Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1>O1CCOCC1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:48]1[CH:49]=[CH:50][C:45]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][C:2]=2[C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:46][CH:47]=1
Reactant: Brc1ccncc1
Reactant: O=Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccccn3c2-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
0.2 g (0.9 mM) 4-imidazo[1,2-a]pyridin-2-ylbenzaldehyde (prepared as described by Sundberg et al.; J. Heterocyclic Chem., 25, 129, 1988) is dissolved in 5 mL of Dioxane. To this is added CsCO3 (1.1 eq), palladium acetate (8 mol %), triphenyl phosphine (16 mol %), triethylamine (2 eq) and 4-bromo-pyridine (1.4 eq). The reaction mixture is heated (microwave) for 45 min at 100° C. The reaction mixture is cooled to RT, diluted with DCM. The organic layer is washed with water, dried and concentrated. The crude product purified by column chromatography to obtain the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.[Br:31]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:15][C:8]1[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 58.2 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylate (411 mg), N-bromosuccinimide (NBS) (214 mg), 2,2'-azobis(isobutyronitrile) (10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (10:1, v/v), ethyl 2-bromomethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (285 mg, 58%) was obtained and recrystallized from ethyl acetate/hexane.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][C:16]2[N:12]([CH:13]=[CH:14][N:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38]C(O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl>[C:29]([O:33][C:34](=[O:35])[NH:36][CH:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38][C:6](=[O:7])[N:8]1[CH2:17][C:16]2[N:12]([CH:13]=[CH:14][N:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2-n2ccnc2C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2ccnc2C1)Cc1cc(F)c(F)cc1F

Procedure:
4H,6H-3,5,10b-Triaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester was deprotected using trifluoroacetic acid and the resulting salt was coupled with (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid using HOBT, EDC and DIPEA to afford [3-oxo-3-(4H,6H-3,5,10b-triaza-benzo[e]azulen-5-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[NH:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][N:9]3[C:5]4[C:6](=[O:8])[CH2:7][N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]=4[CH:11]=[CH:10]3)[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: CN1CC(=O)c2[nH]ccc2S1(=O)=O
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 79.7 %

Procedure:
A suspension of 200 mg (1 mmol) of Compound 12, 385 mg (1.5 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and 207 mg (1.5 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby 335 mg of the title compound were obtained (yield: 80%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH:9]=[C:10]1[C:15](=[O:16])OC(C)(C)OC1=O.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[N:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:9]=[CH:10][C:15]2=[O:16]
Reactant: COc1nccc(NC=C2C(=O)OC(C)(C)OC2=O)c1Br
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ncc2c(=O)cc[nH]c2c1Br
Temperature: 250 °C

Procedure:
A two neck RBF equipped with an air condenser was charged with 5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture was heated at 250° C. for 30 min under nitrogen atmosphere after which it was cooled to RT, diluted with hexane and filtered to obtain a dark solid. The crude product was refluxed in hexane for 30 min and filtered to obtained 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1H NMR (DMSO-d6): δ 4.06 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.77-7.68 (m, 5H), 7.84 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 8.67 (d, J=6.9 Hz, 1H), 10.38 (s, 1H), 12.79 (br s, 1H); MS (m/z): 540.92 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)N[N:8]=[CH:7]2.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.C[N:23](C=O)C>[Cl-].[Na+].O>[Br:3][C:4]1[CH:5]=[C:6]2[CH:10]=[CH:11][N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:7]2=[N:23][CH:12]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (60% suspension in oil, 0.305 g, 7.63 mmol) was added to a stirred solution of 5-bromo-7-azaindole 24 (1.00 g, 5.08 mmol) in DMF (10 mL). After the mixture was stirred for 30 min, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl; 1.35 mL, 7.63 mmol) was added. The mixture was stirred for 2.5 days and poured into brine and extracted with AcOEt. The organic layer was washed with brine twice, dried (MgSO4), and concentrated. The residue was purified by means of SGC with hexane:AcOEt as eluent to afford 51 (1.50 g, 90%) as a tan syrup. 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.94-0.99 (m, 2H), 3.53-3.61 (m, 2H), 5.71 (s, 2H), 6.53 (d, J=0.36 Hz, 1H), 7.42 (d, J=0.36 Hz, 1H), 8.09 (d, J=0.22 Hz, 1H), 8.42 (d, J=0.22 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[Br-].[Na+].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]2=[O:14])[CH2:23][CH2:24]1
Reactant: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cn(CCCCN2CCN(Cc3ccc(Cl)cc3Cl)CC2)c(=O)[nH]c1=O
Yield: 33.4 %

