Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6].[ClH:34]>O.CO.C1COCC1>[ClH:22].[ClH:34].[ClH:22].[Cl:22][C:21]1[C:16]([C:13]2[S:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[C:15]=3[CH:14]=2)=[N:17][C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)O)cccc4s3)n2)CC1
Temperature: 70 °C
Yield: 94 %

Procedure:
Aqueous 2 N LiOH (1.1 mL, 2.2 mmol) is added to a stirred solution of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methyl ester (280 mg, 0.610 mmol) in water (3 mL), MeOH (6 mL) and THF (12 mL). The mixture is heat at 70° C. for 2 hours. While at 70° C., 5 N HCl (1 mL) is added to the solution, then the solution is allowed to cool to room temperature. After concentration, the yellow solid is suspended in THF (20 mL), sonicated, filtered, and dried to give the title compound as a solid (320 mg, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)COc1ccc(NC(=O)c2ccn(-c3ccc(F)cc3)c2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
1-(4-Fluorophenyl)pyrrole-3-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (1.8 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.7 g), melting point: 167–169° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Br-:17].[Li+].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCOCC.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:17])[CH:20]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(Br)ccc21
Reactant: c1ccccc1
Reactant: [Br-]
Agent: Cl[Pd]Cl
Agent: [Li+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Product: CCn1c2ccccc2c2cc(-c3cccc(Br)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
1.00 g of N-ethyl-3-bromocarbazole was dissolved in 3.2 ml of dehydrated ether in a Schrenck tube which was flame-dried and argon gas-replaced. This solution was cooled to −78° C., and 2.4 ml of n-butyl lithium (2.64M hexane solution) was added dropwise. After raising the temperature to 0° C., and stirring for 1 hour, it was cooled again to −78° C., an ether solution of magnesium bromide prepared from magnesium 0.4 g and 1,2-dibromoethane 0.8 g was added dropwise. After raising the temperature to room temperature and stirring for 12 hours, this reaction solution was added dropwise into a solution which was prepared by suspending lithium bromide 0.28 g, 3-trifluoromethanesulfoxybromo benzene 0.82 g, and dichloro[1,3-bis(diphenylphosphino)propane]palladium(II) 0.09 g in dehydrated diethylether 2 ml, and cooled at 0° C. After stirring for 7 hours, 20 ml water was added dropwise and partitioned. The aqueous phase was extracted twice with 40 ml toluene, and the combined aqueous phase was washed with water and saturated NaCl aqueous solution, then concentrated, and 1.61 g of crude product was obtained. It was purified with silica gel column chromatography (eluent, hexane:ethyl-acetate=25:1), 0.33 g of N-ethyl-3-(3-bromophenyl)carbazole was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[CH2:14](O)[CH2:15][OH:16]>C1(C)C=CC=CC=1.CCOC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:16][CH2:15][CH2:14][O:6]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Br)cc(C2OCCO2)c1
Yield: 85.2 %

Procedure:
A mixture of 3-bromo-5-trifluoromethyl benzaldehyde (10 gm, 39.523 mmol), ethylene glycol (6.63 ml, 118.568 mmol) and PTSA.H2O (150 mg, 0.79 mmol) in anhydrous toluene (60 ml) was heated to reflux under Dean-stark conditions for 6 h. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (150 ml) and brine solution (150 ml). Organic layer was dried over Na2SO4, filtered and evaporated in vacuum to afford 11 g crude as a colorless liquid which was purified by column chromatography (100-200 silica gel mesh), eluted with 5% EtOAc in Hexane to afford the desired compound (10 g) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: Fc1cccc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3-fluorobenzyl chloride gave the title compound. ES-MS m/e (%): 567.3(M+H+).
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH3:15])C=C.C(OC([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29](=[O:44])[CH:30]([NH:32][C:33](=[O:43])[C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([NH2:41])=[C:36]([Cl:42])[CH:35]=1)[CH3:31])=O)(C)(C)C.O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29](=[O:44])[CH:30]([NH:32][C:33](=[O:43])[C:34]2[CH:39]=[C:38]([Cl:40])[C:37]([NH2:41])=[C:36]([Cl:42])[CH:35]=2)[CH3:31])=[O:16])[CH2:11][C:10](=[O:12])[O:9]1)[CH3:15]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Reactant: CC(NC(=O)c1cc(Cl)c(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 54 %

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 1-[2-(4-amino-3,5-dichloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester according to the method used for 98a to afford 158 mg of title compound (54% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.08-1.30 (m, 3H), 1.32-1.52 (m, 3H), 1.72-2.44 (m, 4H), 2.40-3.05 (m, 2H), 3.50-3.97 (m, 4H), 4.25-4.70 (m, 3H), 4.70-4.86 (m, 1H), 5.33 (s, 0.4H), 5.47 (s, 0.1H), 5.56 (d, 0.4H), 5.62 (d, 0.1H), 7.50 (s, 1H), 7.80 (s, 1H). Analytical HPLC: 10.84 min. LC-MS (ES+): m/e=501.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A mixture of 4-fluoro-2-nitrophenol(1 g, 4.64 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(622 mg, 85%). 1H NMR (CD3OD): d 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[O:4].[C:16]([CH:18]1[CH2:20][CH2:19]1)#[CH:17]>C(N(CC)CC)C.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]#[C:16][CH:18]2[CH2:20][CH2:19]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[O:4]
Reactant: C#CC1CC1
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Reaction time: 1 h

