Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 0.5 h

Procedure:
A solution of 4.0 g of N-[3-(1,6-dihydro-6-oxo-3-pyridazinyl)phenyl]acetamide in 100 ml of phosphorus oxychloride was heated at 55°-65° C. for 1.5 hours and then the excess phosphorus oxychloride was removed in vacuo. The residue was dissolved in dichloromethane and the solution poured onto 200 g of crushed ice. After stirring for 30 minutes the acidic mixture was neutralized with aqueous sodium bicarbonate. The mixture was filtered, giving 0.8 g of solid. The dichloromethane layer of the filtrate was separated, dried and evaporated, giving 2.93 g of solid. The two solids were combined (3.73 g) and a 2.9 g portion chromatographed on a silica gel column, eluting with dichloromethane-methanol (95:5). The fractions containing product were combined, evaporated and the solid (1.5 g) recrystallized from dichloromethane-acetone, to give the desired compound as tan crystals, mp 203°-205° C. (dec.).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>C(Cl)CCl>[CH2:26]([O:25][C:21](=[O:24])[CH2:22][O:23][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:27]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CO
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Trityl chloride (279 g, 1.0 mol) was dissolved in EDC (680 ml, 5 ml/g with respect to ethyl glycolate), and ethyl glycolate (135 g, 1.3 mol) was added to the mixture. Pyridine (99 g, 1.25 mol) was added thereto, and the mixture was stirred for 19 hours at 40° C. After completion of the reaction was confirmed by HPLC, 0.5 N aqueous hydrochloric acid solution (270 ml, 2 ml/g with respect to ethyl glycolate) was added to make the reaction solution a two-phase solution, which was then extracted. After the extraction was performed once again, EDC was distilled under reduced pressure. In order to obtain the compound of formula (8) as a solid form, hexane (680 ml) was added to the concentrated compound, the temperature was lowered to 0° C., and the mixture was stirred for about 3 hours and filtered.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=1.C([O-])(O)=[O:17].[Na+]>Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:17])[N:9]=1
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2ccccc2F)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1nc(-c2ccccc2F)cc[nH]1
Yield: 89 %

Procedure:
A solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine (943 mg, 4.28 mmol) in 37% HCl (18 ml) was heated at 100° C. for 21 hours. The mixture was diluted with water then basified with solid NaHCO3. The suspension was extracted with DCM; the organic layer was dried (Na2SO4), filtered and evaporated to give the title compound that was used without further purification in the next step (725 mg, 89% yield)
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.CCOCC.O.[NH2:20][CH:21]([CH3:24])[CH2:22]O>>[CH3:24][CH:21]1[N:20]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:3][CH2:22]1
Reactant: CC(N)CO
Reactant: Clc1ccc(-c2cccnc2)nn1
Solvent: CCOCC
Solvent: O
Product: CC1CN=C2C=CC(c3cccnc3)=NN21

Procedure:
A 4.0 g sample of 3-chloro-6-(3-pyridinyl)pyridazine in 56 ml of 2-amino-1-propanol was heated at 140° C. for 8 hours. The solution was cooled, then poured into a mixture comprised of 200 ml of ether and 300 ml of water. The water layer was concentrated under vacuum and the 2-amino-1-propanol was removed by bulb to bulb distillation under high vacuum. The residue in 50 ml of thionyl chloride was refluxed for 0.5 hours then the volatiles were removed in vacuo. To the residue was added 150 ml of ethanol and 5 g of potassium carbonate. The mixture was refluxed for 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with three 50 ml portions of dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo. Ether was added to the residue and a brown solid was removed by filtration. The addition of hexane to the filtrate on chilling gave crystals which were recrystallized from ether-hexane to give 1.2 g of 2,3-dihydro-3-methyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine as orange crystals, mp 103.5°-105° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1([F:25])[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21](B(O)O)[C:15]=2[O:14]1>>[F:25][C:13]1([F:12])[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[C:18]([C:9]3[N:10]=[C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][N:4]4[N:8]=3)[C:16]=2[O:17]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: Clc1nc2c(Br)cccn2n1
Product: FC1(F)Oc2cccc(-c3nc4ccccn4n3)c2O1

