Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[F:15].[CH2:16]([N:23]([CH2:29]OC)[CH2:24][Si](C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:23]1[CH2:29][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[C:3]([F:15])=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:13])([F:12])[F:11])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (10 g, 38.61 mmol) in DCM (150 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (36.6 g, 154.44 mmol) at room temperature and reaction mixture was cooled to 0° C. followed by slow addition of TFA (0.29 mL, 3.861 mmol). Resulting reaction mixture was stirred at room temperature for 5 hours. After complete consumption of starting material, the reaction mixture was quenched with aqueous Na2CO3 and extracted with DCM (3×100 mL). Combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford brown oil (9.7 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4% ethyl acetate in hexane to afford product as brownish solid (6.1 g, impure). Impure compound was used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 2.24-2.31 (m, 1H), 2.53-2.59 (m, 1H), 2.68-2.78 (m, 1H), 2.80-2.83 (m, 1H), 3.01-3.08 (m, 2H), 3.61-3.69 (m, 2H), 7.29-7.34 (m, 7H). (m/z): 280.4 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]#[C:8][C:9]([OH:11])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:9](=[O:11])[C:8]#[C:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COCCOCC#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.72 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid and 0.57 mL of isobutyl chloroformate in 15 mL of tetrahydrofuran at 0° C. was added 0.5 mL of N-methylmorpholine followed by 1.2 g of solid N-(3-bromophenyl)-4,6-quinazolindiamine. Stirring was continued for 1 hr at 0° C. and 30 min at room temperature. The mixture was stored over night at −10° C. The mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate, choroform, and methanol solvent mixtures to give 0.55 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a yellow solid: mass spectrum (m/e): M+H 454.9, 456.9.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][O:49][C:50]([N:52]1[CH2:56][CH:55]([C:57]2[C:65]3[C:60](=[CH:61][C:62]([F:66])=[CH:63][CH:64]=3)[NH:59][CH:58]=2)[CH:54]2[N:67]([C:70](=[O:79])[CH:71]([NH2:78])[CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[CH2:68][CH2:69][CH:53]12)=[O:51]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:48][O:49][C:50]([N:52]1[CH2:56][CH:55]([C:57]2[C:65]3[C:60](=[CH:61][C:62]([F:66])=[CH:63][CH:64]=3)[NH:59][CH:58]=2)[CH:54]2[N:67]([C:70](=[O:79])[CH:71]([NH:78][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[CH:72]3[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77]3)[CH2:68][CH2:69][CH:53]12)=[O:51]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(N)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing Boc-N(Me)Ala-OH (76 mg, 0.37 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (141 mg, 0.37 mmol) and DIPEA (148 mg, 1.14 mmol) were added followed by the addition of crude 51 (172 mg, 0.39 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 255 mg of crude 52 as an off-white-colored foam which was used without further purification. Mass spectrum, m/z [628.5] (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([CH2:13][CH2:14][CH3:15])[N:7]=1>O1CCOCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[N:9]=[C:10]([NH:1][CH2:2][CH2:3][OH:4])[N:11]=1
Reactant: CCCc1nc(Cl)nc(Cl)n1
Reactant: NCCO
Solvent: C1COCCO1
Product: CCCc1nc(Cl)nc(NCCO)n1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
24.4 g (0.4 mole) of 2-aminoethanol, dissolved in 100 ml of dioxane, are added dropwise into a solution of 38.4 g (0.2 mole) of 2,4-dichloro-6-propyl-1,3,5-triazine in 100 ml of dioxane at room temperature. After the addition, stirring is continued overnight. The 2-aminoethanol hydrochloride is filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is recrystallized from a mixture of ethyl acetate-hexane 50:50 (v/v). 41.5 g of 2-[(4-chloro-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol are obtained.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[C:13](Cl)[N:12]=1>O=P(Cl)(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[N:17]=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][C:15]=2[N:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncc2nc(-c3ccccc3)oc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.82 g (64.0 mmol) benzoic acid and 20 mL POCl3 are stirred together at 100° C. for 30 min. Within 45 min 7.00 g (42.7 mmol) 2,6-dichloro-5-aminopyrimidine are added by several portions. The reaction mixture is stirred for additional 2 h at the same temperatur. After that the mixture is carefully added to an ice cold aq. NaOH solution. The resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[C:28]2[S:35][CH:34]=[CH:33][C:29]=2[N:30]=[CH:31][N:32]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9](=[O:16])[N:10]1[CH2:11][CH2:12][N:13]([C:27]2[C:28]3[S:35][CH:34]=[CH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Reactant: Clc1ncnc2ccsc12
