Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[S:2].[Na+:6].[Na+].[I-].[Na+].Cl[CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH3:24].O>C(O)C>[S:1]([O-:5])([S:2][CH2:11][CH2:12][N:13]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH3:24])(=[O:4])=[O:3].[Na+:6]
Reactant: Cc1ccc2c(c1)N(CCCl)C(C)CO2
Reactant: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)N(CCSS(=O)(=O)[O-])C(C)CO2

Procedure:
Sodium thiosulfate (0.2 m), sodium iodide (1 g), N-(2-chloroethyl)-3,6-dimethyl-2H-1,4-benzoxazine (0.2 m), water (150 ml), and ethanol (75 ml) were mixed and heated at reflux for 3 hrs. The alcohol was distilled off and the reaction mixture was cooled. The product, a white solid, was collected by filtration and dried in air. The yield was essentially quantitative.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)(C)C.[N+]([O-])(O)=O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
207 parts of 2,6-dichloro-4-nitro-aniline are introduced into 500 parts of isopropanol, and 780 parts of 65 percent strength by weight nitric acid are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C., as described in Example 1. The mixture is cooled, 400 parts of water are added and the product is filtered off. 172 parts (90% of theory) of 3,5-dichloro-nitro-benzene, of melting point 55°-57° C., are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:41].CO>>[ClH:41].[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C@H:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH:15]=2)=[CH:21][CH:22]=1
Reactant: ClCCl
Reactant: COc1ccc(-c2cccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3OCc3ccc4ccccc4c3)c2)cc1
Solvent: CO
Product: COc1ccc(-c2cccc([C@H]3CCNC[C@@H]3OCc3ccc4ccccc4c3)c2)cc1
Product: Cl

Procedure:
The title compound is prepared analogously as described for the title D compound in Example 1 from (3R*,4R*)-4-(4′-methoxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester: MS 424.5 [M+H]+; Rf 0.24 (DCM/MeOH 9:1).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][N:6]=[C:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]=[CH2:3].[OH-].[Na+].ClCCl>O1CCCC1>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][N:6]=[C:5]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2ccccc2)ncc(C(=O)OCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCn1c(-c2ccccc2)ncc(C(=O)O)c1=O
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of ethyl 1-allyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (25.6 g) in tetrahydrofuran (300 mL) at 0° C. was added a solution of 0.5N sodium hydroxide (198 mL). The resulting solution was allowed to stir for 1 h, was poured into dichloromethane and the organic layer removed. The remaining basic aqueous fraction was extracted with dichloromethane, made acidic with 1N hydrochloric acid (to pH 2), and extracted with dichloromethane. The organic layers from the acidic extractions were dried and evaporated to give an oil which crystallized upon addition of ether. The resulting white solid was collected and washed with ether:hexane (1:1) to give 1-allyl-2-phenylpyrimidin-6(1H)-one-5-carboxylic acid (11.1 g); 300 MHz NMR: 13.0 (s broad,1), 8.69 (s,1), 7.58 (m,5), 5,82 (m,1), 5.16 (d,1), 4.87 (d,1), 4.51 (d,2).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][CH2:15][C:9]=3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1.[Mg].C(O)(=O)C.Cl>CO>[OH:1][CH2:3][CH2:2][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1
Reactant: O=c1[nH]c2cc(C3CO3)ccc2c2c1CCC2
Agent: Cl
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2cc(CCO)ccc2C2CCCC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
A solution of 0.59 g (2.6 mmol) of 7-oxiranyl-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one in 100 ml of methanol is mixed with 1.26 g (52.0 mmol) of magnesium and 0.06 ml of acetic acid. The batch is stirred for 4 hours at room temperature and mixed with another 0.63 g (26.0 mmol) of magnesium. After 15 hours at room temperature, the reaction mixture is acidified with 200 ml of 10% hydrochloric acid and extracted with ethyl acetate (3×200 ml). The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 0.39 g of product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[N:9][C:8]=2[C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1N=NC(C2C=CC(C=O)=CC=2)=C(C2C=CC=CC=2)C=1.[NH:50]1[CH2:55][CH2:54][CH:53]([C:56]2[N:60]=[C:59]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=3)[NH:58][N:57]=2)[CH2:52][CH2:51]1.N1CCC(C2C=C(C3C=CC=CN=3)NN=2)CC1>>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[N:9][C:8]=2[C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:50]3[CH2:55][CH2:54][CH:53]([C:56]4[N:60]=[C:59]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=5)[NH:58][N:57]=4)[CH2:52][CH2:51]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Reactant: O=Cc1ccc(-c2nnc(-c3cccnc3)cc2-c2ccccc2)cc1
Agent: CN(C)c1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Agent: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Product: c1ccc(-c2cc(-c3cccnc3)nnc2-c2ccc(CN3CCC(c4n[nH]c(-c5ccccn5)n4)CC3)cc2)cc1

