Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CCOC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: BrCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromopropan-1-ol (1.25 g, 9.0 mmol) and 3,4-dihydro-2H-pyran (2.04 ml, 22.5 mmol) in dichloromethane (50 ml) at 0° C. was added p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol). The reaction mixture was stirred at 0° C. for 15 min then warmed to room temperature and stirred for 2 h. The reaction was diluted with EtOAc and washed with water, sat NaHCO3, and brine then dried over MgSO4 and concentrated to afford 2-(3-bromopropoxy)-tetrahydro-2H-pyran as a light brown oil which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
To a solution of 1 g (4.7 mM) of [5-(3-thienyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and the precipitated crystal was filtered off, washed with water and recrystrallized from ethyl alcohol, to give 620 mg (yield 50%) of [5-(3-thienyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: O=P(O)(O)CCl
Reactant: NCCCCCCCCN
Solvent: O
Product: NCCCCCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (7.5 g, 58 mmoles) and 1.8-diaminooctane (50.0 g, 347 mmoles) were dissolved in water (130 cm3) and heated under reflux for 20 hours. The water was then removed and ethanol (250 cm3) added to the solid residue. The phosphonic acid was filtered off and dried. The crude yield was 13.3 g (90%). A sample was purified by recrystallization from water/ethanol to give N-(8-aminooctyl)-aminomethanephosphonic acid monohydrate as fine white solid having a melting point of 242° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[NH2:35].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:2]2[CH:3]=[C:4]([C:8]3[N:16]4[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]5[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=5)=[N:15]4)=[C:10]([CH3:30])[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:36]=[CH:37][C:38]=1[N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5ccc(N6CCOCC6)c(Cl)c5)c4)n3n2)cc(OC)c1OC
Temperature: 130 °C
Yield: 39.1 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 3-chloro-4-morpholin-4-ylaniline (21.7 mg, 0.102 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (11.4 mg, 0.12 mmol) was added 1,4-dioxane (1.5 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 130° C. for 30 minutes. After cooling to room temperature, removed solvent under reduced pressure and diluted residue in DMSO (1.0 mL). Filtered and injected (2×0.5 mL) on an Agilent reverse phase prep LC subjected to a gradient elution using acetonitrile (0.1% Formic acid):water (0.1% Formic acid) (10:90 to 90:10). Combined appropriate fractions and removed solvent under reduced pressure. Added methanol, dichloromethane and silica gel (100 mg) followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (30:70) to ethyl acetate:hexanes (90:10) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 7-{3-[(3-chloro-4-morpholin-4-ylphenyl)amino]phenyl}-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.020 g) as a yellow solid. 1H NMR (CDCl3): δ8.79 (s, 1H), 8.09 (dd, J=2.0, 1.9 Hz, 1H), 8.01-7.98 (m, 1H), 7.33 (dd, J=8.0, 7.9 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.15 (ddd, J=8.2, 2.3, 0.9 Hz, 1H), 7.02 (dd, J=8.6, 2.5 Hz, 1H), 6.95-6.93 (m, 3H), 6.90 (s, 1H), 5.95 (s, 1H), 3.88-3.86 (m, 4H), 3.84 (s, 9H), 3.01-2.98 (m, 4H) 2.60 (s, 3H). MS m/z 602 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCC=Cc1ccc(Br)cc1
Temperature: -78 °C

