Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][C:15]1=[O:24].Cl>CN(C)C=O>[C:5]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[NH:14][C:15](=[O:24])[NH:16][CH2:17]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NCc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1NCc2cc(C(=O)c3ccccc3)ccc2N1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
To a vigorously stirred amount of 45 parts of aluminum chloride were added dropwise 7.05 parts of N,N-dimethylformamide. After stirring for 5 min. at 70° C., there were added 5 parts of benzoyl chloride and, dropwise, 4.7 parts of 3,4-dihydro-2(1H)-quinazolinone. Stirring was continued for 2 hours at 70° C. The reaction mixture was poured into ice-water and there were added 63.5 parts of HCl. The precipitate was filtered off and recrystallized from 2-methoxyethanol, yielding 6.5 parts (76.4%) of 6-benzoyl-3,4-dihydro-2(1H)-quinazolinone; mp. 264.8° C. (interm. 1).
Reaction SMILES: CS(O[C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:9][O:8][CH2:7]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([C@H:6]1[C@@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:9][O:8][CH2:7]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1
Temperature: 110 °C

Procedure:
To a solution of trans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate (133.2 g, 0.395 mol) in dimethylformamide (3 L) was added sodium azide (192.6 g, 2.96 mol) and the reaction was heated at 110° C. for 66 hours. The reaction was cooled to room temperature and water (12 L) was added. This reaction was carried out a total of three times on the same scale, and the combined batches were extracted with tert-butyl methyl ether. The organic layers were then dried over sodium sulfate and concentrated in vacuo to afford product as a red-brown oil, contaminated with 18% dimethylformamide. Corrected yield: 286.7 g, 1.01 mol, 85%. 1H NMR (400 MHz, CDCl3) δ 3.93-3.97 (m, 2H), 4.00 (m, 1H), 4.09 (dd, J=8.7, 5.8 Hz, 1H), 4.17 (dd, J=10.0, 5.6 Hz, 1H), 4.90 (ddd, J=5.4, 5.4, 4.4 Hz, 1H), 6.83 (d, J=9.1 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[NH:16][C:17]3[CH:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[NH:16][C:17]3[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc2ccc(CO)cc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-3H-benzo[d]imidazole-5-carboxylate (Example 14, 65 mg, 0.156 mmol), in dry THF (6 mL) was added to a cooled (0° C.) solution of LiAlH4 in THF (0.39 mL, 1.0 M solution). After 2 h, the reaction was allowed to warrn to rt and stirred for 24 h. The mixture was cooled to 0° C., the excess of LiAlH4 was destroyed very with a saturated solution of NH4Cl. The product was extracted with EtOAc (4×20 mL), dried over MgSO4 and evaporated to yield a white solid. Example 145 was obtained after preparative HPLC purification (continuous gradient from 10% B to 60% B; A=90:10:0.1 H2O:MeOH:TFA; B=90:10:0.1 MeOH:H2O:TFA). tR=4.589 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C23H25N4O2 [M+H]+389.1978, found 389.1972.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][NH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][N:11]3[C:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)=[CH:22][C:23](=[O:24])[NH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cn[nH]c2N)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cnn3c(-c4ccc(F)cc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
4-(4-Methylphenyl)-1H-pyrazol-5-amine (170 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (250 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 180 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[I:12]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(C(=O)O)cc1I
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-bromo-4-methylbenzoic acid in 96% sulphuric acid (˜0.58 M reaction concentration) was added N-iodosuccinimide (1.1 equiv.) over 1 h maintaining the temperature between 10 and 30° C. The reaction mixture was aged for 10 min then quenched into water. The slurry was filtered and washed with water, sodium bisulfite solution and then finally with water to give the title compound as an off-white solid. 1H NMR (400 MHz, dmso-d6): δ 13.4 (br s, 1 H); 8.30 (s, 1 H); 8.00 (s, 1 H); 2.64 (s, 3 H). HRMS (ES, M−H) Calcd 338.8518. Found 338.8516.
Reaction SMILES: C([Sn](CC)(CC)[C:4]1[O:5][CH:6]=[CH:7][N:8]=1)C.[CH2:13]([N:16]([CH2:30][CH2:31][CH3:32])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27](I)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:14][CH3:15]>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:30]([N:16]([CH2:13][CH2:14][CH3:15])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([C:4]2[O:5][CH:6]=[CH:7][N:8]=2)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:31][CH3:32]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: CC[Sn](CC)(CC)c1ncco1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A stirred solution of 2-triethylstannyloxazole (Chem. Mater. 1994, 6, 1023)(1.5 g, 5.5 mmol) and methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.8 g, 4.6 mmol) in dimethylformamide (12 mL) was degassed under reduced pressure for 15 min and purged with argon. Palladium(0) tetrakis(triphenylphosphine) (158 mg, 0.14 mmol) was added and the reaction mixture was degassed under reduced pressure for 15 min and then purged with argon. The reaction mixture was heated at reflux for 2 d, cooled to room temperature, diluted with ethyl acetate, washed with water (3×50 mL), dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided methyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (423 mg): 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 3.97 (s, 3H), 3.49 (br s, 2H), 3.18 (br s, 2H), 1.72 (d, J=7 Hz, 2H), 1.55 (d, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H)
Reaction SMILES: Cl.FC1C([O:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[CH:17]=2)=O)=C(F)C(F)=C(F)C=1F.N1C=CC=CC=1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][NH2:59])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>C1COCC1>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][NH:59][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:9])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NCC2CN(C(=O)OC(C)(C)C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (0.18 mmol, 0.1 g, Example 90) and 0.1 mL of pyridine in 2 mL of THF was added 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester (0.4 mmol, 0.09 g). The mixture was shaken at room temperature, and upon completion of the reaction, the solvent was removed. The residue was chromatographed with 4% methanolic solution of ammonia (2.0 M ammonia in methanol) in EtOAc to provide 2-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester. LCMS: m/z 553.0 [M+1].
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:24]2[CH2:28][C:27]([O:29][C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])=[CH:26][C:25]2=[O:38])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:24]2[CH2:28][C:27]([O:29][C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])=[CH:26][C:25]2=[O:38])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([OH:18])[CH2:21][OH:20])[N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CC3CCCC3)N3CC(Oc4c(F)cccc4F)=CC3=O)n2)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CC1CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
A solution of (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-propionamide (prepared as in Example 87, 120 mg, 0.22 mmol) in tetrahydrofuran (20 mL) was treated with 2N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was adjusted to neutral and diluted with ethyl acetate, washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated to afford (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (70 mg, 63%) as an off-white solid: HR-ES-MS m/z calculated for C24H28F2N4O5 [M+H]+ 491.2101, observed 491.2102; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (br. s., 1H) 1.28 (br. s., 1H) 1.36-1.95 (m, 9H) 3.19-3.30 (m, 2H) 3.64-3.80 (m, 1H) 3.80-3.91 (m, 1H) 4.07 (dd, J=13.6, 3.9 Hz, 1H) 4.28 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.69 (t, J=5.6 Hz, 1H) 4.79 (dd, J=10.3, 4.8 Hz, 1H) 4.92 (d, J=5.4 Hz, 1H) 5.01 (s, 1H) 6.39 (d, J=2.1 Hz, 1H) 7.22-7.48 (m, 3H) 7.51 (d, J=2.1 Hz, 1H) 10.78 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC.[F-].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]1([CH2:9][O:8][C:5]2[N:4]=[CH:3][C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:7][N:6]=2)[CH2:12][CH2:11]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(OCC2CC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
760 mg (3.32 mmol) of 5-bromo-2-cyclopropylmethoxypyrimidine in 15 mL of dioxane, 1.36 mL (3.82 mmol) of tributyl(1-ethoxyvinyl)tin, 58.22 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride, 1.12 g (7.30 mmol) of cesium fluoride. This mixture is subjected to microwave irradiation at 110° C. for 1 hour. The reaction mixture is evaporated to dryness and the residue is taken up in 100 mL of ethyl ether. A solution of 2.80 g of cesium fluoride in 10 mL of water is added. After stirring for 1 hour at room temperature, the mixture is filtered through Celite. The filtrate is washed with aqueous NaHCO3 solution and then with saturated NaCl solution. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give 480 mg of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C=O)C.[H-].[Na+]>[CH3:28][O:29][CH2:30][CH2:31][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)n(C2CCOCC2)c2nc(-c3cnn4ccc(C#N)cc34)ncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then 2-bromoethyl methyl ether (0.032 mL, 0.34 mmol) was added and the reaction mixture was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 36 mg of the desired compound (62% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:30]2[CH:29]=[C:28]([CH3:27])[CH:33]=[CH:32][N:31]=2)=[O:35])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: Cc1ccnc(C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccn2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-methyl-pyridine-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[C:13]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].Cl>ClCCl>[C:13]([C:15]1[CH:16]=[C:17]([S:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1nccs1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Yield: 66.6 %

