Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:4]#[C:5][CH2:6][CH2:7][C:10]2[O:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[N:3][CH:4]=1
Reactant: c1ccc2ocnc2c1
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(C#CCCc2nc3ccccc3o2)nc1
Yield: 9.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoropyridine (200 mg, 1.14 mmol) and 2-but-3-ynyl)benzo[d]oxazole (195 mg, 1.14 mmol, Example 8(A)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH 94:5:1 to 90:8:2) to yield 15 mg (56 μmol, 5%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].[CH2:9]([N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](=O)[CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:20]1([N:16]([C:17](=[N:1][C:2]2[NH:6][CH:5]=[N:4][C:3]=2[C:7]#[N:8])[CH3:18])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1nc[nH]c1N
Reactant: CC(=O)N(Cc1ccccc1)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=Nc1[nH]cnc1C#N)N(Cc1ccccc1)c1ccccc1

Procedure:
5-Aminoimidazole-4-carbonitrile is condensed with N-benzyl-N-phenyl-acetamide in the presence of phosphoryl chloride in acetonitrile at room temperature to yield 5-[1-(N-phenyl-N-benzylamino)ethylideneamino]-imidazole-4-carbonitrile. Such is cyclized with sodium hydride in dioxane to yield 7-amino-N-phenyl-N-benzyl-3H-imidazo[4,5-b]pyridine-5-amine. Hydrogenolysis in ethanol with palladium on charcoal yields 7-amino-N-phenyl-3H-imidazo[4,5-b]pyridine-5-amine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:12]([CH3:15])([O-:14])=[O:13].CN(C)C(=N)N(C)C.S(=O)(=O)(O)O>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH:3]([CH2:15][N+:12]([O-:14])=[O:13])[C:2]([F:10])([F:11])[F:1])[CH3:9]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CC(C[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 98 %

Procedure:
A mixture of 4.203 g (25 mmol) of ethyl 4,4,4-trifluorocrotonate, 20 mL of nitromethane and ca 0.576 g (5 mmol) of tetramethyl guanidine were stirred for 13 hours at room temperature, and then diluted with water and acidified by the addition of 0.5 M sulfuric acid. The mixture was extracted three times with diethyl ether. The combined ether extracts were washed with water, and then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.601 g (98%) of 4,4,4-trifluoro-3-nitromethyl-butyric acid ethyl ester as an amber oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2>C(O)C>[CH:19]1[C:20]2[C:15](=[C:14]([NH:13][C:4]3[C:5](=[O:12])[C:6](=[O:11])[C:7]=3[O:8][CH2:9][CH3:10])[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc2cnccc12
Solvent: CCO
Product: CCOc1c(Nc2cccc3cnccc23)c(=O)c1=O
Yield: 29.2 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was added a suspension of 5-aminoisoquinoline (4.24 g, 29.4 mmol) in ethanol (50 mL). The mixture was heated to reflux overnight and then filtered to yield 2.30 g (29%) of solid: mp 182(dec) ° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:23]2[CH2:24][CH2:25][N:20]([C:26]3[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=3)[CH2:21][CH2:22]2)=[O:11])[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(OCC2CCC2)c(C(=O)O)c1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CS(=O)(=O)c1ccc(OCC2CCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid (Example A6) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 61%). MS (m/e): 461.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9])[CH:5]=[CH2:6].O>C1COCC1>[CH3:1][N:2]([CH3:3])[C:14]([C:13]1[CH:17]=[CH:18][C:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])=[CH:11][CH:12]=1)=[O:15]
Reactant: C=CCOC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of dimethylamine (40% in water) were introduced into a round-bottomed flask and a solution of 2.5 g (11.6 mmol) of 4-(allyloxycarbonyl)benzoyl chloride in 50 ml of THF was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 2.7 g (100%) of the expected amide were recovered in the form of a slightly yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]=[C:6]=[S:7])[CH3:4].[NH2:8]/[C:9](/[C:16]([F:19])([F:18])[F:17])=[CH:10]\[C:11](OCC)=[O:12]>CN(C=O)C>[CH2:3]([N:5]1[C:11](=[O:12])[CH:10]=[C:9]([C:16]([F:19])([F:18])[F:17])[N:8]=[C:6]1[SH:7])[CH3:4]
Reactant: CCN=C=S
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(S)nc(C(F)(F)F)cc1=O
Yield: 99 %