Procedure:
Firstly bis(triphenylphosphine)palladium(II) chloride (602 mg) and then copper(I) iodide (164 mg) were added to a mixture of 5-bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester (1 g), ethynylcyclopropane (463 mg) in triethylamine (9.5 mL) and THF (4.5 mL). After one hour, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 276.36 (C14H16N2O2S) was obtained in this way; MS (ESI): 277 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.4 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 1.3 g; 0.0325 mol) in THF (60 mL) at 0° C. under N2 was added dropwise a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 17) (4.077 g; 0.013 mol) in THF (50 mL). Gas evolution was observed. The resultant mixture stirred at 0° C. for 30 min prior to addition of a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (4.754 g; 0.013 mol) in THF (20 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was carefully quenched with H2O (15 mL) and partitioned between EtOAc (250 mL) and H2O (75 mL). The aqueous layer was extracted with EtOAc (3×100 mL). Combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/hexanes gradient) to afford 6.4 g (82.5%) of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.1 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.03 (d, J=8.2 Hz, 1 H), 7.90 (s, 1 H), 7.79 (s, 2 H), 7.58 (s, 1 H), 7.30 (dd, J=8.2 Hz, J=2.0 Hz, 1 H), 5.76 (d, J=8 Hz, 1 H), 4.88 (d, J=15.8 Hz, 1 H), 4.37 (d, J=15.8 Hz, 1 H), 4.09-4.02 (m, 1 H), 0.8 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]1([Cl:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]1[N:18]=[C:19]=[S:20]>>[Cl:11][C:12]1([Cl:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]1[N:18]=[C:19]1[N:7]([CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9][S:20]1
Reactant: ClCC[NH2+]CC1CCC1
Reactant: S=C=NC1C=CC=CC1(Cl)Cl
Agent: [Cl-]
Product: ClC1(Cl)C=CC=CC1N=C1SCCN1CC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,2-dichlorophenyl isothiocyanate to give 2-(2,2-dichlorophenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=O)[CH2:22][CH2:21]4)[CH:8]=2)[CH2:3][CH2:2]1.O.[OH:29][N:30]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:46][N:47]([CH2:49][C:50]([OH:52])=O)[CH3:48]>CN(C=O)C>[CH3:46][N:47]([CH3:48])[CH2:49][C:50]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:9]([C:18]3[CH:26]=[C:25]4[C:24](=[CH:20][CH:19]=3)[C:23](=[N:30][OH:29])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:3][CH2:2]1)=[O:52]
Reactant: On1nnc2ccccc21
Reactant: CN(C)CC(=O)O
Reactant: O=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of the product from Example 31 Step 5 (0.17 g, 0.47 mmol), N-cyclohexylcarbodiimide,N′-methyl polystyrene resin (0.4 g, 0.65 mmol, 1.7 mmol/g), and 1-hydroxybenzotriazole hydrate (0.081 g, 0.6 mmol) were suspended in DMF (4 ml) and treated with triethylamine (0.084 ml, 0.6 mmol) and dimethylamino-acetic acid (0.048 g, 0.47 mmol). The reaction was stirred at room temperature for 16 hours and filtered on to a 10 g SCX cartridge (Varian Mega Bond Elute). The cartridge was then washed with methanol and then a 1:90.880 ammonia:methanol solution. The ammonia containing fractions were then reduced in vacuo and the residue purified by chromatography on silica gel eluting with a mixture of 0.880 ammonia/methanol/chloroform (0.5:4.5:95) to afford the title compound (0.097 g, 47%); MS (ES+) m/e 444 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]4[C:23]=3[NH2:24])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](Br)[CH3:28].CC(=O)OCC.C(Cl)Cl>CN(C=O)C>[CH2:27]([NH:24][C:23]1[N:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:13]1[S:14][C:10]([C:9]#[C:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)[CH3:28]
Reactant: Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
395 mg (1.25 mmol) of 2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-ylamine hydrochloride (Example 83) were dissolved in DMF (8 ml). After addition of 100 mg (2.5 mmol) of sodium hydride (60% dispersion in mineral oil), the mixture was stirred at RT for 1 h. A solution of 74 μl (0.8 mmol) of ethyl bromide in DMF (2 ml) was then added dropwise. The reaction solution was stirred at RT for 16 h, quenched with water (10 ml) and extracted with EA (2×50 ml). The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 253 mg (0.74 mmol, 58% of theoretical) of ethyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained by means of column chromatography (silica gel, EA/DCM 4:1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][NH:12][C:13](=O)[CH3:14]>>[CH3:11][N:12]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:13]1[CH3:14]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CNC(C)=O
Product: Cc1nc2ccccc2n1C
Yield: 84.8 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and N-methylacetamide (44 mg, 0.6 mmol) yielded the title compound as pale yellow solid (62 mg, 85%). mp 101° C. to 103° C. 1H NMR (DMSO) δ 2.79 (s, 3H), 3.92 (s, 3H), 7.46-7.55 (m, 2H), 7.78 (d, J=7.4Hz, 1H), 7.89 (d, J=7.1Hz, 1H); 13C NMR δ 11.6, 30.8, 112.3, 114.1, 124.9, 125.3, 132.6, 151.9, 158.3. HRMS (FAB): cal. for C9H11N2 [M+H+]: 147.0922; found: 147.0917. Method C afforded 38 mg of the title compound (52% yield).
Reaction SMILES: COC([C:5]1[N:9]([Cl:10])[C:8]([Cl:11])=[CH:7][N:6]=1)C.C1C(=O)N([Br:19])C(=O)C1.[C:20]([O:23][CH2:24]C)(=O)[CH3:21]>C(#N)C>[Br:19][C:5]1[N:9]([Cl:10])[C:8]([Cl:11])=[C:7]([CH:20]([O:23][CH3:24])[CH3:21])[N:6]=1
Reactant: COC(C)c1ncc(Cl)n1Cl
Reactant: CCOC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(C)c1nc(Br)n(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methoxyethyl-3,4-dichloroimidazole (1.95 g, 10 mmol) in acetonitrile (50 mL) is added NBS (1.86 g, 1.05 mmol) at room temperature in portions. The reaction mixture is stirred at rt for 30 min. Ethyl acetate (100 ml) is added and washed with water, brine, dried over MgSO4, filtered and evaporated in vacuo to dryness. The crude product is purified by flash chromatography (hexane/ethyl acetate 100/5) to obtain 2-bromo-1-methoxyethyl-3,4-dichloroimidazole.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[C:17](Br)([Br:23])[CH2:16][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.O>CO>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([OH:22])=[C:17]([Br:23])[CH:16]=[CH:15]2)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2CCC1(Br)Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Add 1M sodium methoxide (215 mL, 0.99 mol) into a solution of 6-benzyloxy-2,2-dibromo-3,4-dihydro-2H-naphthalen-1-one (205 g, 0.5 mol) in methanol (1.3 L). Heat the suspension to dissolution. Cool the reaction mixture to 0° C. and add 1N HCl (540 mL). Add H2O (3 L) and cool to 3° C. to obtain a solid. Filter and dry the solid to obtain 152 g (92%) of 6-benzyloxy-2-bromo-naphthalen-1-ol.
Reaction SMILES: Br[C:2]1([F:20])[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].O>COCCOC>[F:20][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1Cc2ccccc2C1)C1=CCC(F)(Br)C=C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(NC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2C1)c1ccc(F)cc1
Yield: 44.5 %

