Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH:28]1[CH2:30][CH2:29]1.[Si:31]([O:38][CH2:39][C:40]([CH3:52])([CH3:51])[O:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:45]2[CH:44]=[CH:43][C:42]([O:41][C:40]([CH3:52])([CH3:51])[CH2:39][O:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])=[CH:47][CH:46]=2)=[C:3]([CH:28]2[CH2:29][CH2:30]2)[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C2CC2)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A mixture of 4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.6 g), [4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronic acid (0.79 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution (6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.69 g, 80%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][NH:15][C:14](=O)[CH:13]=1.N.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]cn1
Agent: N
Product: COCCOc1ccccc1-c1cc(Cl)ncn1
Temperature: 5 °C

Procedure:
A stirred suspension of 6-[2-(2-methoxy-ethoxy)-phenyl]-3H-pyrimidin-4-one (0.2 g, 0.81 mmol) in POCl3 (2 mL) was heated at reflux for 1 h. The reaction mixture was cooled to about 5° C. and poured cautiously into 10 ml ice-water, ammonia (10 mL) was added and extracted with ethyl acetate (2×10 mL), organic layers were combined, washed with water (5 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was triturated with hexane yielding 0.18 g (84%) 4-chloro-6-[2-(2-methoxy-ethoxy)-phenyl]-pyrimidine as white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To 20.0 g of N-(tert-butoxycarbonyl)-L-alanine in 352 ml of dichloromethane, 12.4 g of N,O-dimethylhydroxylamine hydrochloride, 15.7 g of 1-hydroxybenzotriazole monohydrate, 24.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 42.7 g of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was washed with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 1N aqueous hydrochloric acid and 500 ml of water in this order, the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 200 ml of hexane to obtain 13.1 g of the desired product as white crystals.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl-].[NH4+]>CCO.O.ClCCl.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH:4]([CH:2]3[CH2:3][CH2:1]3)[C:9](=[O:10])[NH:8][C:7]=2[CH:11]=1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C(C1CC1)O2
Temperature: 90 °C

Procedure:
To a solution of 200 mg of 2-(2-cyclopropyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine (1 g) in EtOH/water (20 mL; 2:1 v/v) was added 5 eq of iron and 5 eq of ammonium chloride and the reaction was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered. The layers were separated, the aqueous was extracted once with dichloromethane, the combined organics layers were dried over magnesium sulfate, the solution filtered and the filtrate evaporated in vacuo to give the desired product 6-amino-2-(2-cyclopropyl)-3-oxo-4H-benz[1,4]. MS (m/e): 191 (MH+).
Reaction SMILES: NN.[S:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[CH2:16][O:17][N:18]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C>[NH2:18][O:17][CH2:16][C:4]1[S:3][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nc2cnc3ccccc3c2s1
Agent: NN
Solvent: CCO
Product: NOCc1nc2cnc3ccccc3c2s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 131.9 %

Procedure:
Hydrazine (3.4 g, 3.3 mL, 106 mmol) was added to a suspension of 2-[([1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione (19.2 g, 53.1 mmol) in ethanol (300 mL), and the reaction was stirred at room temperature for 2.5 hours and filtered. The filter cake was washed with ethanol and dried overnight in a vacuum oven to provide 16.2 g of 2-(aminooxy)methyl[1,3]thiazolo[4,5-c]quinoline as a tan solid containing some phthalhydrazide. The filtrate was concentrated under reduced pressure to provide 5.89 g of the same mixture as a yellow solid. Some of the phthalhydrazide was removed from the mixture by recrystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=[O:12])[N:7]([CH2:14][CH2:15][O:16][CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)cnc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: COCCn1cnc2cc(Br)cnc2c1=O