Procedure:
With stirring under ice-cooling, sodium hydride (60% in oil, 3.73 g, 56.0 mmol) and ethyl isothiocyanate (4.38 ml, 56.0 mmol) were added in that order to DMF (35 ml) solution of ethyl 3-amino-4,4,4-trifluorocrotonate, Followed by stirring overnight while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, water (20 ml) was added to the thus obtained residue, and then concentrated hydrochloric acid (15 ml) was added. The thus precipitated solid was isolated by filtration, washed with water (100 ml) and then thoroughly dried to obtain 3-ethyl-2-mercapto-6-trifluoromethyl-4-(3H)-pyrimidinone (11.0 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:16][Mg+].[Br-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16])=[N:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cn1
Agent: [Br-]
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cn1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of (R)-2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-2-yl)-meth-(E)-ylideneamide (6.04 g, 20.9 mmol) in 100 mL of CH2Cl2 was cooled to −50° C. MeMgBr (10.4 mL, 31.3 mmol, 3M in Et2O) was added slowly dropwise via syringe pump over 1 h. The reaction mixture was stirred at −50° C. for 30 min and then quenched by the addition of 100 mL of satd aqueous NH4Cl solution. The mixture was partitioned between 200 mL of CH2Cl2 and 150 mL of water. The organic phase was washed with 150 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 50-90% EtOAc in hexanes, to provide 5.38 g (84%) of (R)-2-methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-pyridin-2-yl)-ethyl]-amide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[C:12](Cl)=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)([O-:10])=[O:9]>N1C=CC=CC=1.CCOC(C)=O>[N+:8]([C:11]1[C:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1c(Nc2ccccc2)ccc2cccnc12
Temperature: 170 °C
Yield: 90.3 %