Procedure:
To 2-aminothiazole (12.55 g, 125.3 mmol) was added pyridine (46 ml) and dichloromethane (75 mL) and the mixture stirred to give a solution. A solution of 3-cyano-4-fluorobenzenesulfonyl chloride (25 g, 114 mmol) in dichloromethane (50 ml) was added over approx 20 minutes at room temperature. The reaction was stirred at this temperature for 2 days before decanting the supernatant and concentrating in vacuo to furnish a dark oil. 2M HCl (200 ml) was added and the mixture triturated until solidification occurred. A brick red solid was filtered off, washed with water and dried to furnish 21.5 g of the title product. 1HNMR (d6-DMSO): δ 6.9 (d, 1H), 7.3 (m, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.3 (d, 1H), 12.9 (br s 1H). LCMS Rt=2.34 min MS m/z 284 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OCC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.CC(C[AlH]CC(C)C)C.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-bromo-benzofuran-2-carboxylate (5 g; 18.6 mmol) in 65 mL THF under nitrogen, was added DIBAL (46 mL, 46 mmol) dropwise over 30 minutes, then stirred overnight at room temperature. After dropwise addition of 25 mL of water, the mixture was evaporated, extracted with ethyl acetate, filtered, washed, dried (MgSO4) and evaporated to yield 4.2 g of crude product which was further purified by chromatography to afford (5-bromo-benzofuran-2-yl)-methanol.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][C:12]([OH:14])=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2>CO>[ClH:1].[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][C:12]([Cl:1])=[O:14])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)CCC12CCN(CC1)CC2
Agent: Cl
Solvent: CO
Product: O=C(Cl)CCC12CCN(CC1)CC2

