Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH2:20]([NH:23][C:24](=[O:27])[O:25][CH3:26])[C:21]#[CH:22]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[N:5]=[C:6]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:7]=[CH:8][C:9]=2[C:10](=[O:16])[C:11]=1[C:12](=[O:13])[NH:14][CH3:15]
Reactant: C#CCNC(=O)OC
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CCNC(=O)OC)nc21

Procedure:
A suspension of 0.8 g (2.85 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 22 ml of a DMF/Et3N (v/v; 2.2/1) mixture is placed in a 10 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 0.98 g of methyl (prop-2-yn-1-yl)carbamate (8.66 mmol), 0.076 g of CuI (0.40 mmol) and 0.139 g of bis(triphenylphosphine)palladium(II)dichloride (0.20 mmol) are successively added.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][N+:10]([O-])=O)[O:6][CH2:5][CH2:4][O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH2:10])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCC[N+](=O)[O-])OCCO1
Agent: [Pd]
Solvent: CO
Product: CC1(CCCN)OCCO1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a mixture of 2-methyl-2-(3-nitro-propyl)-[1,3]dioxolane (1.80 g, 10.27 mmol) and Pd/C 10% (176 mg) in dry MeOH (35 mL) was stirred at rt under atmospheric H2 for 11 h. The reaction mixture was then filtered and concentrated under reduced pressure to give the title compound as a colorless oil. LC-MS-conditions 02: tR=0.25 min; [M+H]+=146.41.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][C:16]([N:18]([CH2:32][CH3:33])[CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:32]([N:18]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:16](=[O:17])[O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:33]
Reactant: CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2.5 ml) was added at 0° C. to a solution of tert-butyl 4-((benzyloxycarbonyl)(ethyl)-amino)piperidine-1-carboxylate (1.5 g, 414 mmol, 1.0 eq) in DCM (10 ml) and the mixture was stirred for 2 hours at RT. After monitoring by TLC, the reaction mixture was concentrated under reduced pressure and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (1.51 g, 3.1 mmol, Intermediate 10: step a) was added 1,4-dioxane (50 mL) followed by activated manganese dioxide (1.31 g, 15.1 mmol) and the reaction mixture was heated to reflux. After 1 hour, the contents were filtered while still hot through a pad of Celite® and rinsed with THF. The resulting light yellow solution was concentrated and chromatographed on silica gel (10% acetone-hexane increasing to 25% acetone) to provide the title compound as a light yellowish amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+].C[O-].[Na+].CO>ClCCl.CO>[CH3:8][C:7]1[C:2]([CH:1]=[O:18])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(C)c(C)c1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(C=O)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
In dichloromethane (15.0 ml), 2,3,5-trimethyl-pyridine (1.29 g) was dissolved. The reaction solution was cooled to 0° C. and added with meta-chloroperbenzoic acid (2.53 g), followed by stirring at room temperature for 1.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in dichloromethane (25.0 ml). The reaction solution was added with trifluoroacetic anhydride (2.8 ml) and subjected to thermal reflux for 3.5 hours. After the reaction solution had been cooled to room temperature, the solvent was distilled off. The residue obtained was dissolved in methanol (60.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution to adjust to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent had been distilled off, the residue was added with distilled water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in chloroform (30.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (6.10 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.14 g) as a yellow oily substance.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:23]=[CH:13][CH:12]=[CH:4][N:3]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.071 g, 0.16 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 5% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.65 (s, 2 H) 7.25 (d, J=5.15 Hz, 1 H) 7.45 (s, 1 H) 7.59 (m, 3 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=7.72 Hz, 2 H) 8.16 (t, J=7.72 Hz, 1 H) 8.24 (d, J=5.15 Hz, 1 H) 8.72 (d, J=5.51 Hz, 1 H) 14.10 (s, 1 H) 14.87 (s, 1 H). MS (ESI−) m/z 452(M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([NH:6][C@@H:7]2[CH2:11][C@H:10]([CH2:12][OH:13])[CH:9]=[CH:8]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[CH2:20](O)CC>[Ni]>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([C@@H:7]3[CH2:8][CH2:9][C@H:10]([CH2:12][OH:13])[CH2:11]3)[CH:20]=[N:17][C:4]=2[CH:3]=1
Reactant: CCCO
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@H]1C=C[C@@H](CO)C1
Agent: [Ni]
Product: OC[C@H]1CC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of (±)-cis-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol (5.00 g, 16.5 mmol) and Raney nickel (Aldrich, slurry in water, 500 mg wet) in n-propanol (250 mL) was shaken under hydrogen (50 psi) on a Parr shaker for 2 hours. The catalyst was filtered off, solvent evaporated in vacuo, and the residue dissolved in triethylorthoformate(300 mL)-methanesulfonic acid (200 mg). After 18 hours, the solution was concentrated to a syrup which was dissolved in 1N hydrochloric acid (40 mL) and stirred at ambient temperature overnight. The pH was adjusted to 7 with 1N sodium hydroxide and the solution extracted with chloroform (3×50 mL). The contents of the dried (sodium sulfate) chloroform solution was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as a colorless oil which solidified from ethyl acetate-hexanes to give white powder (3.98 g, 85%). m.p. 142°-145° C.; 1H-NMR(DMSO-d6) and mass spectrum(CI) consistent with structure.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:3][C:4]([NH:20][CH2:19][CH2:18][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCN
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]-S-methylisothiourea with excess ethylenediamine at room temperature afforded the title compound m.p. 164°-167° (from acetonitrile-ethanol). (Found: C, 46.9; H, 6.5; N, 35.1; S, 11.1% C11H19N7S requires: C, 47.0; H, 6.8; N, 34.8; S, 11.4%).
Reaction SMILES: O([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)C1C=CC=CC=1.[NH2:17][CH2:18][C:19]1[CH:20]=[C:21]([CH2:27][CH:28]([O:34][CH:35]([CH3:37])[CH3:36])[C:29]([O:31]CC)=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH:35]([O:34][CH:28]([CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([CH2:18][NH:17][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:8]3[CH:16]=[CH:15][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:15]=2)[CH:20]=1)[C:29]([OH:31])=[O:30])([CH3:36])[CH3:37]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using 4-phenoxybenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(4-phenylbenzoyl)amino]methylphenyl)propanoic acid was obtained in the same method as in Example 19d) and then in Example 19e)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[O:35]=[S:36]1(=[O:54])[CH2:41][CH2:40][C:39]([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH3:51])[C:48](Br)=[C:47]([CH3:53])[CH:46]=2)([OH:42])[CH2:38][CH2:37]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:48]2[C:49]([CH3:51])=[CH:50][C:45]([O:44][CH2:43][C:39]3([OH:42])[CH2:40][CH2:41][S:36](=[O:35])(=[O:54])[CH2:37][CH2:38]3)=[CH:46][C:47]=2[CH3:53])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1Br
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(O)CCS(=O)(=O)CC6)cc5C)ccc(F)c43)ccc21
Temperature: 110 °C
Reaction time: 3 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (190 mg), 1,1-dioxo-4-((4-bromo-3,5-dimethylphenoxy)methyl)tetrahydro-2H-thiopyran-4-ol (150 mg), K3PO4 (250 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (21 mg) are suspended in N,N-dimethylformamide (2 mL) and water (100 μL). The mixture is purged for 10 minutes with argon. Palladium-(II)-acetate (6 mg) is added, the vial is sealed and the mixture is stirred at 110° C. for 3 hours. After cooling to room temperature the mixture is partitioned between diethylether and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petrole ether/ethyl acetate 50:50→0:100) to give the title compound. Yield: 90 mg; LC (method 8): tR=0.53 min; Mass spectrum (ESI+): m/z=625 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[OH:11].[C:14](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:14][O:11][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH:12]=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C=O)c2c(c1O)CCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C)cc(C=O)c2c1CCC2
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a stirred suspension of 6-Methyl-7-hydroxy-indan-4-carbaldehyde (5 gm, 0.0284 mole) and Potassium carbonate (4.7 gm, 0.0340 mole) in dimethyl formamide, Methyl iodide (2.2 ml, 0.0312 mole) was added at 0° C. The reaction mixture was stirred at 25-30° C. for 4 hours, then water (200 ml) was added and extracted with Ethylacetate (2×100 ml). The Ethylacetate layer was dried over Sodium sulphate and evaporated to give a crude mass which was purified by column chromatography using Ethyl acetate:Hexane (10:90) as a mobile phase. The fractions were distilled under vacuum to give 4.8 gm of desired product as viscous oil.
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=[C:26]([CH3:34])[CH:25]=4)=[CH:18][CH:17]=3)[CH2:12]2)[CH:10]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH2:37][CH:10]1[CH2:9][NH:8][CH2:36][CH2:35][C:11]21[O:15][N:14]=[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=1)[CH2:12]2
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCC12CC(c1ccc(OCc3cc(C)nc4ccccc34)cc1)=NO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC1CNCCC12CC(c1ccc(OCc3cc(C)nc4ccccc34)cc1)=NO2
Reaction time: 1 h
Yield: 139.6 %