Procedure:
1-(4-Chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione (0.69 mmol, 0.15 g), 1-(2,4-dichlorobenzyl)piperazine (0.62 mmol, 0.15 g), sodium bromide (3.46 mmol, 0.36 g) and diisopropylethylamine (6.92 mmol, 0.89 g) were heated in N-methylpyrrolidinone (0.6 ml) at 120° C. for 5 hours. The reaction mixture was then allowed to cool, the suspension was filtered with suction, and the filtrate was concentrated. The residue was then then taken up in ethyl acetate and washed with saturated brine. The organic layer was dried, filtered to remove the desiccant and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel (eluent: methyl tert-butyl ether/methanol (0-100%), resulting in 88.0 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:33][CH2:34][CH3:35])=[C:25]([CH:32]=2)[O:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:33][CH2:34][CH3:35])=[C:25]([CH:32]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:17][CH:16]=1
Reactant: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of methyl 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetate (1.16 g), tetrahydrofuran (4 mL) and methanol (4 mL) was added 1N aqueous sodium hydroxide solution (4.5 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.01 g, 90%) of 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-propylphenoxy]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:17][CH2:18][C:19]([CH3:25])([OH:24])[C:20]([F:23])([F:22])[F:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(Cl)(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:19]([OH:24])([CH3:25])[CH2:18][NH:17][C:13]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=1)=[O:15]
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: CC(O)(CN)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(O)(CNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate A) (397 mg, 1.392 mmol), 3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (250 mg, 1.392 mmol) and HATU (529 mg, 1.392 mmol) were dissolved in DMF (10 ml) and stirred at RT for 2 min. 4-Methylmorpholine (0.413 ml, 4.18 mmol) was added and stirring continued at RT for 3 h. The reaction mixture was poured onto ice/water (100 ml) and extracted with EtOAc (250 ml). The organic extract was washed with sat NH4Cl solution (˜50 ml), dried over MgSO4 and concentrated in vacuo to give a pale brown oil. The oil was dissolved in CHCl3 (˜3 ml) and loaded onto a 24 g ISCO (silica) column eluting with iso-hexane:EtOAc to afford the title product; LC-MS Rt=1.46 mins; [M+H]+ 410.1, Method 2minLC_v002. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, b s), 6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s). 19F NMR (400 MHz, DMSO-d6) δ −62.71 (CF3, s), −80.48 (CF3, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])[C:9](=[O:16])[CH:8]=[CH:7]1)=[O:4].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([OH:16])[CH:10]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])=[O:4]
Reactant: CC/C=C\CC1C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC/C=C\CC1C(O)CCC1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 180 mg quantity of 4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone and 90 mg of sodium borohydride are dissolved in 20 ml of methanol, and the solution is refluxed at 80° C. for one hour. The reaction mixture is thereafter cooled to room temperature, and 20 ml of acetic acid is added to the mixture. The resulting mixture is stirred for 30 minutes and then concentrated at reduced pressure. The concentrate is distilled in a vacuum, giving 3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (3), R2 =CH3) in a yield of 94%, b.p. 63°-67° C./0.01 mm Hg.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)[CH:8]=[CH:9][CH:10]=1)#[N:4].OO.C(O)(=[O:33])C>O>[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)[CH:8]=[CH:9][CH:10]=1)(=[O:33])[NH2:4]
Reactant: CC(=O)O
Reactant: Cc1[nH]n(Cc2cccc(C#N)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]n(Cc2cccc(C(N)=O)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A mixture of potassium hydroxide (0.7 g, 9.9 mmol) in water (75 ml) was stirred in an ice-bath for 30 minutes and 1-(3-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (1.1 g, 3.3 mmol), followed by 30% hydrogen peroxide (1.7 ml, 16.5 mmol) were added. The mixture was slowly warmed to room temperature and stirred for 24 hours. The mixture was chilled in an ice-bath and neutralized with acetic acid. The product was collected by filtration and washed with water, ethanol and ether. The product was recrystallized from DMF to afford 0.87 g (73%) of 1-(3-carbamoylphenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. >300° C. when dried at 120° C. for 24 hours in high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C(Cl)(=O)C(Cl)=O.[NH3:17]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:17])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: N
Reactant: Cn1cc(Br)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a suspension of 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (Matrix Scientific, Columbia, S.C.; 390 mg, 1.91 mmol) in 5 mL of DCM at RT was added oxalyl chloride (2.0 M solution in DCM, 1.912 mL, 3.82 mmol) followed by 3 drops of DMF. After stirring at RT for 30 min, the mixture was concentrated under reduced pressure. The remaining off white solid was cooled with an ice bath, NH3 (0.5 M solution in 1,4-dioxane, 15.3 mL, 7.65 mmol) was added. After stirring at RT for 30 min, the mixture was diluted with 50 mL of EtOAc and washed with 2×15 mL of water. The organic layer was dried over Na2SO4 and concentrated to give 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (329 mg, 85% yield) as a brown crystalline solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (1H, br.), 7.08 (1H, d, J=1.8 Hz), 7.01 (1H, br.), 6.86 (1H, d, J=1.8 Hz), 3.80 (3H, s). m/z (ESI, +ve) 202.9/204.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:44](Cl)=[O:45].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([O:25][C:44](=[O:45])[C:43]1[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=[C:41]([C:40]([F:39])([F:54])[F:55])[CH:42]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69.3 %