Procedure:
A solution of 7-bromopyrido[3,2-d]pyrimidin-4(3H)-one (200 mg, 0.89 mmol), 1-bromo-2-methoxyethane (148 mg, 1.06 mmol) and K2CO3 (184 mg, 1.3 mmol) in acetone (10 mL) and DMF (3 mL) was stirred at room temperature for 4 h. Then the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 284, 286 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH3:28])=[CH:3][CH:4]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CNC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(C)(C)O
Product: CN(c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1)C1CCCCC1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
A suspension of (S)-2-(4-bromophenyl)-1,4-di(t-butoxycarbonyl) piperazine (1.21 g, 2.75 mmol), N-methylcyclohexylamine (0.43 mL, 3.30 mmol), palladium acetate (25 mg, 0.11 mmol), 2-(di-t-butylphosphino)biphenyl (66 mg, 0.22 mmol), and sodium t-butoxide (370 mg, 3.85 mmol) in t-butanol (15 mL) was heated at 80° C. for 8 h. The resulting solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-15% ethyl acetate-hexane to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazine (917 mg) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[N:11]1([CH2:16][CH2:17]O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[CH3:10]
Reactant: OCCN1CCCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(OCCN2CCCC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (555 mg) were added 2-pyrrolidine-1-yl-ethanol (0.3 mL), PPh3 (721 mg), and DEAD (0.43 mL). The mixture was stirred room temperature for 16 h. The reaction mixture was concentrated. The residue was treated with Et2O, filtered and the filtrated was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=10:80 to 80:20) to give 1-[2-(4-bromo-3,5-dimethyl-phenoxy)-ethyl]-pyrrolidine as a white solid: MS (m/z) 300 (M+1).
Reaction SMILES: [CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>CO>[CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:6]1[OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1O
Yield: 77.2 %

Procedure:
To a solution of 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (500 mg) in methanol (20 ml) was added sodium borohydride (68 mg) with stirring in an ice bath. The mixture was stirred for half an hour in an ice bath and then sodium borohydride (136 mg) was added thereto at the same temperature. The solution was stirred for 1.5 hours at ambient temperature, followed by the addition of sodium borohydride (68 mg). The mixture was stirred at ambient temperature for half an hour and then poured into water with stirring in an ice bath. The separated solid was collected by filtration, washed with water (50 ml), dried, and recrystallized from methanol to yield 2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthol (388 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]#[N:27]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[CH:23]=[N:24][C:25]([C:26]#[N:27])=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Yield: 35.1 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (125 mg, 35%). MS (ISP) 357.0 [(M+H)+]; mp 202° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1

Procedure:
To a solution of 1.3 g (3.03 mmol) of 2-{2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethyl}-isoindole-1,3-dione, prepared in step 1.3. in 30 mL of ethanol is added slowly at room temperature 0.485 g (15.13 mmol) of hydrazine monohydrate. The reaction mixture is then refluxed for 3 hours.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[NH2:32][C:11]1[N:12]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:31]4)=[CH:20][CH:21]=3)[CH2:16]2)[CH:14]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)[N:10]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC(C)OC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and isopropyl chloroformate. LCMS (M+H)+: m/z=508.3.
Reaction SMILES: O.O1[CH:8]2[CH:3]1[CH2:4][CH:5]1[C:12](=O)N(CC=C)[C:9](=[O:10])[CH:6]1[CH2:7]2>C1(C)C=CC=CC=1>[CH2:5]([CH:6]([CH2:7][CH2:8][CH2:3][CH3:4])[CH2:9][OH:10])[CH3:12]
Reactant: C=CCN1C(=O)C2CC3OC3CC2C1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC(CC)CO
Yield: 0.3 %

Procedure:
In a 300 ml four-necked flask equipped with a reflux condenser, Dean-Stark water separator, thermometer, stirrer, dropping funnel and oil bath there were charged 22.8 g of the 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide obtained in Reference Example 2, 180 g of toluene and 0.05 g of a 2-ethylhexanol solution containing 2 wt % platinic chloride, after which the oil bath kept at 140° C. was used for azeotropic dewatering while circulating for 1 hour, and after confirming lack of water runoff, a total of 36.3 g of the silicon compound represented by the following formula (X):
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH3:29])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Yield: 45.6 %

