Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Reactant: c1cc2c(cn1)OCCN2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCOc3cnccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (60 mg, 0.441 mmol) and 3-chloro-4-methoxy-benzoyl chloride (108 mg, 0.529 mmol) were dissolved in dichloromethane (3 ml). Triethylamine (0.12 ml, 0.881 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate:n-hexane=1:1. The fractions containing the product were collected and evaporated to obtain white solid (134 mg, 99.8%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][CH:14]([CH3:35])[CH2:15][C:16]1([CH2:31][C:32](O)=[O:33])[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]1=[O:30].Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN1CCOCC1>C(Cl)Cl>[CH2:37]([O:44][NH:45][C:32](=[O:33])[CH2:31][C:16]1([CH2:15][CH:14]([CH3:13])[CH3:35])[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]1=[O:30])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC1(CC(=O)O)CC(=O)N(CCc2ccccc2)C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC1(CC(=O)NOCc2ccccc2)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
CDI (153 mg, 0.945 mmol) is added to a mixture of 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (300 mg, 0.945 mmol) and CH2Cl2 (7.5 mL) at room temperature. Afar stirring at room temperature for 1 hour, O-benzylhydroxylamine hydrochloride (181 mg, 1.13 mmol) and 4-methylmorpholine (124 μL, 1.13 mmol) are added to the solution. The mixture is allowed to stir overnight at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by column chromatography (1.5% MeOH/CHCl3) affordes 70 mg (18%) of the title compound as a white solid (mp 115°-117° C.).
Reaction SMILES: C([Li])(C)(C)C.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.[CH:29](=[O:31])[CH3:30]>O1CCCC1>[OH:31][CH:29]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH3:30]
Reactant: CC=O
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.7M solution of t-butyllithium in hexane (8.03 ml, 13.65 mmol) was added dropwise, under nitrogen, to a stirred solution of 5-bromo-3-(N-methyl-4-piperidyl)-1H-indole (EP-A-0303507, 1.0 g, 3.4 mmol) in dry tetrahydrofuran (35 ml) at about -70° C., ensuring that the temperature of the reaction mixture did not rise above -50° C. during the addition. The resulting mixture was allowed to warm to room temperature over a period of 1 hour, then cooled to about -70° C. and treated, dropwise, with a solution of acetaldehyde (0.15 g, 3.4 mmol) in dry tetrahydrofuran (5 ml). After being stirred for a further 0.5 hour at about -70° C., the reaction mixture was quenched with water and allowed to warm to room temperature. The bulk of the organic solvents was removed by evaporation under reduced pressure and the remaining mixture partitioned between ethyl acetate and 10% aqueous ammonium chloride solution. The organic phase was separated, combined with two further ethyl acetate extracts of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure to give an oil which was purified by column chromatography on silica gel, eluting with 0.880 aqueous ammonia:methanol:dichloromethane (1:20:79), to provide the title compound which was employed in the following Example without further characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2
Reactant: Nc1ncnn2c(CCCCBr)cc(Br)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(Br)c12
Temperature: 55 °C
Yield: 80.3 %

Procedure:
To a solution of 5-bromo-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (597 mg, 1.72 mmol) in DMF (10 mL) was added pyrrolidine (158 μL, 1.89 mmol), triethylamine (717 μL, 5.15 mmol), and sodium iodide (26 mg, 0.17 mmol). The reaction was heated (55° C.) for 22 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (1×50 mL), brine, dried (Na2SO4) and evaporated to afford 467 mg (80%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1 H), 6.60 (s, 1 H), 2.81 (t, 2 H), 2.40-2.31 (m, 6 H), 1.70-1.59 (m, 6 H), 1.50-1.40 (m, 2 H); ES-MS m/z 338.1 [M+H]+, HPLC RT (min) 1.12.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:41]2[CH:42]=[CH:43][C:44]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[CH:22][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C2CCCC2)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclopentylphenylboronic acid (38 mg, 0.2 mmol) to give 5-{-4-[2-(4′-cyclopentyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:15][C:16]1[C:24]2[N:23]=[C:22](Cl)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Br:15][C:16]1[C:24]2[NH:23][C:22]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:6][CH2:5]3)=[N:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1
Reactant: OCc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: OCc1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(Br)c3[nH]2)CC1