Procedure:
A solution of (1R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 4; 0.98 g, 2.25 mmol), triethylamine (0.6 ml), N,N-dimethylaminopyridine (100 mg) and 3,5-bis(trifluoromethyl)benzoyl chloride (0.6 ml, 3.33 mmol) in dry dichloromethane (10 ml) was stirred at room temperature for 6 days. The reaction mixture treated with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 5-30%) to give the title compound (1.05 g, 69%).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([N:38]([CH3:39])[CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Yield: 164.2 %

Procedure:
1.04 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.426 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-N,N,2-trimethylpropionamide were stirred at 190-200° C. for 60 minutes. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (85:15:1). The desired fraction was collected; the residue was dissolved in 10 ml of ethyl acetate; 1.5 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration under reduced pressure. The residue was recrystallized from acetone to yield 0.823 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[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:17])[N:5]=2.[CH3:25][O:26][CH2:27][C:28]([CH3:32])([OH:31])[C:29]#[CH:30]>CN(C)C=O.C(N(CC)CC)C.[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>[ClH:17].[NH2:1][C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[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]([C:30]#[C:29][C:28]([OH:31])([CH3:32])[CH2:27][O:26][CH3:25])[N:5]=2
Reactant: C#CC(C)(O)COC
Reactant: CNC(=O)c1c(N)n(Cc2ccccn2)c2nc(Cl)ccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N)n(Cc2ccccn2)c2nc(C#CC(C)(O)COC)ccc2c1=O
Product: Cl

Procedure:
A suspension of 1 g of 2-amino-7-chloro-N-methyl-4-oxo-1-(pyridin-2-ylmethyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (2.91 mmol) in a mixture of 20 ml of dimethylformamide and 5.7 ml of triethylamine is placed in an 80 ml microwave tube. This suspension is sparged with argon and then 0.498 g of (±)-1-methoxy-2-methyl-3-butyn-2-ol (4.36 mmol), 0.055 g of CuI (0.29 mmol) and 0.102 g of bis(triphenylphosphine)palladium(II)dichloride (0.15 mmol) are successively added.