Procedure:
The title compound was prepared from 3-(quinuclidin-4-yl)-propionic acid hydrochloride (0.18 g, 0.0008 moles) as in the method of Example 8, Step 4 0.19 g (100%). MS (+ve ion electrospray) m/z 198 (MH+, 100%)-methyl ester from reaction with methanol).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=O)[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:11][CH2:12][N:13]1[C:32](=[O:31])[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: CCn1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Product: CCn1nc(C2CCC2)c2cc(N3CCN(C(=O)Cc4nnc[nH]4)[C@@H](Cc4ccccc4)C3)ccc21
Yield: 10 %

Procedure:
Prepared using the same procedure described in Example 275 from 5-((S)-3-benzyl-piperazin-1-yl)-3-cyclobutyl-1-ethyl-1H-indazole and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 7 days to afford the title compound as a colorless solid (19 mg, 10%). LC/MS (Method B) 3.39 min, [M+1]+ 484.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.[I:17]I>C1COCC1.O>[F:9][C:10]1[C:15]([I:17])=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1
Reactant: Cc1ccc(F)nc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 499.3 %

Procedure:
A solution of 2M LDA in THF (371 mL, 742 mmol) was added to THF (1400 mL) at −78° C. under an atmosphere of nitrogen. To this stirred, cooled solution was added 2-fluoro-5-methylpyridine (75.0 g, 67.6 mmol) in THF (280 mL) dropwise. The reaction mixture was allowed to stir at −78° C. for 2 h and then a solution of iodine (171.5 g, 67.6 mmol) in THF (560 mL) was added dropwise. The reaction mixture was allowed to stir at −78 for 2 h and then diluted with water (875 mL). The mixture was allowed to warm to rt and was then extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-fluoro-3-iodo-5-methylpyridine (80 g, 50%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:10]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][N:30]=[C:31](F)[CH:32]=3)[N:27]=[CH:26][C:25]=2[C:35]#[N:36])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][N:30]=[C:31]([NH:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)[CH:32]=3)[N:27]=[CH:26][C:25]=2[C:35]#[N:36])=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cc2ccccc2)cc1
Reactant: NCCN1CCOCC1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(Cc2ccccc2)cc1
Yield: 144 %

Procedure:
Following the procedure described above in Example 1,4-(4-benzylphenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.675 g, 1.90 mmol) was reacted with 4-(2-aminoethyl)morpholine (5.0 mL, 5.0 g, 38 mmol). This process was repeated with three additional aliquots of 4-(4-benzylphenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.62 g, 0.62 g, 0.30 g). The contents of all four tubes were worked up together, and the crude product purified by flash chromatography over silica gel (5-6% MeOH in CH2Cl2) to give pure product as bright yellow crystals (1.17 g, 40% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.43 (br s, 4 H) 2.56 (t, J=6.7 Hz, 2 H) 3.31-3.39 (m, 2 H) 3.50-3.66 (m, 4 H) 3.99 (s, 2 H) 6.58 (t, J=4.9 Hz, 1 H) 7.04 (s, 1 H) 7.13-7.35 (m, 9 H) 8.22 (s, 1 H) 8.82 (s, 1 H) 9.56 (s, 1 H); HRMS (ESI+) calcd for C28H29N6O (MH+) 465.2398, found 465.2396.
Reaction SMILES: [C:1]([PH:4](=[O:6])[O-:5])(=O)[CH3:2].[Na+:7].[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].C1(C)C=CC=CC=1>C(O)C>[CH3:2][C:1]1([P:4]([O-:6])[O-:5])[NH:12][CH2:11][CH2:10][CH2:9][NH:8]1.[Na+:7].[Na+:7]
Reactant: CC(=O)[PH](=O)[O-]
Reactant: NCCCN
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(P([O-])[O-])NCCCN1

Procedure:
Sodium acetylphosphinate (2.6 g, 0.02 mol) and 1,3-diaminopropane (1.7 ml, 1.5 g, 0.02 mol) were stirred together in ethanol (60 ml) for 21/2 days, giving a cloudy pale yellow solution. This was evaporated inder reduced pressure, giving a sticky hydroscopic yellow solid, which contains ethanol by nmr. The solid was dissolved in ethanol, toluene added and re-evaporated to dryness, giving a yellow foam, mp 144°-6°, decomp (3.2 g, 86%). NMR was consistent with the desired structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=3)[O:10][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1ccc(O)cn1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ccc(O)cn3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
5-Hydroxy-2-pyridinecarboxylic acid (24 mg, 0.17 mmol) and CDl (31 mg, 0.19 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (68 mg, 0.19 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP and the product fractions concentrated to give the title compound as a white solid (19 mg, 24%).