Procedure:
The intermediate 6-methoxycarbonylmethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-1-oxa-2,8-diaza-spiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester from Example 33 (0.43 g, 1.87 mmol) was dissolved in methylene chloride (12 mL) and TFA (12 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred for 1 h and concentrated in vacuo to give {3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-1-oxa-2,8-diaza-spiro[4.5]dec-2-en-6-yl}-acetic acid methyl ester (1.2 g, 100%) crude product. MS found: (M+H)+=460.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[F:27])[O:15]C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=2[F:27])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=C1CCN(Cc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of the 1-benzyl-4-[(2-fluoro-4-trifluoromethyl-phenyl)-methoxy-methylene]-piperidine (9.9 g, 26.1 mmol) in acetone (100 mL) and conc. HCl (10 mL) in a sealed vessel was heated at 60° C. for 2 hours. Upon cooling to room temperature the solution was basified with the addition of 3 N NaOH. The resulting mixture was extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and evaporated yielding 8.8 g (92%) of the desired product as a solid.
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][NH:5]1.I[CH3:15]>CN(C=O)C.CCOC(C)=O>[CH3:15][N:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3]
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiH (10 mg, 1.3 mmol) was added to the solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, iodomethane (0.08 mL, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to room temperature. After stirring for 3 days, the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product. 1H NMR (400 MHz, CDCl3) δ 8.17 (dd, 1H), 7.58 (dd, 1H), 6.27 (t, 1H), 3.91 (s, 3H), 3.61 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[O:9][C:8](=[O:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH:4]1[O:9][C:8](=[O:10])[CH:7]=[C:6]([OH:11])[CH2:5]1
Reactant: COC(OC)c1cc(O)cc(=O)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(OC)C1CC(O)=CC(=O)O1