Procedure:
Aniline (2 ml, 21 mmol) was added to a solution of 8-nitro-7-chloroquinoline 40 (200 mg, 0.96 mmol) in pyridine (1 ml) and the mixture was heated in a microwave at 170° C. under nitrogen for 3 h. The residue was dissolved in EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 (30 ml) and concentrated in vacuo to give the title compound (230 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])CCCC1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH3:30])[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(-c3ccncc3)nn3c(NC4CCCC4)cccc23)n1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (From example 1, 0.13 g, 0.35 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:20 methanol-ethyl acetate) to give the title compound (100 mg, 75%) as a yellow solid. 1H NMR (CDCl3): δ 8.72 (d, 2H), 8.13 (d, 1H), 7.65 (m, 3H), 7.35 (t, 1H), 6.43 (d, 1H), 6.10 (d, 1H), 6.05 (d, 1H), 5.10 (m, 1H), 4.05 (m, 1H), 3.05 (d, 3H), 1.2–2.2 (m, 8H); MS m/z 386 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]#[N:21])[CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]#[N:21])[CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#CC[C@@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Agent: [Pd]
Solvent: CO
Product: N#CC[C@@H]1CC[C@H](Nc2c(N)cnc3ccsc23)C1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of {(1R,3S)-3-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclopentyl}acetonitrile (8 mg, 0.03 mmol) and 10% palladium on carbon (4 mg) in methanol (0.3 mL) was stirred under an atmosphere of H2 (balloon) overnight. The mixture was filtered and concentrated to give 7 mg of the desired product. LCMS calculated for C14H17N4S (M+H)+: m/z=273.1. Found: 273.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[Si]([N:11]=[C:12]=[O:13])(C)C>C(O)(C)C>[N:1]1([C:12]([NH2:11])=[O:13])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)N1CCSCC1
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a stirred solution of thiomorpholine (1.0 g, 9.7 mmol) in isopropanol (25 mL) at rt was added trimethylsilylisocyanate (1.9 mL, 13.45 mmol) and the resulting solution stirred overnight. The resulting suspension was filtered and the filtrate concentrated in vacuo to give thiomorpholine-4-carboxylic acid amide (1.18 g, 89%); 1H-NMR (300 MHz, d6-DMSO) 6.00 (2H, s), 3.53-3.57 (4H, m), 2.46-2.51 (4H, m, obscured by solvent).
Reaction SMILES: C(N[C:5]1[C:6]([Cl:34])=[C:7]([NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1C=CC(NCCO)=C[CH:15]=1)(=O)=O)(=O)C.C[O-].[Na+].C([I:40])C.CCOC(C)=O>C1COCC1>[CH2:14]([S:11][C:10]1[CH:9]=[CH:8][C:7]([NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])=[C:6]([Cl:34])[C:5]=1[I:40])[CH3:15]
Reactant: CCI
Reactant: CC(=O)Nc1c(S(=O)(=O)c2ccc(NCCO)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1I
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-N-[4-mercapto-3-iodo-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 29) (5.85 g) in anhydrous THF (40 ml) under argon was added sodium methoxide (0.44 g) followed by ethyl iodide (0.65 ml) and the mixture was heated under reflux for 1 hour and allowed to cool to ambient temperature. EtOAc (200 ml) was added, the organic phase was washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by flash column chromatography eluting with 5-30% EtOAc/isohexane to give the title compound (2.08 g) as a pale yellow solid. NMR (CDCl3) 1.36 (t, 3H), 1.75 (s, 3H), 2.92-2.99 (q, 2H), 7.15 (d, 1H), 8.34 (d, 1H), 8.89 (s, 1H); m/z: 452.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:32])[CH:24]=1.O>CN(C)C=O>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([C:15]2[C:8]3[NH:7][C:6]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:11][NH:10][C:9]=3[CH:12]=[CH:13][CH:14]=2)=[O:28])=[C:25]([Cl:32])[CH:24]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Br)cc1Cl)c1cccc2c1Nc1ncccc1CN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepine (3 g, 15.2 mmol) in N,N-dimethylformamide under nitrogen were added solid potassium carbonate (6.3 g, 45.6 mmol). The mixture was treated dropwise with a solution of the crude 4-bromo-2-chlorobenzoyl chloride (22.9 mmol) in N,N-dimethylformamide. After stirring at room temperature for 15 minutes, water was added under stirring. The resulting solid was collected, dissolved in chloroform, and the solution washed with 1N NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue (purple foam) was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided 3.4 g of the title compound as a foam which crystallized as a white solid by trituration from ethanol-ether, m.p. 165-168° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)(O)[CH3:12])=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[C:19]([N:17]1[CH:18]=[C:14]([C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[CH2:12])[N:15]=[CH:16]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccnc2ccccc12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccnc2ccccc12
Reaction time: 2 h

Procedure:
1-Quinolin-4-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate G3) (4.78 g, 9.93 mmol) in dichloromethane (100 mL) was treated with triethylamine (11.0 mL, 78.9 mmol) at 0° C. Methanesulfonyl chloride (MsCL) (2.3 mL, 29.7 mmol) was added via syringe and the mixture was stirred for 2 h. (see procedure found in Toshima, K et al J Amer. Chem. Soc. 1995 117, 10825; incorporated herein by reference). The mixture was subjected to a typical aqueous work-up. The crude material was purified by chromatography on silica gel with 2% NH3-MeOH: dichloromethane to give 4-[1-(1-trityl-1H-imidazol-4-yl)-vinyl]-quinoline (Intermediate G4) as a tan solid, 3.51 g (76%).
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH:3]([P:8]([Cl:11])([Cl:10])=O)[O:4][C:5](=[O:7])[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>>[Br:1][CH:2]([CH3:12])[CH:3]([P:8]([Cl:11])([Cl:10])=[S:14])[O:4][C:5](=[O:7])[CH3:6]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)OC(C(C)Br)P(=O)(Cl)Cl
Product: CC(=O)OC(C(C)Br)P(=S)(Cl)Cl

Procedure:
One and one-quarter grams of (2-bromo-1-acetoxypropyl)phosphonic dichloride is heated with 0.55 g. of finely pulverized P2S5 under nitrogen at 130°C. for three hours. The reaction mixture is fractionally distilled to give threo (2-bromo-1-acetoxypropyl)phosphonothioic dichloride.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1Oc1ccc(CBr)cc1
Yield: 52.7 %

