Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:5][C:6](=[O:36])[C@@H:7]([CH3:35])[NH:8][C:9](=[O:34])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.[C:49]([O:53][C:54]([NH:56][C@H:57]([C:67]([OH:69])=O)[CH2:58][O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:5][C:6](=[O:36])[C@@H:7]([CH3:35])[NH:8][C:9](=[O:34])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[NH:11][C:67](=[O:69])[C@H:57]([CH2:58][O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[NH:56][C:54]([O:53][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:55]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Nα -t-Butoxycarbonyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared by deprotecting 11.4 g. (20 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester with 50 ml. of trifluoroacetic acid in 40 ml. of dichloromethane at 20° C. for 12 minutes. The mixture is evaporated to dryness at 40° C. under reduced pressure and the residue twice taken into dichloromethane and evaporated to dryness followed by drying under high vacuum for 2 hours. The oily product is dissolved in 70 ml. of dimethylformamide and treated at 10° C. with 10 ml. of triethylamine so that a pH of 7 is obtained. Additional triethylamine, 2.8 ml. (20 mmol) is added, followed by 6 g. (20 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-serine, 2.7 g (20 mmol) of 1-hydroxybenztriazole and (at -5° C.) 4.4. g. of dicyclohexylcarbodiimide. The mixture is slowly stirred to room temperature for two days. The mixture is filtered and the filtrate evaporated at 50° C. under reduced pressure. The residue is dissolved in dichloromethane and filtered. The solution is evaporated to yield an oil which crystallizes from dichloromethane and ether; 10.7 g.; m.p. 67°-71° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cc1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 4-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as an off white solid. MS (ESI): m/z=385.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C.Cl>C(#N)C>[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][N:30]1[CH2:2][C:3]2[C:8](=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=2)[C:9]1=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CN1Cc2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Methyl 6-bromomethyl-3-nitrobenzoate (430 mg, 1.64 mmol), N-glycyl-3(R)-methyl-β-alanine benzyl ester hydrochloride 2-4 (611 mg, 2.13 mmol) and trimethylamine (0.68 mL, 4.92 mmol) were stirred fin acetonitrile (10 mL) for 16 hours. The solution was poured into 1N HCl and extracted with EtOAc (3×), washed with brine, dried (MgSO4) and evaporated. Purification by column chromatography eluting with EtOAc afforded 2-6 as a solid. Rf (silica; EtOAc)=0.45. ##STR60## N-{[6-Amino-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-β-alanine (2-7)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](F)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH2:23])[CH3:22]>C(Cl)CCl>[CH3:22][CH:21]([NH:23][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:24][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1
Reactant: O=C(F)c1ccc(OC(F)(F)F)cc1
Reactant: CC(N)CCCCCCN
Solvent: ClCCCl
Product: CC(CCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 137°-138° C., 15.1 g., was prepared as in Example 20 using 18.7 g. of 4-trifluoromethoxybenzoyl fluoride in 50 ml. of ehtylene dichloride, 6.0 g. of 1,7-octanediamine in 100 ml. of ethylene dichloride, 13.8 g. of anhydrous potassium carbonate, and recrystallization from chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([O:41][CH3:42])[C:39]#[CH:40]>ClCCl.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>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][O:41][CH3:42])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (18 mg), and CuI (10 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (10 mL), Et3N (0.14 mL), and methyl propargyl ether (0.046 mL). The reaction is stirred at room temperature for 4 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium carbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is flash column chromatographed on silica gel eluting with 1% to 4% methanol in dichloromethane. The product containing fractions are combined and concentrated under reduced pressure to give a yellow solid which is crystallized from toluene to afford 0.13 g of the title compound as tan needles.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:3]1.[N:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([O:1][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:22])[N:3]=2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1ccc(-c2ccn(O)n2)cc1
Product: COc1ccc(-c2ccn(OC(=O)N3CCOCC3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (62%, crystals).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:17](=[O:20])[CH:18]=[CH2:19])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A dry round-bottom flask was charged with 1-methylpiperazine (0.15 mL, 1.36 mmol), diisopropylethylamine (0.65 mL, 3.72 mmol) and CH2Cl2 (6 mL) and then the solution was cooled with an ice-water bath. Acryloyl chloride (0.10 mL, 1.24 mmol) was then added dropwise and the reaction was allowed to warm to room temperature. After 3 hours TLC indicated reaction completion. The CH2Cl2 was removed and the residue taken up in EtOAc, washed with NaHCO3 (sat.) (1×), brine (2×) and then dried over MgSO4. The EtOAc was removed in vacuo which yielded after drying, the title compound as an orange-brown oil. (400 MHz, CDCl3) 6.57 (dd, J1=16.8 Hz, J2=10.5 Hz, 1H), 6.29 (d, J=16.8 Hz, 1H), 5.70 (d, J=10.5 Hz, 1H), 3.73 (bs, 2H), 3.60 (bs, 2H), 2.46-2.41 (m, 4H), 2.34 (s, 3H); MS ESI 155.0 [M+H]+, calcd for [C8H14N2O+H]+
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].[Br:29]C(Cl)(Cl)C(Cl)(Cl)Br>C1CCCCC1.C1COCC1>[Br:29][C:21]1[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1cc(C(F)(F)F)cc(Br)c1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To −75° C. cooled THF (70 ml) was added dropwise 36 ml (50.0 mmol) of a 1.4 M sec-BuLi solution in cyclohexane within 5 minutes keeping the temperature below −70° C. 7.5 ml (50.0 mmol) TMEDA were added dropwise at temperature below −70° C. within 5 minutes. A solution of 5.0 g (22.71 mmol) 2-methoxy-4-(trifluoromethyl)benzoic acid (commercial) in THF (25 ml) was added dropwise at over a period of 20 minutes. The dark green solution was stirred at −75° C. for 2 hours. A solution of 29.6 g (90.84 mmol) 1,2-dibromotetrachloroethane in THF (30 ml) was added dropwise. The off-white suspension was stirred at −75° C. for 1 hour and then allowed to warm to room temperature. The yellow solution was quenched by dropwise addition of 60 ml water under ice bath cooling. The mixture was diluted with ethyl acetate (70 ml) and water (30 ml). The aqueous layer was extracted with ethyl acetate (50 ml), acidified with HCl 25% and extracted with ethyl acetate (3×50 ml). The extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was stirred in heptane, filtered and dried. The solid was recrystallized from heptane (7 ml) and ethyl acetate (2 ml) to provide 815 mg (12%) of the title compound as a white solid. MS (m/e): 298.9 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1B(O)O.[F-].[Cs+].Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]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.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OC2CCCCO2)c1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a 2 dram vial charged with 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (3.17 g, 18.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.719 g, 0.622 mmol), cesium fluoride (1.15 mL, 31.1 mmol), and 26.2 (1.96 g, 6.22 mmol), was added DME (20 mL). The reaction mixture was then heated at 90° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude product was purified by combiflash (0 to 10% EtOAc/hexanes) yielding 26.3 (1.61 g, 71.8% yield).
Reaction SMILES: N.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[C:12]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)=[N:13][C:14]([N:17]=CN(C(C)C)C(C)C)=[N:15][CH:16]=2)=[CH:5][CH:4]=1.NC1N=C(N)C(C#CC2C=CC(Cl)=CC=2)=CN=1>>[NH2:17][C:14]1[N:13]=[C:12]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[C:11]([C:10]#[C:9][C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)=[CH:16][N:15]=1
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Nc2ccc(O)cc2)n1)C(C)C
Agent: N
Agent: Nc1ncc(C#Cc2ccc(Cl)cc2)c(N)n1
Product: Nc1ncc(C#Cc2ccc(Cl)cc2)c(Nc2ccc(O)cc2)n1

Procedure:
The brown solution was evaporated in vacuo (bath temperature 30° C.) to obtain a brownish-burgundy solid. The residue was stirred in dichloromethane and filtered to yield 0.4 g of 5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneamino-4-(4-hydroxyanilino)pyrimidine. The 1H NMR spectrum (CDCL3) was consistent with this structure. A mixture of 0.37 g of this product was heated in a bomb with 32 mL of methanolic ammonia at a temperature of 100° C. for five hours. The cooled bomb contents were evaporated in vacuo and triturated with ice cold water and dried to yield a mixture of the desired 2-amino-5-(4-chlorophenylethynyl)-4-(4-hydroxyanilino)pyrimidine with 2,4-diamino-5-(4-chlorophenylethynyl)pyrimidine.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([NH:15][C:16]1([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:15][C:16]1([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CCC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1(N)CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4N hydrochloric acid-ethyl acetate solution (12.9 mL, 51.6 mmol) was added in a ethyl acetate (40 mL) solution of ethyl 3-(4-t-butoxycarbonylamino-tetrahydro-pyran-4-yl)-propionate (2.59 g, 8.6 mmol), which had been obtained in 4), in an ice bath. The reaction mixture was stirred at room temperature for 4 hours, and 4N hydrochloric acid-ethyl acetate solution (4.3 mL, 17.2 mmol) was added and the reaction mixture was further stirred at room temperature for 1 hour. The formed solid was filtered to give a colorless solid (BB05, 1.28 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][C:19]=1[O:26][CH3:27].CC1CCCO1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([O:26][CH3:27])[CH:20]=2)=[O:14])[N:3]=1
Reactant: COc1cc([Mg]Br)ccc1F
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2nc(Cl)c3ccccc3n2)ccc1F
Temperature: -35 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a stirred mixture of ethyl 4-chloroquinazoline-2-carboxylate (500 mg, 2.11 mmol) in THF (17 mL) at −40° C. was added dropwise 1 M 4-fluoro-3-methoxyphenylmagnesium bromide/2-methyltetrahydrofuran (2.53 mL, 2.53 mmol). The reaction mixture was stirred at −30 to −40° C. for 3 h. Additional 1 M 4-fluoro-3-methoxyphenylmagnesium bromide/2-methyltetrahydrofuran (1.05 mL, 1.05 mmol) was added and stirring was continued at −30 to −40° C. for an additional 1.5 h. To the mixture was added saturated aq ammonium chloride (25 mL) and the mixture was allowed to warm to rt. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried to afford (4-chloroquinazolin-2-yl)(4-fluoro-3-methoxyphenyl)methanone as a colorless solid (417 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (s, 3H), 7.42 (dd, J=11.1, 8.7 Hz, 1H), 7.64 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.04 (m, 1H), 8.23-8.25 (m, 2H), 8.43 (d, J=8.4 Hz, 1H); LC-MS (ESI) m/z 317 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:8]=[CH2:9])=[CH:6][CH:7]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(Cl)nn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(Cl)nn1
Yield: 62 %

Procedure:
A mixture of 3-chloro-6-vinyl-pyridazine (1 g, 7.09 mmol), palladium on carbon (10% wt, 200 mg) in ethyl acetate (14 mL) under a hydrogen atmosphere was stirred vigorously at ambient temperature for 4 hours. The mixture was then filtered through a pad of celite and the filtrate concentrated onto silica gel and purified via flash column chromatography (SiO2, hexane:ethyl acetate 90:10-50:50) to return the title compound as a white solid (627 mg, 63% yield). 1H NMR (CDCl3): δ 1.27 (3H, t), 2.93 (2H, q), 7.72 (1H, d), 7.83 (1H, d). MS m/z=143 (M+H+)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].[CH:30]1N=[CH:33][N:32]([C:35](N2C=NC=C2)=O)[CH:31]=1.CN(C)CCO.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:30][CH2:31][N:32]([CH3:35])[CH3:33])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(C(=O)OCCN(C)C)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (443 mg, 4.98 mmol) 2-(dimethylamino)ethanol and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[CH2:30]([OH:35])[CH2:31][CH2:32][C:33]#[CH:34]>N1CCCCC1.[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.[Cu]I>[CH3:3][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][OH:35])=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:11][CH:12]=1)([CH3:4])[CH3:1]
Reactant: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc32)cc1
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(-n2ccc3cc(C#CCCCO)ccc32)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To 1.62 g (3.7 mmol) Trifluoro-methanesulfonic acid 1-(4-trimethylsilanylethynyl-phenyl)-1H-indol-5-yl ester in 5 ml piperidine, 230 mg (0.2 mmol) tetrakis-(triphenylphosphine)-palladium and 40 mg (0.2 mmol) CuI were added. The solution was evaporated and purged with argon three times, before 0.56 ml (6 mmol) 4-pentyn-1-ol were added. The solution was stirred at 80° C. for 2 h. The solution was concentrated and the residue dissolved in 0.5M HCl and ether. The inorganic phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Purification on silica gel with CH2Cl2 yielded 980 mg (71%) 5-[1-(4-Trimethylsilanylethynyl-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol as orange viscous oil, MS: 371 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:11]N(C)C)[CH:9]=O.[NH2:15][C:16]([NH2:18])=[O:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:11]=[N:15][C:16](=[O:17])[NH:18][CH:9]=1
Reactant: CN(C)C=C(C=O)c1ccccc1Cl
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=c1ncc(-c2ccccc2Cl)c[nH]1

Procedure:
10 g of 2-(2-chlorophenyl)-3-dimethylaminoprop-2-enal (Example 1a) and 6 g of urea are heated under reflux in 40 ml of ethanol, in the presence of 10 ml of hydrochloric acid, for 4 hours.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[N:14][N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:11]2[CH2:12][CH2:13][N:9]([CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]2=[N:14][N+:15]([O-:17])=[O:16])=[CH:27][N:26]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])N=C1N(C=C(c2ccccc2)c2ccccc2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture comprising 15.4 g of 1-(2,2-diphenylvinyl)-2-nitroiminoimidazolidine, 8.1 g of 2-chloro-5-chloromethylpyridine, 6.9 g of potassium carbonate and 80 ml of dimethylsulfoxide was stirred at 60° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give a crude product. To this was added 100 ml of ethyl acetate for recrystallization, and 13 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2,2-diphenylvinyl)imidazolidine was obtained.