Procedure:
150 mg (0.45 mmoles) 4-bromo-N-indan-2-yl-4-fluoro-benzamide, 102 mg (0.54 mmoles) 3-trifluoromethylbenzeneboronic acid, 211 mg (0.67 mmoles) barium hydroxide octahydrate and 20 mg tetrakis-triphenylphosphine-palladium were suspended in 10 ml 1,2-dimethoxyethane and 10 ml water and heated to reflux for 7 h. Subsequently, the reaction mixture was evaporated to dryness, the residue taken up in methylenchloride and extracted twice with water. The oil remaining after evaporation of the organic phase was purified using prep. HPLC chromatography. (RP18, acetonitrile/water, 1% trifluoroacetic acid). 80 mg (45%) of the title compound were obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.O>C1COCC1.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:13][CH2:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:16][CH:17]=1
Reactant: OCC1CCCC1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCC2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (550.6 mg, WAKO) in dehydrated THF (10 ml) was added with cyclopentane methanol (450 μl), and then added with a solution of 2,5-dibromopyridine (982.8 mg, TCI) in dehydrated THF (15 ml) under ice cooling. The reaction mixture was stirred for 30 minutes, then warmed to room temperature, and stirred for 11 hours. The reaction mixture was added with water (100 ml) and ethyl acetate (60 ml) for extraction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine sequentially, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=15:1) to obtain the title compound (Intermediate 28, 896 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNS(=O)(=O)c3ccccc3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with benzene sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 507.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.82 (s, 1H), 8.76 (bs, 1H), 8.27 (d, 1H, J=5.0 Hz), 8.13 (s, 1H), 7.81 (d, 2H, J=8.0 Hz), 7.62 (t, 1H, J=8 Hz), 7.55 (t, 2H, J=8 Hz), 4.63 (s, 2H), 4.43 (m, 2H), 3.43 (s, 3H), 2.06˜1.65 (m, 10H), 0.88 (t, 3H, J=7.5 Hz).