Procedure:
(2-piperazin-1-ylpyridin-3-yl)methanol (0.48 g, 2.5 mmol, Example 46a) reacted with 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.60 g, 2 mmol, Example 6b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 456 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([NH2:14])=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[NH2:14][C:4]1[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]=1[NH:13][C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
An ice-cold solution of 3,5-bis(trifluoromethyl)-1,2-phenylenediamine (880 mg, 3.6 mmol) and pyridine (104 mg, 1.3 mmol) in methylene chloride (20 mL) was treated with ethyl 3-chloro-3-oxopropionate (181 mg, 1.2 mmol). The mixture was stirred at 0° C. for 3 h, then allowed to warm to room temperature and stirred for four days. The solution was diluted to 100 mL with methylene chloride, washed with saturated NH4Cl (3×20 mL), water (20 mL), and brine (20 mL), then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over silica gel, eluting with 20%-30%-40% EtOAc/heptane, to yield 330 mg of a white solid as product. 1H NMR (500 MHz, DMSO) δ ppm 1.22 (t, J=7.15 Hz, 3 H) 3.52 (s, 2 H) 4.14 (q, J=7.15 Hz, 2 H) 6.16 (s, 2 H) 7.54 (s, 1 H) 7.71 (m, 1 H) 9.60 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([NH2:16])[C:14]#[CH:15].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:16][CH2:13][C:14]#[CH:15]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: C#CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C#CCNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,4-dimethoxybenzaldehyde (2.51 g, 15.13 mmol) in methanol (100 ml) was added prop-2-yn-1-amine (1.0 g, 18.16 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, and cooled to 0° C. NaBH4 (1.0 g, 27.2 mmol) was added in portions over 15 minutes. The mixture was warmed up to room temperature and stirred for additional 2 hours. The reaction mixture was quenched with brine (200 mL), and partitioned between brine and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated to afford the title compound. MS (DCI/NH3) m/z 206 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][C:29]1[C:34](=[O:35])[C:33]([CH3:36])=[C:32]([CH3:37])[C:31](=[O:38])[C:30]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=1)[C:45](O)=[O:46]>C(Cl)Cl>[CH3:28][C:29]1[C:34](=[O:35])[C:33]([CH3:36])=[C:32]([CH3:37])[C:31](=[O:38])[C:30]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=1)[C:45]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:46]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
4-Trifluoromethylaniline (0.176 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (1:2) to obtain the titled compound (0.220 g, 0.453 mmol, 62%).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[CH2:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]=1[O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:22]=[CH2:23].O>C1COCC1>[Si:34]([O:33][C:27]1[C:28](/[CH:29]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:31][CH:32]=[C:25]([O:24][CH2:21][CH:22]=[CH2:23])[C:26]=1[O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Reactant: C=CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
n-Butyllithium (0.37 mL, 0.59 mmol, 1.6 M in hexanes) was added dropwise over 5 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.27 g, 0.52 mmol) in THF (3 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70° C. and a solution of 41 (0.10 g, 0.24 mmol) in THF (3 mL) was added and the reaction mixture was allowed to warm to rt with stirring overnight (16 h). The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with t-BuOMe (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and evaporated to dryness to give crude product (0.3 g). Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane) gave 42 (83 mg, 60%) as an 85:15 mixture of Z:E isomers.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: CSc1ccc(O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc(OCCO)cc1
Yield: 28.5 %

Procedure:
A mixture of 105.46 g (0.753 mole) of 4-(methylthio)phenol, 62.0 g (0.772 mole) of 2-chloroethanol and 105 g (0.761 mole) of potassium carbonate in approximately one liter of acetonitrite was refluxed overnight. The cooled mixture was filtered, and the solvent was removed in vacuo to give a solid. This was recrystallized from diethyl ether-hexane to give 39.59 g (28.6%) of the product as a white, crystalline solid, mp 55°-56° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[CH3:8][O:9][N:10]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:21](=[O:23])[CH3:22]
Reactant: CCCCCCCCC(=O)NOC
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)N(OC)C(C)=O
Reaction time: 8 h

