloric acid and 450 mL of dichloromethane were added. The organic phase was separated off, washed with water (3×150 mL), dried over sodium sulfate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[N:35]([CH:36]=3)[CH:34]=[CH:33][S:32]4)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:39][N:38]=[N:37][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[N:35]([CH:36]=3)[CH:34]=[CH:33][S:32]4)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn4ccsc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[CH:3][N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
Reactant: CC1(C)OB(c2ccc(C#N)cc2)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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(OC)nccc21
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (200 mg) obtained in Step A-2 of Example 17 in DMF (4 mL)/water (0.40 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (191 mg), tetrakis(triphenylphosphine)palladium(0) (64.2 mg) and potassium carbonate (154 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (40.0 mg).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[C:8](N)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[FH:11].N1C=CC=CC=1.N([O-])=O.[Na+].[NH4+].[OH-]>>[F:11][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][S:1][C:5]2=[CH:6][N:7]=1
Reactant: F
Reactant: Nc1cc2ccsc2cn1
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1cc2ccsc2cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 32.6 %

Procedure:
To a solution of thieno[2,3-c]pyridin-5-ylamine (24.0 mg, 0.160 mmol) in pyridine hydrofluoride (0.50 mL, 5.50 mmol) in a plastic bottle was added sodium nitrite (33.1 mg, 0.479 mmol). The reaction mixture was stirred at RT for 50 min. Another portion of sodium nitrite was added and the mixture was stirred at RT for another 30 min, then at 100° C. for 1 h. The reaction mixture was then poured into 1:1 NH4OH:water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water (2×10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo. Purification by ISCO chromatography (0 to 30% EtOAc:heptane) afforded 8 mg (33%) of the title compound as a beige solid. 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1 H), 7.81 (d, J=5.6 Hz, 1 H), 7.35 (d, J=5.2 Hz, 1 H), 7.29-7.31 (m, 1 H); MS (ESI): 154.12 [M+H]+; HPLC tR=3.40 min (ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[N:46]=[C:47]=[O:48]>C(Cl)Cl>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[NH:46][C:47](=[O:48])[NH:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of aniline 46 (500 mg, 0.948 mmol) in DCM (10 ml) was added 2,4-difluoro-1-isocyanatobenzene (441 mg, 3 eq, 2.84 mmol) and the reaction mixture was stirred at RT for 24 hours. The mixture was concentrated and purified via column chromatography (eluent 10% MeOH in EtOAc) to afford 350 (600 mg, 93%) as a white solid. MS (m/z)=683.7 (M+H)
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18]Br>C(COC)OC.CCOCC>[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18][CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Cc1ccccc1
Reactant: Clc1ccccc1C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(=O)C(CC=Cc1ccccc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (6.30 g., 0.15 mole, oil dispersion) is suspended in glyme (200 ml.) and phenyl acetone (20.13 g., 0.15 mole) is added dropwise with stirring. After complete addition, the mixture is heated to reflux for one hour. The mixture is cooled to room temperature, and a solution of crude o-chlorocinnamyl bromide (39.05 g., 0.17 mole) in glyme (100 ml.) is added dropwise with stirring. When addition is complete, the mixture is heated on a steam bath for 24 hours then allowed to cool. Filtration and removal of solvent in vacuo produces a yellow oil. This oil is taken up in ether (400 ml.), washed with a very dilute hydrochloric acid solution, followed by a washing with brine, and is finally dried over Na2SO4. Filtration and removal of solvent in vacuo yields the crude product as a dark oil. Vacuum distillation provides 24.9 g., b.p. 153°-155°/0.1 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:31])[C:20]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:21][C:22]=3Br)[C:17]2=[O:32])=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[CH:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(Cl)Cl.O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:31])[C:20]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:21][C:22]=3[C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]4)=[N:47][CH:48]=3)[C:17]2=[O:32])=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCc3c(Br)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77e, 60 mg, 0.110 mmol), tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (64 mg, 0.164 mmol), Na2CO3 (200 μL, 0.400 mmol, 2 M solution), PdCl2(dPPf)-DCM (9 mg, 0.011 mmol), and 1,4-dioxane (2 mL) was stirred at 120° C. in microwave for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine (1×20 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-100% EtOAc/heptanes) to give tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate (77f, 46 mg, 58% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)=[C:4]([CH3:15])[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([Cl:30])=[CH:19][N:18]=1.Cl>CC(O)C>[Cl:30][C:20]1[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:22][C:17]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]3[CH2:13][O:12][C:11](=[O:14])[NH:10]3)=[C:4]([CH3:15])[CH:3]=2)=[N:18][CH:19]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: Cc1cc([C@H]2COC(=O)N2)c(C)cc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4COC(=O)N4)cc3C)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
To a reaction tube was added (S)-4-(4-amino-2,5-dimethylphenyl)oxazolidin-2-one (48 mg, 0.23 mmol), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (77 mg, 0.32 mmol), iPrOH (2 mL) and HCl (0.13 mL, 0.52 mmol, 4N in dioxane). The tube was then sealed and heated at 130° C. for 6 h. After cooling down to room temperature, the mixture was concentrated and purified by preparative RP-HPLC to provide (S)-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethyl-phenyl)oxazolidin-2-one; ESMS m/z 414.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(NC(C)C)(C)C.[Li].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CCOC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:7]1[C:6]([F:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Fc1cncc(Br)c1
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask is added 3-bromo-5-fluoropyridine (475 mg, 2.7 mmol) in 4 ml of dry THF at −78° C., followed by the addition of lithium diisopropylamine (1.62 ml, 3.24 mmol). The reaction mixture is stirred at −78° C. for 1 hour, followed by the addition of ethyl chloroformate (586 mg, 5.4 mmol). The reaction mixture is warmed up to room temperature and stirred for 1 hour. The reaction mixture is diluted with EtOAc, washed with saturated NH4Cl/water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 670 mg of 3-bromo-5-fluoro-isonicotinic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:16]=[CH:15][C:5]2[C:6](=O)[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[C:5]2[CH:15]=[N:16][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]2[N:10]=[C:11]([CH3:13])[CH:12]=[C:8]2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Product: Cc1cc2nc(Cl)c3cnc(Cl)cc3n2n1
Reaction time: 1 h