Procedure:
4-Phenyl-6-pyridin-3-yl-3-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazine (3-4) was prepared according to the procedure described in Scheme 1, except 4-(4-phenyl-6-pyridin-3-ylpyridazin-3-yl)benzaldehyde (3-2) is substituted for 4-[6-(dimethylamino)-4-phenylpyridazin-3-yl]benzaldehyde (1-3) and 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine (3-3; see synthesis below) for 2-(3-piperidin-4-yl-1H-pyazol-5-yl)pyridine (1-4). NMR (CDCl3): δ9.34 (1H, s), 8.76 (1H, d, J=4 Hz), 8.64 (1H, d, J=4.3 Hz), 8.58 (1H, d, J=8 Hz), 8.14 (1H, d, J=7.8 Hz), 7.88 (1H, s), 7.83 (1H, t, J=7.8 Hz), 7.44-7.53 (3H, m), 7.30-7.42 (5H, m), 3.57 (2H, s), 2.98 (2H, br s), 2.87 (1H, m), 2.06-2.22 (4H, m), 2.00 (2H, m); m/e (m+1): 551.5
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:21]>ClCCl>[OH:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:20]([C:22]1([CH3:37])[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:21]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C2(C)CCCN2C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.576 g, 3.45 mmol) and pyridine (0.546 g, 6.9 mmol) in anhydrous dichloromethane (20 mL) was added drop wise a solution of benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate (1.07 g, 3.8 mmol) in anhydrous dichloromethane (5 mL). After the addition, the mixture was stirred at room temperature overnight. Removed the solvents and purified by silica gel chromatography (petroleum ether/ethyl acetate=100:1 to 25:1) to obtain a yellow oil of benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (1 g, yield 66%). 1H-NMR (400 MHz, DMSO-d6): δ 1.53-1.58 (m, 3H), 1.88-1.91 (m, 3H), 1.28 (brs, 1H), 3.53-3.65 (m, 2H), 3.92 (s, 3H), 5.02-5.15 (m, 2H), 6.92-6.96 (m, 1H), 7.16-7.34 (m, 5H), 7.55-7.57 (d, J=7.8 Hz, 1H), 7.88-8.12 (m, 1H), 8.72-8.89 (d, 1H), 10.82 (s, 1H); LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.C1COCC1.[N:43]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]=[O:45].CCN(C(C)C)C(C)C>O>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][NH:43][C:44]([N:31]1[CH2:30][C:29]([CH3:37])([CH3:36])[N:28]([CH2:27][C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)[CH2:33][C:32]1([CH3:35])[CH3:34])=[O:45])[CH3:51]
Reactant: CCOC(=O)CN=C=O
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CNC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(OCOC)cc3)nc3c2c(C)nn3C2CCCCO2)CC1(C)C
Yield: 27.9 %