Procedure:
To a solution of ethyl trans-4-bromocinnamate [CAS 24393-53-1] (8 mL, 42.6 mmol) in anhydrous dichloromethane (150 mL) under N2 was added dropwise diisobutylaluminum hydride in dichloromethane (128 mL, 1M, 128 mmol) at −78° C. Following the addition, the mixture was allowed to warm from −78° C. to −30° C. over two hours. The mixture was then cooled back to −78° C. and aqueous 1 N HCl was added. The organic layer was separated, dried with MgSO4, filtered and concentrated under reduced pressure to provide the title compound, 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 214 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 2-chloro-3-methylbenzoic acid (25.0 g, 146 mmol), conc. sulfuric acid (2 mL) and methanol (160 mL) was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, was diluted with ethyl acetate and neutralized with 8N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure to give the title compound (18.0 g, 66%) as a pale-orange oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCCOCc1ccccc1
Reactant: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C1(OCCCCOCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
1 g (3.79 mmol) of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate dissolved in 5 ml of N,N-dimethylformamide is added dropwise to a suspension of 455 mg (11.4 mmol) of 60% sodium hydride in oil, precooled to 20° C. After stirring for 15 minutes, 2.77 g (11.4 mmol) of 4-benzyloxybutyl bromide are added and stirring is continued for 15 hours at room temperature. The reaction medium is hydrolysed with water and then extracted with ethyl acetate. The organic phase is washed three times with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue obtained is purified by chromatography on silica gel eluted with a heptane/ethyl acetate mixture, the polarity being increased from 100/0 to 90/00. 1.43 g of tert-butyl 3-(4-benzyloxybutoxy)-3-o-tolylazetidine-1-carboxylate are obtained in the form of a colourless oil in a yield of 80%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](/[C:11](/[S:25][CH3:26])=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:30]O>C(O)(=O)C.ClCCl>[CH2:1]([C:5]1[CH:10]=[C:9](/[C:11](/[S:25]([CH3:26])=[O:30])=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(/C(=C/c2cc(OC)c(OC)c(OC)c2)SC)n2nccc2n1
Reactant: OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1cc(/C(=C/c2cc(OC)c(OC)c(OC)c2)S(C)=O)n2nccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.50 g of the compound obtained in Example 12 was dissolved in 5 ml of acetic acid. To the solution was added 0.14 ml of 30% aqueous hydrogen peroxide solution, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with water, sodium bicarbonate solution and saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1→ethyl acetate→dichloroethane:methanol=10:1) and recrystallized from ethyl acetate-n-hexane. 0.38 g of the desired compound was obtained as crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH:40]([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:40]([CH3:49])[CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1)([CH3:36])[CH3:35]
Reactant: CC(Cl)C(=O)N1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OC(C)CN3CCCCC3)cc2)C(C)C)c1
Yield: 60.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-yl propan-1-one (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: [CH:1]1([N:7]([CH:32]([CH3:34])[CH3:33])[C:8](=[O:31])[C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[C:11]([O:29][CH3:30])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C>[CH:1]1([N:7]([CH:32]([CH3:34])[CH3:33])[C:8](=[O:31])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[C:11]([O:29][CH3:30])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C(O)c1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Cc1cc(OC)c(OC)c(OC)c1

Procedure:
The compound of Example 45 (800 mg, 1.81 mmol) in EtOH (20 mL) containing concentrated sulfuric acid (4 drops) is hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is dissolved in ethyl acetate and washed twice with aqueous NaHO3 solution and then with saturated aqueous NaCl solution. After drying (Na2SO4) the organic layer is filtered and concentrated in vacuo. Purification to give the title compound is carried out by chromatography of the residue on silica gel using mixtures of ethyl acetate and hexane as the eluents.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:40][C:41]2[N:46]=[C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([O:56]C)=[O:55])=[C:50]([O:58][CH3:59])[CH:49]=3)[C:44]([F:60])=[CH:43][N:42]=2)[CH:33]=[CH:34][C:35]=1[C:36]([O:38]C)=[O:37].[OH-].[Na+]>>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([NH:40][C:41]2[N:46]=[C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([OH:56])=[O:55])=[C:50]([O:58][CH3:59])[CH:49]=3)[C:44]([F:60])=[CH:43][N:42]=2)=[CH:31][C:30]=1[O:29][CH3:28])([OH:38])=[O:37]
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(OC)c3)n2)cc1OC
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Nc2ncc(F)c(Nc3ccc(C(=O)O)c(OC)c3)n2)ccc1C(=O)O
Yield: 70 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (30 mg, 0.06 mmol) and NaOH (200 mg, 5 mmol) gave N2,N4-bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (18 mg, 64%) as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10](C)[C:11](=O)OC(C)(C)C.[ClH:19].O1CCOCC1>ClCCl.C(O)C.O>[ClH:19].[CH3:11][NH:10][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: CN(C(=O)OC(C)(C)C)N1Cc2ccccc2C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNN1Cc2ccccc2C1
Temperature: 25 °C
Yield: 81 %