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccsc23)CC1
Yield: 86.8 %

Procedure:
The solution of [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (60 mg, 0.163 mmol) and 4-Chlorothieno[3,2-d]pyrimidine 950 mg, 0.293 mmol) in Toluene (5 mL)/TEA (1 mL) was refluxed for 12 hours. After the solvent was removed, the residue was subject to chromatography on silica gel to afford [1-(4-chlorobenzyl)-2-oxo-2-(4-thieno[3,2-d]pyrimidin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (71 mg, 86.7%). 1H NMR (CDCl3, 400 Hz) δ 8.60 (s, 1H), 7.76 (d, J=5.2 Hz, 1H), 7.45 (d, J=5.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 5.39 (d, J=8.8 Hz, 1H), 4.88-4.82 (m, 1H), 3.94-3.76 (m, 4H), 3.69-3.58 (m, 3H), 3.25-3.22 (m, 1H), 2.98 (d, J=7.2 Hz, 2H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 503.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1C(CCO)=CC=[CH:23][N:22]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)=[CH:3][CH:2]=[CH:23][N:22]=1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: COc1ncccc1CCO
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ncccc1CCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
4-[2-(2-Methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid (16m) is synthesized analogous to 16a from 4-[2-(2-methoxy-pyridin-3-yl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:21][CH:22]=1>>[CH:25]1(/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: ClCc1coc(/C=C/C2CCCCC2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C(=C/C1CCCCC1)\c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-cyclohexylethenyl]oxazole to give 2-[(E)-2-cyclohexylethenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 67%. Recrystallization from isopropylether gave colorless prisms, mp 62-63° C.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:18]([N:26]1[CH2:31][CH2:30][CH2:29][C:28]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)([CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[OH2:2].[ClH:46].[C:18]([N:26]1[CH2:31][CH2:30][CH2:29][C:28]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)([CH2:32][CH2:33][CH2:34][N:9]2[CH2:8][CH2:7][C:6]([O:5][CH2:4][CH2:3][OH:2])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10]2)[CH2:27]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: OCCOC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)N1CCCC(CCCN2CCC(OCCO)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A mixture of 1 g of 4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride, 1.7 g of the compound obtained in step B of EXAMPLE 1 and 0.65 g of K2CO3 in 15 ml of DMF is heated at 60° C. for 2 hours and the reaction mixture is then stirred overnight at RT. It is poured into water and extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product, m.p.=120-123° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.CCOC(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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][OH:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: OCc1ccccc1B(O)O
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: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Yield: 93 %

Procedure:
A solution (0.04 M) of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO2004/087714) in DME/EtOH 5:2 was treated with [2-(hydroxymethyl)phenyl]boronic acid (1.2 eq), Na2CO3 (6 eq) and Pd(PPh3)4 (0.1 eq) at 80° C. After 1 h the mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, then dried and concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 (7:3 PE/EtOAc) to give the title compound (93%) as a solid. MS (ES+) m/z 364 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]([OH:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.Cl[SiH3]>C1(C)C=CC=CC=1>[C:21]([C:7]1[CH:8]=[C:9]([CH:11]([O:20][Si:27]([CH3:30])([CH3:29])[CH3:26])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(C(O)CCc2ccccc2)cc(C(C)(C)C)c1O
Agent: [SiH3]Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(CCc2ccccc2)O[Si](C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a nitrogen-purged 250 mL three-neck round-bottom flask were added 141 grams (0.41 mole) of the 2,6-di-t-butyl-4-(1-hydroxy-3-phenylpropyl)phenol produced in step (A) of this example, 100 mL of toluene, and 54.3 grams (0.50 mole) of trimethylchlorosilane. The addition of the chlorosilane produced a several degree exotherm. The mixture was allowed to stir overnight at ambient temperature. After this time, the reaction mixture was washed with water (3×200 mL), dried with sodium sulfate, and filtered. Removal of the hexane gave 148.9 grams of desired product (87.1 percent).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=1)[C:33]([N:35]([CH3:37])[CH3:36])=[O:34].BrC1C=C(C=C(O)C=1)C(N(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[NH2:1][C:2]1[C:3]([C:39]2[CH:38]=[C:32]([CH:31]=[C:30]([OH:29])[CH:40]=2)[C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: CN(C)C(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(=O)N(C)C)c3)n(-c3ccccc3)c(=O)c12