Procedure:
To a solution of 200 mg 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine in 3 ml abs. THF were added 51 mg ethyl isocyanatoacetate and 51 mg Hünig's base. After 16 h at rt water was added, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried and concentrated in vacuo. 70 mg of the title compound were obtained, which were subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([O:29]CC)=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CCO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([CH2:26][C:27]([OH:29])=[O:28])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCn1ccc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCn1ccc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (10 ml). The aqueous layer was neutralized with 2N HCl and extracted with AcOEt (50 ml). The AcOEt layer was washed successively with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11].O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+].O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[C:10]=[S:11])=[C:4]([CH3:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Cl)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)nnc1N=C=S
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a solution of 6-chloro-4-methylpyridazin-3-amine (2.86 g, 20.0 mmol) in aqueous sodium bicarbonate (10 mL) and tetrahydrofuran (40 mL) was added thiophosgene (1.69 mL, 22.0 mmol) dropwise at 0° C. After stirring for 1 hr. water and ethyl acetate were added to the mixture and the insoluble materials were filtered off. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (304 mg, 1.64 mmol, 8%) as a pale yellow solid.
Reaction SMILES: COC1C=CC(C([O:22][C@@H:23]2[C:27]([CH2:30][OH:31])([CH2:28][OH:29])[O:26][C@@H:25]([N:32]3[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]3=[O:34])[CH2:24]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(O)(=O)C.O>[OH:29][CH2:28][C:27]1([CH2:30][OH:31])[O:26][C@@H:25]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:24][C@@H:23]1[OH:22]
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)OC2(CO)CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cn([C@H]2C[C@H](O)C(CO)(CO)O2)c(=O)[nH]c1=O
Yield: 90.8 %

Procedure:
A solution of 3′-O-(4,4′-dimethoxytrityl)-4′-C-hydroxymethylthymidine (6.32 g, 11.0 mmol) in 80% acetic acid in water (50 ml) stood at room temperature for 4 h. Solvents were removed under reduced pressure and water (200 ml) added. The resulting cloudy mixture was washed with ether (3×80 ml) and water was evaporated. The residue was dissolved in methanol and toluene and the resulting solution was concentrated. This process was repeated twice. 4′-C-hydroxymethylthymidine (2.72 g, 91%) was obtained as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:22])=[N:20][NH:21][C:15]=2[CH:14]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.CS(O)(=O)=O>C(Cl)Cl.O1CCCC1>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:22])=[N:20][N:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[C:15]=2[CH:14]=1
Reactant: C1=COCCC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.45 g, 1.0 mmol) (Example 28, Step 4), dihydropyran (270 μL, 3.0 mmol) and methanesulfonic acid (13 μL, 0.20 mmol) in methylene chloride (9 mL) and tetrahydrofuran (3 mL) in reaction flask was stirred at r.t. overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.34 g, 64%). LC/MS (M+H)+=534.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:15]CCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: ClCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=C(CCl)c1cccc2ccccc12

Procedure:
A solution of 2-bromoacetylnaphthalene (7.00 g) and tetra-n-butyl ammonium bromide (0.905 g) in 1,2-dichloroethane (226 ml) was refluxed for 3.5 hours, evaporated in vacuo and extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with n-hexane to afford 2-chloroacetylnaphthalene (5.43 g) as a yellow powder.
Reaction SMILES: [C:1]([CH2:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[CH2:14][NH:15][NH2:16]>O1CCOCC1>[NH2:2][C:1]1[N:15]([CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[F:11])[N:16]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: NNCc1ccccc1F
Reactant: CCOC(=O)C(=O)CC#N
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1