Procedure:
2-Chloro-8-(2,2-difluoro-1,3-benzodioxol-4-yl-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.71 g, 3.0 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (0.64 g, 3.2 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.84 (d, J=7.5 Hz, 1H), 7.78-7.67 (m, 2H), 7.33-7.23 (m, 2H), 7.36 (d, J=6 Hz, 1H), MS=310 (MH)+. 243b) 7-[8-(2,2-difluoro-1,3-benzodioxol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2,2-difluoro-1,3-benzodioxol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (0.78 g, 2.5 mmol), and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.99 g, 3.778 mmol), in a manner analogous to Example 2d. Product was isolated as a foam (0.78 g, 58%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6 Hz, 1H), 7.61 (d, J=6 Hz, 1H), 7.51-7.42 (m, 4H), 7.00-6.89 (m, 3H), 6.79 (s, 1H), 3.62-3.45 (m, 4H), 2.84-2.74 (m, 4H), 1.52 (s, 9H). MS=536 (MH)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH2:36]([O:35][C:34](=[O:43])[NH:33][CH2:32][CH2:31][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
In around-bottomed flask equipped with a mechanical stirrer, 4-hydroxyacetophenone (5.00 g, 36.7 mmol) was dissolved in toluene (122 ml), and triphenylphosphine (14.4 g, 55.1 mmol), and benzyl N-(2-hydroxyethyl)carbamate (10.8 g, 55.1 mmol) were added. The reaction mixture was cooled to about 0° C., and 1,1′-(azodicarbonyl)dipiperidine (13.9 g, 55.1 mmol) was added in one portion. The mixture was allowed to warm to room temperature, and after stirring for about ten minutes, an additional 122 ml of toluene and 122 ml of tetrahydrofuran were added to the thick orange solution. The mixture was stirred for an additional twenty-four hours, and the solids were filtered off. The filtrate was concentrated in vacuo and the resulting solid was purified by column chromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) to afford 9.68 g (84% yield) of the desired product as a white solid. LRMS ([M−1]−)=312.2.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1.[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1)=[O:29]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1)c1cc(Cl)cnc1Cl
Yield: 44.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 180 using Compound 182 (50 mg, 0.16 mmol) and 2,5-dichloro-nicotinoyl chloride (36 mg, 0.17 mmol) to provide 183 (35 mg, 45% yield) as a dark solid. LC-MS (M+H=496, obsd.=496).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([N:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[CH:39][N:40]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 27.8 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.936 g, 2.68 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 10.8 mmol) were added to toluene (5 ml) and heated to 100° C. 1 hour. Diethyl ether (10 ml) was added causing a solid to precipitate. This solid was collected by filtration, washed with diethyl ether, and dried in vacuo yielding 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a yellow solid (0.42 g, 28%). MS (APCI); M++1: Calc'd 564.29. Found 564.3.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:5]1[CH:4]1[CH2:3][CH2:2][NH:1][CH2:9][CH2:8]1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccccc1O
Product: c1ccc2oc(C3CCNCC3)nc2c1

Procedure:
The title compound was prepared from isonipecotic acid and 2-aminophenol using the method described in Description 14. MH+ 203.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:5].C([NH2:26])C1C=CC=CC=1>CO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH2:26])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CC(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NCc1ccccc1
Solvent: CO
Product: CC(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 33.3 g of N-benzyl-3-(4'-fluoro-4-biphenylyl)-1-butylamine [obtainable by reacting 3-(4'-fluoro-4-biphenylyl)-butanol with SOCl2 ] to give 1-chloro-3-(4'-fluoro-4-biphenylyl)-butane and reaction with benzylamine in 500 ml of methanol is hydrogenated over 8 g of 5% Pd-on-charcoal at 20° and normal pressure. After filtration and evaporation, 3-(4'-fluoro-4-biphenylyl)-butylamine is obtained. Hydrochloride, m.p. 222°-224°.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[C:14](#[N:16])[CH3:15].[H-].[Na+].CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([CH2:15][C:14]#[N:16])=[O:6]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A mixture of 43.8 g of ethyl 2,4-dichloro-benzoate and 8.2 g of anhydrous acetonitrile is added dropwise to a suspension of 6.1 g of 80% strength sodium hydride in 100 ml of anhydrous tetrahydrofuran in the course of about 1 hour under reflux. The mixture is heated at the boiling point under reflux for a further hour and cooled to room temperature and 150 ml of ether are added. The precipitate is filtered off with suction and dissolved in 50 ml of ice-water and the solution is acidified to pH=6 with 10% strength hydrochloric acid. The precipitate is filtered off cold with suction, rinsed with ice-water and dried in vacuo at 40° C. 12 g of 2,4-dichlorobenzoylacetonitrile of melting point 96°-98° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH3:21])[C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12]([CH3:21])=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C

Procedure:
A suspension of 4-fluorobenzamide (12.9 g) and ethyl 4-bromo-3-oxopentanoate (Chem Abs No. 36187-69-6; 5.24 g) in anhydrous toluene (120 ml) was heated at 140° C. for 19 h, using a Dean-Stark trap. The solution was allowed to cool, filtered, and the residual solid washed with toluene (30 ml). The combined filtrate and washings were concentrated in vacuo to give a brown oil, which was purified by Biotage flash chromatography on silica gel (90 g column), eluting with ethyl acetate:cyclohexane (5:95, 7.5:92.5, 10:90), to give thetitle compound as a yellow solid (2.98 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:20])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenyl)benzoic acid (100 mg, 0.2369 mmol) and morpholine (41 mg, 0.4712 mmol) were dissolved in methylene chloride (20 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (136 mg, 0.7094 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the title compound (80 mg, 0.1629 mmol, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: COc1ccccc1O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1OCC(=O)c1ccccc1

Procedure:
A mixture of 1 mole of 2-methoxyphenol and 1 mole of potassium carbonate in acetone is heated at reflux while adding 1 mole of alpha-bromoacetophenone. The mixture is refluxed for several hours to provide alpha-(2-methoxyphenoxy)acetophenone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][C:2]=1[NH2:8].Cl[CH2:10][CH:11]=O>C(O)C.C([O-])(O)=O.[Na+]>[N:8]1[CH:10]=[CH:11][N:1]2[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][C:2]=12
Reactant: O=CCCl
Reactant: Nc1ccnc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccn2ccnc2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To the solution of pyrimidine-2,4-diamine (3.0 g, 0.027 mol) in ethanol (90 mL) and aqueous NaHCO3 (2M, 20 mL) was added 2-chloroacetaldehyde (4.3 g, 0.055 mol). The mixture was stirred at 70° C. overnight. TLC showed the starting material disappeared. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3×30 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 1:5 petroleum ether/ethyl acetate to afford 199a as a white solid (2.2 g, 60%). MS: [M+H]+ 135.1.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH2:8]([C:3]1[N:4]([CH3:7])[N:5]=[CH:6][C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cn1ncc(Br)c1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Br)c1Cc1ccccc1
Temperature: 50 °C

Procedure:
(4-Bromo-2-methyl-2H-pyrazol-3-yl)-phenyl-methanol (0.50 g; 1.87 mmol) is treated with 3.0 ml TFA and Triethylsilane (1.49 ml; 9.36 mmol) and is heated to 50° C. for 16 hours. The product is purified via reversed phase chromatography under acid conditions.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:2]1[NH:10][N:11]=[N:12][C:1]=1[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cccc(-c2nn[nH]n2)c1
Temperature: 160 °C

Procedure:
A mixture of 3-cyanophenol (4.14 g, 34.75 mmol) (Aldrich), sodium azide (2.49 g, 38.23 mmol) (Aldrich) and ammonium chloride (2.05 g, 38.23 mmol) in N,N-dimethylformamide (30 mL) were heated to 160° C. for 18 hours. The reaction mixture was concentrated. The residue was purified by C18 column eluting with acetonitrile-water to give 3-(2H-tetrazol-5-yl)-phenol. (Yield 0.9 g, 16%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:21]2[N:17]([CH3:16])[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1cccn1C
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C#N)cc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5.0 g. (0.03 mole) of p-cyanobenzoyl chloride in 60 ml. of methylene chloride is added to a suspension of 40 g. of aluminum chloride in 30 ml. methylene chloride. The resulting mixture is added dropwise to a chilled solution of 5.0 g. (0.03 mole) of ethyl 1-methylpyrrole-2-acetate in 15 ml. of methylene chloride. The resulting mixture is stirred at room temperature for 20 minutes, and then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated, washed successively with N,N-dimethylaminopropylamine, 3N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo. The resulting solid, which separates from the oily residue on standing, is recrystallized from methanol to give pure ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate, m.p. 117°-120°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]([Br:17])([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc(S(C)(=O)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Mixture of 2-(4-Methanesulfonyl-phenyl)-propionic acid methyl ester (0.939 g, 0.3.88 mmol), N-bromosuccinimide (0.69 g, 3.88 mmol) and catalytic amount of benzoyl peroxide (0.01 g) in carbon tetrachloride (75 ml) was refluxed for 1 hour under nitrogen atmosphere, RM was cooled to room temperature and poured onto water (50 ml) under stirring, layer separated, organic layer was washed with water (2×25 ml). Removal of solvent gave the 2-Bromo-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (1.22 g) as white solid which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 3.08 (s, 3H), 3.82 (s, 3H), 7.78 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCO
Solvent: c1ccncc1
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
Compound 22 was prepared using the method described for the synthesis of compound 18. The reagents used were as follows, p-toluene sulphonyl chloride (170.4 g, 0.894 mol.), pyridine (400 ml) and 2-(2'-(2"-methoxy ethoxy)ethoxy)ethanol (148.7 g, 0.907 mol.) (Aldrich). The final product was a pale yellow liquid (122 g, 42%): 1H-NMR (CDCl3), d (ppm) 7.3-7.7 (m, 4H aromatic), 3.3-4.2 (m, 12H) 3.35 (s, 3H), 2.4 (s, 3H). Mass spectroscopy, m/e: 318 M+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([OH:15])=O)[NH:3]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:32](=[CH:33][CH:34]=1)[CH2:31][C:21]1([C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]1=[O:30])[CH2:20]2>>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:32](=[CH:33][CH:34]=2)[CH2:31][C:21]2([C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]2=[O:30])[CH2:20]3)=[O:15])[NH:3]1
Reactant: O=C(O)CNc1cccc2c1CC(=O)N2
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Product: O=C(CNc1cccc2c1CC(=O)N2)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
Essentially following the procedures described for Example 1, but using N-(2-oxo-2,3-dihydro-1H-indol-4-yl)glycine (described in Intermediate 8) in place of 3-phenylpropionic acid and (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 4) in place of (+)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, the title compound was obtained. MS: m/z=440 (M+1). HRMS: m/z=440.1750; calculated m/z=440.1717 for C25H22N5O3.