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with methylene chloride (22.5 mL), triethylamine (3.80 g, 2 eq) and N-methoxynonanamide (3.5 g, 1 eq). The reaction mixture is stirred and cooled in an ice bath. Acetic anhydride (2.88 g, 1.5 eq) is then added dropwise. The reaction slowly warms to room temperature overnight. The reaction mixture is diluted with methylene chloride (50 mL) and washed with 0.05 M hydrochloric acid solution (1×50 mL), saturated aqueous sodium bicarbonate solution (3×50 mL) and brine (1×50 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH3:32][O:33][C:34](=[O:39])[C@H:35]([CH2:37][OH:38])[NH2:36]>C1COCC1>[CH3:32][O:33][C:34](=[O:39])[CH:35]([NH:36][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1([CH3:3])[O:5][CH2:6][CH2:7][O:8]1)[CH2:37][OH:38]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC1(CCCCC(=O)O)OCCO1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)CCCCC1(C)OCCO1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoic acid (4.78 g, 25.40 mmol) in THF (165 mL) at −30° C. was treated sequentially with Et3N (7.50 mL, 53.33 mmol) followed by isobutyl chloroformate (3.81 mL, 27.94 mmol). After stirring for 1 h at −30° C., serine methylester hydrochloride (4.43 g, 37.94 mmol) was added and the reaction mixture was allowed to warm gradually to rt over 3 h and stirred for an additional 16 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (9:1:0→0:9:1 hept-EA-MeOH) gave the title compound as a colorless oil. TLC: rf (1000:50:4 CH2Cl2-MeOH—NH3)=0.1. LC-MS-conditions 02: tR=0.63 min [M+H]+=290.25.
Reaction SMILES: [NH2:1][C:2]1[C:19](I)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.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>[NH2:1][C:2]1[C:19]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C[S@@](=O)(=NC(=O)c1cnc(N)c(I)c1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing (S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (345 mg, 0.86 mmol) in 6.0 mL DMF at room temperature was added triethylamine (0.36 mL, 2.6 mmol), trimethylsilylacetylene (0.24 mL, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.09 mmol), and copper(I) iodide (16 mg, 0.09 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated. Then added 30 mL ethyl ether to the dark oil, filtered to remove the dark precipitate. The organic extracts were concentrated and the residue was purifed by chromatography (silica gel, ethyl ether/EtOAc) to the title compound as a tan foam (317 mg, 99%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1cc2c(cn1)NCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (240 mg, 0.73 mmol) were dissolved in dichloromethane. Triethylamine (0.51 ml, 3.7 mmol) was added thereto and then stirred at room temperature for 5 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain the target compound 2 as white solid (190 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][S:66][CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CSCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCSCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and thiomorpholine in DMSO at ambient temperature.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:14])[C:5]=2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c(Br)csc12
Product: Clc1ncnc2c(Br)csc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
7-bromothieno[3,2-d]pyrimidin-4(3H)-one (5.9 g) was dissolved in POCl3 (20 mL) and the reaction mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature, and remaining POCl3 was concentrated and placed in ice water. The solid thus obtained was washed with sodium bicarbonate and dried using nitrogen gas. The resulting compound was further dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (1.0 g, 39%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>C1(C)C=CC=CC=1.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>[CH:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)=[CH2:10]
Reactant: O=Cc1ccc(Br)s1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C=O)s1
Yield: 86.2 %

Procedure:
A solution of 5-bromo-thiophene-2-carbaldehyde (1 g, 5.23 mmol) in anhydrous toluene (20 mL), at room temperature and under an atmosphere of nitrogen, was treated with tetrakis(triphenylphosphine)palladium(0) (121 mg, 0.1 mmol) and tributylvinyltin (2.3 mL, 7.85 mmol). The reaction was heated to reflux for 1 hour, after which it was cooled and the volatiles removed in vacuo. The product was purified by silica gel chromatography using iso-hexanes/ethyl acetate 10:1 to afford the title compound (623 mg, 85%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 5.42 (d, J=10.9 Hz, 1H), 5.84 (d, J=17.4 Hz, 1H), 6.84 (dd, J=17.4, 10.9 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H), 7.66 (d, J=3.8 Hz, 1H), 9.88 (s, 1H).