Procedure:
The compound (126 g) obtained in step B was dissolved in a mixed solvent of dichloromethane (150 ml) and ethanol (150 ml). A 4N hydrochloric acid-dioxane solution (500 ml) was added with stirring at room temperature and the mixture was stirred at the same temperature for 5 hr. The reaction mixture was diluted with dichloromethane and water and the aqueous layer was extracted. An ice-cooled aqueous sodium hydroxide solution was added to the ice-cooled aqueous layer to give a strongly-alkaline aqueous layer. The aqueous layer was extracted with dichloromethane. The organic layer was dried over potassium carbonate, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure. The obtained oil was dissolved in diethyl ether (500 ml), and 4N hydrochloric acid-dioxane solution (140 ml) was added with stirring under ice-cooling to allow precipitation of a solid. This was filtered, washed with diethyl ether, and dried under reduced pressure to give the title compound (75.89 g, yield 81%) as a gray solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=3[Cl:34])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:16][C:17]2[CH:18]=[C:19](/[C:25](/[O:35][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:26]/[C:27]3[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=3[Cl:34])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)Cc2ccccc2)cc1OC1CCCC1

Procedure:
The compound was obtained starting from phenyl-acetyl chloride and 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethanone following the procedure of Example 7.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=O)[N:5]=[N:4][N:3]=1.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CNC
Reactant: CCOC(=O)Cn1nnnc1S
Solvent: CCO
Product: CN(C)C(=O)Cn1nnnc1S
Reaction time: 168 h

Procedure:
Ethyl 5-mercapto-1H-tetrazol-1-ylacetate (1.5 g) in ethanol (10 ml) and 33% dimethylamine in ethanol (6 ml) were mixed and set aside for seven days. Further 33% dimethylamine in ethanol (6 ml) was added and the solution left for 7 more days then evaporated to dryness in vacuo. The residue was dissolved in water (50 ml), adjusted to pH 1.8, and concentrated to ca 20 ml in vacuo. The solution was cooled in ice and the crystalline product collected, 0.94 g (63.0%), m.p. 204°-205°; ε [(CD3)2CO] 3.02 and 3.28 (6H, 2×s --N(CH3)2), 5.35 (2H,s, --CH2CO--), 7.7 (1H,bs, --SH). Found: C, 32.21; H, 5.01; N, 37.63; S, 16.99. C5H9N5OS requires: C, 32.08; H, 4.85; N, 37.41; S, 17.13%.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:18][CH3:19])(=[N:11]C(=O)C(F)(F)F)=[O:10])=[CH:5][CH:4]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@H:28]([CH3:33])[C:29]([CH3:32])([OH:31])[CH3:30])[C:24]([C:34]([F:37])([F:36])[F:35])=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C.[Cl-].[Na+].CO>[CH2:18]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:21]2[N:26]=[C:25]([NH:27][C@H:28]([CH3:33])[C:29]([OH:31])([CH3:30])[CH3:32])[C:24]([C:34]([F:37])([F:35])[F:36])=[CH:23][N:22]=2)=[CH:8][CH:7]=1)(=[NH:11])=[O:10])[CH3:19]
Reactant: CCS(=O)(=NC(=O)C(F)(F)F)c1ccc(N)cc1
Reactant: C[C@@H](Nc1nc(Cl)ncc1C(F)(F)F)C(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CO
Product: CCS(=N)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(N[C@H](C)C(C)(C)O)n2)cc1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
0.36 ml of 4N solution of hydrogen chloride in dioxane was added to 400 mg (1.43 mmol) of (RS)-S-(4-aminophenyl)-S-ethyl-N-(trifluoroacetyl)sulfoximide and 405 mg (1.43 mmol) of (R)-3-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-2-methyl-butan-2-ol in 7.0 ml acetonitrile and stirred for 4.5 hours at 60° C. The mixture was evaporated to dryness. 25.0 ml methanol and 788 mg (5.70 mmol) of potassium carbonate were added and it was stirred for one hour at room temperature. It was diluted with saturated sodium chloride solution and was extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. 620 mg (1.43 mmol) of the raw product was obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CO.[Pd]>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]2)[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CC1CCC(=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCC(CC(=O)O)CC2)CC1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To 2-(4-oxocyclohexyl)acetic acid (0.576 g, 3.7 mmol) and tert-butyl piperazine-1-carboxylate (0.700 g, 3.7 mmol) in MeOH, was added Pd on carbon (80 mg), and the resultant reaction mixture was stirred under hydrogen atmosphere overnight. The catalyst was removed via filtration and the solvent was removed under reduced pressure to afford the acid as white solid (1.2 g. 99%).
Reaction SMILES: P([O-])([O-])([O-])=O.[B+3].[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[NH3:25]>>[OH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]#[N:25].[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10]
Reactant: N
Agent: CCCCCCCCOC(=O)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Agent: [B+3]
Product: N#Cc1ccccc1O
Reaction time: 0 h