Procedure:
23.5 g. of 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one of Example 1b are refluxed in 100 ml. of phosphorus oxychloride for 12 hours. The excess phosphorus oxychloride is distilled off in vacuo and the oily residue is poured on ice. After standing for 1 hour, 5,8-dichloro2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine is filtered off, yield: 17 g. (67%); m.p. 203.4° (ethyl acetate).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][OH:21])=[N:12][C:11]=2[CH:25]=1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(OCC)(=O)C>[Si:31]([O:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17](/[CH:16]=[CH:15]/[C:13]2[S:14][C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:25][C:11]=3[N:12]=2)[CH:18]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of dimethylformamide containing 2.0 g of 3-(5-fluorobenzothiazol-2-yl-trans-ethenyl)benzyl alcohol and 1.19 g of imidazole was added 1.37 g of t-butyldimethylsilyl chloride and the reaction mixture stirred overnight under nitrogen at room temperature. After 48 hours of reaction time, the mixture was poured into 500 ml of ethyl acetate and washed with water (3×150 ml), a 1N hydrochloric acid solution (2×150 ml), water (1×200 ml) and a brine solution (1×200 ml) The organic layer was separated, dried over sodium sulfate and concentrated to a white solid. The residue was recrystallized from ethyl acetate--hexane, 1.57 g, m.p. 91°-93° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][C:26]#[CH:27]>CCCCCCC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][OH:28])[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cnc3ccccc3c2)cc1
Reactant: C#CCCCCO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: OCCCCC#Cc1cnc2ccccc2c1

Procedure:
This product was prepared from toluene-4-sulfonic acid quinolin-3-yl ester and hex-5-yn-1-ol following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 6:4; yield (110 mg, 98%); 1H NMR δ (CDCl3): 8.89 (s, 1H), 8.21 (s, 1H), 8.11 (d, J=8.62 Hz, 1H), 7.80-7.68 (dm, 2H), 7.62-7.52 (m, 1H), 3.74 (t, J=7.17 Hz, 2H), 2.52 (t, J=7.13 Hz, 2H), 1.83-1.67 (br m, 5H); LCMS m/z: 225.
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][CH2:4]O.C(OC(=O)C)(=O)C.P(Br)(Br)[Br:21]>>[Br:21][CH2:4][CH:3]=[C:2]([CH3:1])[CH:6]=[CH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: BrP(Br)Br
Reactant: CC(C=CCC(C)(C)C)=CCO
Solvent: CC(=O)OC(C)=O
Product: CC(C=CCC(C)(C)C)=CCBr
Temperature: 0 °C

Procedure:
A solution of 1.5 g. of 3,7,7-trimethyl-2,4-octadien-1-ol in 15 ml. of acetyl ether is added dropwise at -20° C. to 1.20 g. of phosphorus tribromide. The temperature is allowed to rise to 0° C. in the course of 30 minutes and then the mixture poured onto 30 ml. of ice-water. The mixture is extracted three times with diethyl ether, the extracts washed with water, 10% by weight aqueous potassium bicarbonate solution and semi-saturated and saturated aqueous sodium chloride solution and then dried over sodium sulfate. After removal of the solvent under reduced pressure in the cold, there is obtained 1-bromo-3,7,7-trimethyl-2,4-octadiene which exhibits a spot in the thin-layer chromatogram [Rf = 0.63; hexane/ethyl acetate (4:1 parts by volume)]. This substance is used in the process without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[I:27]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[I:27]
Reactant: Nc1ccc(F)c(I)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(I)c1
Yield: 58.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 272 mg of 4-fluoro-3-iodoaniline. 309 mg of N-(4-fluoro-3-iodophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained, the characteristics of which are the following: