Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[NH:14]1[CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][C:7]([C:23]3[CH:24]=[CH:25][C:20]([C:17](=[O:19])[CH3:18])=[CH:21][CH:22]=3)=[CH:8][C:9]1=2
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(-c2cnc3c(c2)NCCO3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To 3 ml of tetrahydrofuran/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 4-acetylphenyl boronic acid (71 mg, 0.55 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (21 mg, 0.02 mmol) were added and stirred at 80° C. for 2 hours. After completion of the reaction, the mixture was extracted ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid was recrystallized from n-hexane and diethyl ether to obtain 1-[4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-phenyl]-ethanone as yellow solid (59 mg, 62%).
Reaction SMILES: [C:1](#[N:4])[CH2:2]O.[NH2:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7]>>[C:1]([CH2:2][NH:5][CH:6]([CH3:7])[C:8]([OH:10])=[O:9])#[N:4]
Reactant: N#CCO
Reactant: C[C@H](N)C(=O)O
Product: CC(NCC#N)C(=O)O

Procedure:
One suitable reaction scheme for the synthesis of an intermediate starting with alanine is shown in Scheme I. In step(a) alanine is contacted with glycolonitrile to form 2-(cyanomethylamino)propionic acid (I). The molar ratio of alanine to glycolonitrile is generally about 1:1 with a slight excess of glycolonitrile preferred. ##STR2##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([CH2:7][N:8]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)([CH3:35])[C:33]#N)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C[Mg]Br>C1COCC1>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:51]=[CH:52][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:42][C:43]4[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=4)[N:10]=3)=[CH:17][C:18]([C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)([CH3:33])[CH3:35])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C#N)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-morpholinopropanenitrile (0.500 g, 0.708 mmol) in THF (2 mL) at 0° C. was treated with methylmagnesium bromide (3.0 M in diethyl ether; 1.181 mL, 3.54 mmol). The cooling bath was removed after 10 min, and the reaction was allowed to warm to ambient temperature. After 2 h total, the reaction was cooled to 0° C. and quenched with EtOAc (1 mL) followed by ice and sat'd aq. NH4Cl. The reaction was partitioned between satd NH4Cl and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 10-80% EtOAc/hexane. The product-containing fractions were concentrated to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-morpholinopropan-2-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.363 g, 0.522 mmol, 73.7% yield) as a yellow solid. m/z (ESI, +ve ion) 695 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H); 8.96 (d, J=2.5 Hz, 1H); 8.47 (d, J=2.5 Hz, 1H); 8.13 (dd, J=12.5, 2.2 Hz, 1H); 7.91-8.01 (m, 1H); 7.17-7.26 (m, 4H); 6.75-6.96 (m, 4H); 4.89 (s, 2H); 4.84 (s, 2H); 4.02 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 3.55-3.65 (m, 4H); 2.59 (s, 3H); 2.42-2.51 (m, 4H); 1.35 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.24 mmol, 50 mg) and methyl 4-(aminomethyl)benzoate (0.24 mmol, 40 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCc3c(sc(N)c3C(=O)c3ccccc3)C2)cc1

Procedure:
To a well-stirred and ice-cooled solution of 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.78 mmol, 0.2 g) in dichloromethane (20 ml) under an argon atmosphere, was added triethylamine (0.162 ml) and then p-toluenesulphonyl chloride (0.93 mmol, 177 mg) portionwise. The suspension was stirred a room temperature for 24 h and the precipitated solid was filtered. The organic solution was evaporated under vacuum to give a solid residue which was chromatographed on silica gel eluting with an ethyl ether and petroleum ether mixture to afford 2-amino-3-benzoyl-6-(4-methylphenylsulphonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:25][N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:29][CH2:30][CH2:31][OH:32]>>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[N:25]([CH2:29][CH2:30][CH2:31][OH:32])[N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCI
Reactant: c1ccc(-c2nc3[nH]ncc3c(-c3ccccc3)c2-c2ccncc2)cc1
Product: OCCCn1ncc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc21

Procedure:
Following a similar procedure to that described in examples 6 and 7, but using 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 2) instead of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and 3-iodopropanol instead of iodoethane, the title compounds were obtained.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]12[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH2:26]>>[CH:19]12[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH:26][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1
Reactant: NC1CC2CCC1O2
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: C(#Cc1cnc(NC2CC3CCC2O3)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=292.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-(7-oxa-bicyclo[2.2.1]hept-2-yl)amine (can be prepared in accordance with the literature described in the patent EP 1958666).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>C(OCC)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([CH2:13][CH:12]=[CH2:11])[OH:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under anhydrous condition at 0° C., a mixture of 18.0 g of freshly distilled 2,4-difluorobenzaldehyde and 120 ml of diethyl ether is treated, dropwise, with 139 ml of 1M allyl magnesium bromide. The reaction is stirred at 0° C. for 1 hour then slowly allowed to warm to room temperature. After 5 hours, thin layer chromatography indicates complete reaction. The mixture is cooled to 0° C. and quenched by the dropwise addition of 100 ml of ice cold saturated ammonium chloride. Two hundred ml of diethyl ether is added and the layers are separated. The aqueous layer is extracted with diethyl ether. The organic layers are combined,washed twice with saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is purified by Kugelrohr distillation (100° C.) to give 19.9 g of the desired product as a mixture of isomers.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[CH:11](O)[C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2
Reactant: Cc1c(C(O)C(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CC(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A solution of 0.927 g (2.7 mmol) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-glycolic acid amide in 15 mL of trifluoroacetic acid was treated with 1.0 mL (6.0 mmol) of triethylsilane and the mixture stirred for 1.0 hour. After concentrating at reduced pressure, the residue was chromatographed on silca (eluted with EtOAc) and crystallized from MeOH/CH2Cl2 to give 455 mg (52% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 189-192° C.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[O:15]1[C:19]2([CH2:29][CH2:28][C:22]3([CH2:26][CH2:25][O:24][CH:23]3O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:15]1[C:19]2([CH2:29][CH2:28][C:22]3([CH2:26][CH2:25][O:24][CH2:23]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: OC1OCCC12CCC1(CC2)OCCO1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC2(CCC3(CC2)OCCO3)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triethylsilane (1.965 mL, 12.30 mmol) in DCM (40 mL), under nitrogen, at −78° C. was successively added trifluoroacetic acid (0.948 mL, 12.30 mmol) and [1,4,10-trioxadispiro[4.2.4.2]tetradecan-9-ol](0.878 g, 4.1 mmol) in DCM (40 mL) at −78° C. The resulting mixture was slowly warmed to 0° C. and stirred for 2 hours. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:27]([C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[F:19])(=[O:29])=[O:28])[C:5]=1[F:11]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To 3-amino-2-fluoro-benzoic acid methyl ester (72, 1.08 g, 6.4 mmol) in 40.64 mL of dichloromethane, pyridine (1.29 mL, 16 mmol) is added, followed by 2,5-difluorobenzenesulfonyl chloride (73, 3.391 g, 16 mmol). The reaction is stirred at room temperature overnight, then quenched with 1M aqueous hydrochloric acid. The organic layer is removed and the aqueous layer is extracted with dichloromethane. The organic layers are combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (74, 0.956 g). MS (ESI) [M−H+]−=344.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O

Procedure:
A solution of Example 73C (210 mg), potassium carbonate (150 mg), and pyrrolidine (113 μl) in dichloromethane was stirred for 3 days, treated with potassium carbonate (150 mg) and pyrrolidine (113 μL), stirred for 3 more days, and concentrated; and the concentrate was purified by flash column chromatography on silica gel with a methanol/dichloromethane gradient.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:17]([CH3:21])([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][N:27]1[CH2:32][CH2:31][C@:30]([C:34]2[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=2)([CH3:33])[C@@H:29]([CH3:41])[CH2:28]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[OH:40][C:36]1[CH:35]=[C:34]([C@:30]2([CH3:33])[CH2:31][CH2:32][N:27]([CH2:26][C@@H:25]([NH:24][C:18]([C@@:17]3([CH3:21])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:20])[CH:42]([CH3:43])[CH3:44])[CH2:28][C@@H:29]2[CH3:41])[CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)[C@H](N)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)N[C@H](CN1CC[C@@](C)(c3cccc(O)c3)[C@@H](C)C1)C(C)C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Compound 2.8 (200 mg, 0.623 mmol), 3-{(3R,4R)-1-[(2S)-2-amino-3-methylbutyl]-3,4-dimethylpiperidin-4-yl}phenol (J) (181 mg, 0.623 mmol) and BOP reagent (275 mg, 0.623 mmol) were dissolved in THF (20 mL). Triethylamine (1 mL) was added and the solution was stirred at room temperature for 3 h. The solution was extracted with CH2Cl2 and saturated NaHCO3 solution. The organic layer was dried and purified by column chromatography to afford 250 mg, (68%) of 2.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:7]=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cc(Br)ccc1F
Solvent: ClCCl
Product: C[C@](CO)(NC(=O)CCl)c1cc(Br)ccc1F

Procedure:
A solution of (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (2.7 g) in dichloromethane was divided in 100 mg aliquots which were separated on chiral HPLC (Reprosil Chiral NR 8 μm, 250×30 mm, Dr. Maisch GmbH) using a 85:15-mixture of heptane and isopropanol as the eluent. The first eluting enantiomer (retention time: 9.94 min), the (S)-(−)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was obtained as a light yellow waxy solid (1.05 g, 39%), and the second eluting enantiomer (retention time: 12.92 min), the (R)-(+)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was also obtained as a light yellow waxy solid (1.07 g, 40%), with e.e. >99% each.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:17])[CH2:11][CH3:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCC(=O)Nc1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC(Cl)=Nc1ccccc1C(F)(F)F
Yield: 97.3 %

Procedure:
A solution of 18 g of the product of Step A in 150 ml of toluene was added over 15 minutes to a suspension of 19 g of phosphorus pentachloride in 23 ml of toluene and after gas evolution ceased, the mixture was refluxed for 11/2 hours. The toluene was evaporated under reduced pressure to obtain 19 g of N-(2-trifluoromethylphenyl)-propanimidoyl chloride in the form of a yellow oil which was used as is for the next step.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][N:16]3[C:20]([C:21]([O:23]CC)=O)=[C:19]([CH:26]=O)[N:18]=[CH:17]3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[C:20]4[C:21](=[O:23])[N:2]([CH3:1])[N:3]=[CH:26][C:19]=4[N:18]=[CH:17]3)=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1c(C=O)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cn1ncc2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of methylhydrazine (209 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-formylimidazole-5-carboxylate (6.01 g) in ethanol (10 ml) was refluxed for 2.5 hours. After cooling to room temperature, concentrated sulfuric acid (0.1 ml) was added and the mixture was further refluxed for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=2:1) to provide the title compound as white powder (115 mg, yield 20%). H-NMR (CDCl3) δ: 3.88(3H,s), 5.81(2H,s), 7.46(4H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.77(2H,d,J=8.6Hz), 7.97(1H,s), 8.33(1H,s).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:35]([O:37][CH:38]([O:45][CH2:46][CH3:47])[C:39]#[C:40][C:41]([O:43][CH3:44])=[O:42])[CH3:36]>C1COCC1.O>[CH2:46]([O:45][CH:38]([O:37][CH2:35][CH3:36])/[C:39](/[O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])[CH3:47]
Reactant: CCOC(C#CC(=O)OC)OCC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of 2.79 g (15 mmol) of 4-phenoxyphenol in 40 mL of THF was added 1.14 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.72 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetate-hexane yielded 3.02 g (55%) of an oil, used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].C(Cl)Cl>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:10]4[CH2:9][CH2:8][N:7]5[C:3]([CH2:1][CH3:2])=[N:4][N:5]=[C:6]5[CH2:11]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CCc1nnc2n1CCNC2
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nnc2n1CCN(CCCOc1cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc1OC)C2
Temperature: 80 °C
Yield: 23.2 %

Procedure:
To a solution of 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.12 g) in DMF (5 mL) was added Ag2CO3 (0.73 g, 5 eq). The mixture was then added into a solution of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.21 g) in DMF (2 mL) with stirring. The reaction mixture was heated at 80° C. for 40 h under N2, and cooled to room temperature. To the reaction mixture was added CH2Cl2 (100 mL), and the reaction mixture was washed with brine (100 mL×3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (63.00 mg, 15.56%), HPLC: 90.54%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 512.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.29 (t, J=12.80 Hz, 3H), 2.61-2.69 (m, 2H), 2.70 (t, J=13.60 Hz, 2H), 2.86 (t, J=11.20 Hz, 3H), 3.49 (s, 2H), 3.65 (s, 2H), 3.81 (t, J=13.60 Hz, 2H), 3.91 (s, 1H), 4.08 (t, J=12.40 Hz, 2H), 7.09 (m, 1H), 7.23-7.27 (m, 1H), 7.55-7.59 (m, 2H), 7.76-7.78 (m, 1H), 8.64 (s, 1H), 8.76 (s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])[N:7]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(CNc2cncc(Cl)n2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1cncc(NCc2ccc(F)cc2)n1
Yield: 23.5 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-(4-fluorobenzyl)pyrazin-2-amine (150 mg, 0.63 mmol) and 2-methylimidazole (57 mg, 0.69 mmol) furnished the product (42 mg, 23%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH3:2]
Reactant: CCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCC(CC)Oc1ccccc1Br

Procedure:
Bromo-(4-hexyloxy)-benzene was prepared by alkylation of 4-bromophenol (91.2 g, 527 mmol) with bromohexane (86.0 g, 520 mmol), K2CO3 (80.0 g, 580 mmol) in acetone (200 mL) at reflux for 12 hours. After removal of the salts by filtration, the reaction mixture was concentrated to dryness to give an oil. The oil was dissolved in EtOAc (100 mL) and transferred to a separatory funnel and washed with 5% NaOH (4×200 mL). An additional 200 mL volume of EtOAc was added to the separatory funnel and the contents were washed with NaHCO3 (1×200 mL) and finally dried over MgSO4. Removal of the EtOAc solvents afforded a light yellow oil and was used without further purification. Yield: 119 g, 89%. 1H NMR (500 MHz, CD2Cl2, 25° C.) δ 0.91 (t, 3H), 1.34 (m, 4H), 1.45 (m, 2H), 1.76 (m, 2H), 3.92 (t, 2H), 6.79 (d, 2H), 7.36 (d, 2H).