Procedure:
A reaction tube having an inside diameter of 5 cm was filled with 293 g of a supported catalyst composed of 3.75% by weight of boron phosphate (P2O5 /B2O3 mole ratio=1) deposited on an alumina carrier spherical alumina carrier having a pore diameter of about 1 micron. Octyl salicylate and ammonia were introduced into the reaction tube at a rate of 108.9 g/hr and 148 g/hr, respectively, and reacted in the vapor phase at 415° C. The mole ratio of ammonia to octyl salicylate in the gaseous mixture was 20:1, and the contact time was 11 seconds. When the reaction was continued for 8 hours, 375.3 g of o-hydroxybenzonitrile was obtained from 871.2 g of octyl salicylate. The yield was 90.5% by weight. Gas-chromatographic analysis showed that only 2.6% by weight of phenol was formed as a by-product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH2:27][O:26]1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:34][C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[CH2:25][O:26][CH2:27]4)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc2c(c1)COC2
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)COC4)nc21

Procedure:
A mixture of 0.614 g of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 0.389 g of the compound of formula (III), (1,3-dihydro-5-isobenzofuranyl)amine, is heated in 10 ml of acetic acid at reflux for 20 min; the reaction medium is concentrated by half under vacuum, then taken up in a mixture of ethyl acetate and water and brought to pH 9 with a saturated NaHCO3 solution. After separating by settling, the organic phase is washed with water and then with a saturated NaCl solution, dried over sodium sulfate and then evaporated to dryness. The product is purified by flash chromatography on silica with a gradient of 0 to 50% of ethyl acetate in dichloromethane. 0.140 g of expected product is obtained in the form of a yellow solid.
Reaction SMILES: [NH2:1]C1C=CC(C2CCC(C(OC)=O)C2)=CC=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOC(C)=O>CCO>[NH2:1][C:20]1[CH:19]=[CH:18][C:17]([CH2:23][CH2:24][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Reactant: COC(=O)C1CCC(c2ccc(N)cc2)C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccc(N)cc1)C(=O)OCC
Yield: 10 %

Procedure:
Following the general procedure of Intermediate 84 except that diethyl (3-phenylpropyl)malonate (J. Med. Chem., 2004, 47(12), 3282) was used in place of methyl 3-phenylcyclopentanecarboxylate, nitration and reduction (using EtOAc as solvent in place of EtOH) gave the title compound (purified by chromatography, eluting with 10-50% EtOAc/Isohexane); 1H NMR δ 1.17 (t, 6H), 1.42-1.53 (m, 2H), 1.69-1.78 (m, 2H), 2.40 (t, 2H), 3.45 (t, 1H), 4.07-4.16 (m, 4H), 4.81 (s, 2H), 6.48 (d, 2H), 6.81 (d, 2H); MS m/e MH+ 294.