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.116 g, 0.331 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.015 g, 0.364 mmol, 60% in mineral oil). Let stir for 20 min, then add methyl iodide (0.022 mL, 0.364 mmol) and let stir for 3 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×30 mL). Combine the organic layers and wash with brine (2×30 mL), aqueous NH4Cl (1×30 mL), aqueous NaHCO3 (1×30 mL) and water (1×30 mL). Dry the organic layer over anhydrous Na2SO4, filter and concentrate under reduced pressure. Separate the two regioisomeric products via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes) and concentrate under reduced pressure the purified fractions. Place the residue under vacuum to give the title compound as a white solid (0.055 g); mass spectrum (m/e): 365.07 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:34])([C:21]4[CH:25]=[C:24]([CH2:26][O:27]C5CCCCO5)[O:23][N:22]=4)[CH3:20])[CH:15]=3)[C:10]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])=[N:9]2)[CH:5]=[CH:4][N:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:34])([C:21]4[CH:25]=[C:24]([CH2:26][OH:27])[O:23][N:22]=4)[CH3:20])[CH:15]=3)[C:10]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cc(COC4CCCCO4)on3)ccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cc(CO)on3)ccc12
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A solution of 1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}but-1-yn-1-yl)-N,N-dimethylindazole-3-carboxamide (110 mg, 0.21 mmol) and pyridinium 4-methylbenzenesulfonate (5.18 mg, 0.2 mmol) in methanol (3 mL) was stirred at 60° C. for 1 hr, and then at RT for 3 days. Additional pyridinium 4-methylbenzenesulfonate was then added (20 mg, 0.8 mmol) and the reaction stirred at 55° C. for 1 hr. The reaction mixture was concentrated in vacuo and then saturated aqueous NaHCO3 (3 ml) solution was added. The product was extracted into DCM (5 ml×2). The combined organics were washed with brine and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column). Elution with 3% methanol in DCM gave the title compound: 1H NMR (500 MHz, DMSO) delta 1.88 (3H, s), 3.12 (3H, s), 4.57 (2H, d, J 6.0), 5.67 (1H, t, J 6.1), 6.55 (1H, s), 6.66 (1H, s), 7.10 (1 H, d, J 5.5), 7.16 (2H, s), 7.43 (1H, d, J 8.4), 8.01 (1H, d, J 8.5), 8.35 (1H, d, J 5.5), 8.95 (1H, s); LC-MS m/z=+448.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](O)=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:17][CH:16]=[CH2:15])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: C=CCBr
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(I)cc(C(C)O)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (3.6 g, 12 mmol) in 24 mL of N,N-dimethylformamide at 0° C. is treated with 480 mg (60% in oil, 12 mmol) of sodium hydride and stirred at room temperature for 1 h. The reaction is treated with 1.14 g (13.2 mmol) of allyl bromide and stirred for 2 h. The mixture is poured into 125 mL of ethyl acetate and washed with 4×50 mL of saturated sodium chloride, 2×25 mL of 50% saturated sodium carbonate and dried over potassium carbonate. The dried organics are concentrated in vacuo, diluted with 20 mL of hexanes, and chilled to -15° C. The solid is filtered to provide 3.61 g (89%) of 2-chloro-3-(1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:18]([NH:24][C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:33]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:25]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=4)(=[O:35])=[O:34])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) and 4-(3-hexyl-ureido)benzenesulfonyl chloride (U.S. Pat. No. 5,561,142/1996) according to the procedure of Example 215 as a white flake; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.5 Hz, 3H), 1.20-1.50 (m, 8H), 1.65 (t, J=5.7 Hz, 4H), 3.00-3.10 (m, 2H), 3.14 (t, J=5.7 Hz, 4H), 3.88 (s, 4H), 6.28 (t, J=5.6 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 7.45 (d, J=9.1 Hz, 2H), 7.51 (d, J=9.1 Hz, 2H), 8.82 (s, 1H); MS (ES) m/z: 517.2 (MH+); HRMS Calcd. for C26H37N4O5S(MH+): 517.2485. Found: 517.2377. Anal. Calcd. for C26H36N4O5S: C, 60.44; H, 7.02; N, 10.84. Found: C, 60.29; H, 6.95; N, 10.91.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Yield: 55.9 %

Procedure:
A mixture composed of 15 g of 4-benzyloxybenzyl chloride and 15 g of 4-aminophenol was refluxed in 200 ml of N,N-dimethylformamide for 30 minutes. After water was added to the reaction mixture, the product was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 50:1 mixture of chloroform and acetone as the eluent) to obtain 11 g of 4[-N-(4-benzyloxybenzyl)-amino]phenol.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].[CH3:7][O:8][CH2:9][CH2:10]Br>>[CH3:7][O:8][CH2:9][CH2:10][O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4]
Reactant: COCCBr
Reactant: C#CC(C)(C)O
Product: C#CC(C)(C)OCCOC
Yield: 61.6 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, and using 21.7 g of 3-methyl-1-butyn-3-ol and 39.4 g of 2-bromoethyl methyl ether, 22.6 g of 3-(2-methoxyethoxy)-3-methyl-1-butyne was obtained.