Procedure:
A solution of the product of Step B (200 mg, 0.690 mmol), NBS (117 mg, 0.95 eq) and AIBN (10 mg, catalytic amount) in CCl4 (5 mL) was heated at reflux for 2 hours and then cooled and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (30×130 mm) eluted with 5% ethyl acetate/hexane to yield 128 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(=O)(OC)O[CH2:12][CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:14][CH:13]=[CH2:12]
Reactant: Cc1cccc(C)c1O
Reactant: C=CCOC(=O)OC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOc1c(C)cccc1C
Temperature: 70 °C
Yield: 98.7 %

Procedure:
A mixture of 2,6-dimethylphenol (1.22 g, 10 mmoles), allyl methyl carbonate (1.40 g, 12 mmoles), 5 percent palladium on charcoal (26 mg, 0.0125 mmole paladium) and triphenyl phosphine (20 mg, 0.0375 mmole) is heated at 70° C. for 45 minutes. Filtration of the catalyst and bulb-to-bulb distillation of the residue at 120° C., 10 mm Hg gives 1.60 g of substantially pure allyl 2,6-dimethylphenyl ether, 98.7 percent yield.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CCOCC>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.8 %

Procedure:
4-Cyano-benzoic acid (10.0 g, 68.0 mmol), phenol (6.40 g, 68.0 mmol), DCC (14.73 g, 71.4 mmol), DMAP (0.25 g, 2.04 mmol) and ether (200 mL) were mixed, and stirred at room temperature for 3 days. Ether was removed. To the residue was added CH2Cl2 (200 mL). The solid was filtered. The filtrate was concentrated, and purified by flash chromatography to give the desired product (12.41 g, 82%). MS (DCI/NH3) m/z 224 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 7.19-7.25 (m, 2H) 7.31 (m, 1H) 7.41-7.50 (m, 2H) 7.807.85 (m, 2H) 8.29-8.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37][CH2:38]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (75 mg), potassium carbonate (51 mg), and 1,3-dibromopropane (76 μl) was dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 74 mg (yield 78%) of N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl ]-oxy}-2-chlorophenyl)-N′-propylurea as an intermediate. The intermediate (74 mg), potassium carbonate (51 mg), and morpholine (130 μl ) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 49 mg (yield 63%) of the title compound.
Reaction SMILES: [S:1]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([O:4][CH2:5][C@@:6]1([CH3:13])[CH2:10][O:9]C(C)(C)[O:7]1)(=[O:3])=[O:2].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[S:1]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)([O:4][CH2:5][C@@:6]([OH:7])([CH3:13])[CH2:10][OH:9])(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)COC(C)(C)O2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@](C)(O)CO)cc1

Procedure:
1.42 g (4.74 mmol) of {(R)-2,2,4-trimethyl-1,3-dioxolan-4-yl}methyl tosylate are evaporated twice from 100 ml of methanol in the presence of a catalytic amount of p-toluenesulfonic acid at 16 mbar/40° C. and the residue is finally purified by chromatography over silica gel 60 (0.040-0.063 mm, 20 g) using methylene chloride/diethyl ether (1:1) as the eluent. There are obtained 907 mg (3.49 mmol, 74% of the theoretical yield) of (R)-2,3-dihydroxy-2-methylpropyl tosylate, 99% pure by gas chromatography, [α]365 =-19.0° (1% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH3:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][C@H:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C@H:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21])[C:5]([CH2:9][CH3:10])=[CH:4][N:3]=1
Reactant: CCc1cnc(Cl)nc1Cl
Reactant: CC(C)[C@@H](N)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cnc(Cl)nc1N[C@@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
A solution of 882 mg (5.0 mmol) of 2,4-Dichloro-5-ethyl-pyrimidine and 0.75 ml (5.5 mmol) triethylamine in 5 ml of acetonitrile is mixed with 672 mg (6.5 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 90:10). 742 mg of the product is obtained that still contains considerable amounts of (R)-2-Amino-3-methyl-butan-1-ol. The material is used without further purifications.