Yield: 44 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70.5 mg, 0.16 mmol) was treated with 3-hydroxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (113 mg, 0.39 mmol, prepared from 3-bromo-5-hydroxy-N,N-dimethylbenzamide, as described at WO 2009077385 A1 20090625, and bis(pinacolate)diboron according to the method describe at Preparation 119b), sodium carbonate (40.55 mg, 0.38 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (39.2 mg, 0.05 mmol) in water (1.7 ml) and dimethoxyethane (6.5 ml) according to the method described in Example 3 to give 40.7 mg (44% yield) of the title compound. Purity 90%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:36])([F:37])[CH:33]([F:35])[F:34])=[CH:29][CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: FC(F)C(F)(F)Oc1ccc(I)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC(F)(F)C(F)F)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-iodo-4-(1,1,2,2-tetrafluoro-ethoxy)benzene in analogy to Example 1a): MS (ISN): 494.1 and 496.2 (M−H.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1C
Yield: 73.8 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2,4-dimethylphenylboronic acid (0.075 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.073 g (74%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.O.[C:12]([OH:16])(=[O:15])[CH:13]=O.C(=O)([O-])[O-].[K+:21].[K+]>CO>[C:9]([C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[CH:13][C:12]([O-:16])=[O:15])#[N:10].[K+:21]
Reactant: Cc1cccc(CC#N)c1
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(C#N)=CC(=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (3-methylphenyl)-acetonitrile (21.6 ml, 165 mmol) in methanol (500 ml) were added glyoxylic acid hydrate (22.7 g, 247 mmol) and potassium carbonate (57.0 g, 412 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by 3 hours at reflux. The precipitate was filtered off, washed with methanol (300 ml), dichloromethane (DCM) (300 ml) and then dried under air suction. The desired product was obtained as a white solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH:14]=O)[CH:5]=1)[CH3:2].[C:16]1([C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:31][C:32]([NH2:34])=[O:33].Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH:14]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:34][C:32](=[O:33])[NH:31]2)[CH:5]=1)[CH3:2]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc2oc(=O)[nH]c12
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc2oc(=O)[nH]c12
Yield: 22 %

Procedure:
To a solution of 4-ethoxy-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbaldehyde (Intermediate 76) (70 mg, 0.34 mmol), 1,2-diphenylethanone (70 mg, 0.36 mmol) and urea (82 mg, 1.4 mmol) in 5 mL of ethanol was added 0.2 ml con. HCl under N2. The reaction mixture was refluxed overnight. The reaction mixture was purified by prep-HPLC (0.1% TFA as additive) and solvent removed to give Compound 150 as white solid (32 mg, yield 22%). 1H NMR (CD3OD 400 MHz): 7.27 (m, 5H), 7.06-7.04 (m, 3H), 6.92-6.87 (m, 3H), 6.82 (s, 1H), 5.33 (s, 1H), 4.14-4.08 (m, 2H), 1.41 (t, J=6.8 Hz, 3H). MS (ESI): m/z 428.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.CO.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH3:29])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of (2-chloro-6-nitroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine (48 mg, 0.14 mmol) in 2 mL of dimethylamine in methanol (2M, 25 mmol) was heated overnight in a seal tube at 70° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by chromatography (15% ethyl acetate/hexane) to give the title compound (39 mg, 79%). 1H NMR (CDCl3): 8.08 (dd, J=9.3, 2.4, 1H), 7.71 (d, J=2.4, 1H), 7.35 (d, J=9.3, 1H), 7.14 (m, 2H), 6.97 (2H), 3.85 (s, 3H), 3.55 (s, 3H), 3.33 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[CH2:14]([SnH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[C:10](=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)/[C:11]([NH2:13])=[O:12])[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(CCC(N)=O)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(OC)cc1)C(N)=O
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
3-(4-methoxyphenyl)propionic acid amide (10.3 mg, 0.059 mmol) prepared in Reference Synthetic Example 3 was dissolved in tetrahydrofuran (500 μl) in nitrogen atmosphere, tetrakistriphenylphosphine palladium (1.4 mg, 0.0012 mmol) was added under cooling with ice, and a tetrahydrofuran solution of tri-n-butyltin hydride (20 μl, 0.074 mmol) was dropwise added. After stirring for 10 minutes, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired compound (E)-2-{tri(n-butyl)stannyl}-3-(4-methoxyphenyl)acrylamide (18.6 mg, 68%) as a colorless oily substance.