Procedure:
6-Dimethoxymethyl-4-hydroxypyran-2-one may be reduced in methanol with hydrogen in the presence of a palladium on carbon catalyst to give 6-dimethoxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one;
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.I[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)CCI
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCCC(C)C)cc(C)cn12
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
2.0 g (8.5 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A were initially charged in 122.3 ml of DMF, and 1.23 ml (9.4 mmol) of 1-iodo-3-methylbutane and 6.12 g (18.8 mmol) of caesium carbonate were added. The mixture was stirred at 60° C. for 40 min. The reaction mixture was cooled to RT, 900 ml of water were added and the mixture was stirred at RT for 1 h. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 2.25 g (84% of theory; purity 97%) of the title compound.
Reaction SMILES: N[C:2]1[NH:10][C:9]2[N:8]=[CH:7][N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[C:4](=[O:18])[N:3]=1.N([O-])=[O:20].[Na+]>C(O)(=O)C.O>[CH2:11]([N:6]1[C:5]2[C:4](=[O:18])[NH:3][C:2](=[O:20])[NH:10][C:9]=2[N:8]=[CH:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a mixture of 2-amino-7-benzyl-3,7-dihydro-6H-purin-6-one (25.0 g, 0.104 mol) in acetic acid (750.0 mL) and water (50.0 mL) at 55° C. was added a solution of sodium nitrite (28 g, 0.41 mol) in water (50 ml) dropwise. After the addition, the mixture was continued to stir for about 30 min until no starting material was left and then cooled to room temperature. The reaction mixture was concentrated to about ⅓ of its original volume, then diluted with 250 ml water. The precipitate formed was collected by filtration to provide the desired product (20 g, 79.7%). LCMS calculated for C12H11N4O2(M+H): 243.1. found: 243.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:33]5[CH:32]=[CH:31][C:30]([F:29])=[C:35]([F:36])[CH:34]=5)=[CH:3][C:4]([C:25]([F:27])([F:28])[F:26])=[CH:5][C:6]=4[N:7]=3)[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncc(Cl)cc5Cl)CC4)[nH]c23)cc1F

Procedure:
The reaction of 4-bromo-2-[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (99 mg, 0.2 mmol, Example 9) and 3,4-difluorophenylboronic acid (40 mg, 0.25 mmol, Aldrich) under the conditions of Example 10 gave the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 528 (M+1).
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH:23]([CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)cc(CNc3ccccc3)c2OC1C(F)(F)F
Temperature: 90 °C
Yield: 87.8 %

Procedure:
A mixture of ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.14 g, 0.32 mmole) and aniline (0.03 mL, 0.32 mmole) was dissolved in anhydrous DMF (2 mL), the solution was warmed to 90° C. and treated with K2CO3 (0.05 g, 0.39 mmole). The reaction was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite. The filtrate was condensed to give an oil. The oil was purified by flash chromatography (silica gel) with 70% methylene chloride in hexane to give a light yellow oil (0.11 g, 88%): GCMS m/z 391.00 (M+). 1H NMR (CDCl3/400 MHz) 7.70 (s, 1H), 7.19 (m, 3H), 6.94 (s, 1H), 6.74 (m, I1H), 6.65 (m, 2H), 5.77 (q, 1H, J=7.0 Hz), 4.33 (m, 4H), 4.18 (brs, 1H), 2.25 (s, 3H), 1.36 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
14.6 g (0.045 mol) of ethyl 7,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 59 ml of acetic acid, 59 ml of water and 5.9 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.