Procedure:
The compound of the formula (II) is obtainable in a multi-stage synthesis from the sodium salts of ethyl cyanopyruvate, which is known from the literature (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934, 512, 97). By reaction thereof with 2-fluorobenzylhydrazine with heating and under a protective gas atmosphere in an inert solvent such as dioxane, ethyl 5-amino-1-(2-fluorobenzyl)pyrazole-3-carboxylate is obtained, which cyclizes by means of reaction with dimethylaminoacrolein in the acidic medium under a protective gas atmosphere and with heating to give the corresponding pyridine derivative. This pyridine derivative, ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate, is converted by means of a multi-stage sequence, consisting of conversion of the ester into the corresponding amide using ammonia, dehydration using a dehydrating agent such as trifluoroacetic anhydride to give the corresponding nitrite derivative, reaction of the nitrile derivative with sodium ethoxide and final reaction with ammonium chloride, into the compound of the formula (II).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[C:26]([O:30][C:31](=[O:48])[CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[C:41]([O:46][CH3:47])[CH:40]=2)[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C.COCC(O)C>>[C:26]([O:30][C:31](=[O:48])[CH2:32][N:33]1[CH2:34][CH2:35][CH:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[N:17]4[N:16]=3)=[C:41]([O:46][CH3:47])[CH:40]=2)[CH2:37][CH2:38]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc(C2CCN(CC(=O)OC(C)(C)C)CC2)ccc1N
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(CC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Into an 8-dram vial Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), [4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetic acid tert-butyl ester (133 mg, 0.415 mmol), N,N-Diisopropylethylamine (150 uL, 0.86 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol) were added. The reaction mixture was heated at 80° C. After 3 days, solvent was removed and the product, (4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetic acid tert-butyl ester, was purified by flash chromatography (ISCO, 40 g column, hexane; EtOAc 1:1) as a gum (79 mg, 54%). LCMS (E/I+) 544 (M+H). NMR 1H (MeOH-d4)-8.7 (s, 1H), 8.16 (d, 1H, J=8.28 Hz), 7.82 (d, 1H, J=7.56 Hz), 7.45 (m, 1H), 7.16 (d, 1H, J=8.32 Hz), 7.09 (m, 1H), 6.95 (d, 1H, J=4.67 Hz), 6.89 (d, 1H, J=4.68 Hz), 6.81 (s, 1H), 6.72 (s, 1H), 6.63 (m, 1H), 3.89 (s, 3H), 3.83 (s, 2H), 3.80 (s, 3H), 3.03 (m, 2H), 2.43 (m, 1H), 2.25 (m, 2H), 1.76 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][OH:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OCCCOc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a 250 mL round bottom flask was added 4-bromophenol (16.5 g, 95.3 mmol), 3-bromopropanol (15.9 g, 114.4 mmol), N,N-dimethylformamide (50 mL) and potassium carbonate (22.4 g, 162.0 mmol). The reaction was allowed to stir at room temperature while being monitored by TLC (CH2Cl2). Upon the disappearance of 4-bromophenol the mixture was poured into a separatory funnel containing 50 mL of water. The product was extracted in diethyl ether and the organic layer was washed with 3×25-mL portions of cold water. The solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with dichloromethane. The solvent was removed under reduced pressure. Residual solvent and remaining 3-bromopropanol were removed in vacuo (14.2 g, 64.4%). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 9.0 Hz), 6.77 (d, J=9.0 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.10 (q, J=6.0 Hz, 2H), 1.65 (s, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 107, 40.0 mg, 0.12 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 25.0 mg (69%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH2:11][N:10]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:20])[CH:8]=1)[CH3:2].Cl.[OH:26][C@@H:27]([CH2:57]O)[CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH:34]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:69]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:26][C:27]([CH3:57])([CH3:69])[CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH:34][C:13](=[O:15])[C@@H:12]([N:10]2[CH2:11][C:7]([O:6][C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[O:3][CH2:1][CH3:2])=[CH:8][C:9]2=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:30]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (130 mg, 0.4 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.46 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (353 mg, 0.8 mmol) and N,N-diisopropylethylamine (103 mg, 0.8 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in diethyl ether (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 4 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The solid was filtered to give (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (45 mg, 23%): HR-ES-MS m/z calculated for C25H34N4O5 [M+H]+ 471.2602, observed 471.2603; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.26 (t, J=6.8 Hz, 3H), 1.32-1.64 (m, 2H), 1.64-1.82 (m, 1H), 3.89 (s, 2H), 4.00-4.13 (m, 3H), 4.35-4.62 (m, 2H), 4.74 (s, 1H), 4.89 (dd, J=10.9, 4.5 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 7.15-7.22 (m, 1H), 7.22-7.32 (m, 2H), 7.53 (d, J=2.1 Hz, 1H), 10.77 (s, 1H).