Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([F:29])[CH:6]([C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1)[OH:7])[CH3:2].ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([F:29])[C:6]([C:8]1[N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)C(F)C(O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(F)C(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A mixture of (1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)carbaldehyde obtained in Example 36 (2) (100 mg), ethyl bromofluoroacetate (0.05 ml), zinc powder (28 mg) and tetrahydrofuran (3 ml) was heated under reflux for 15 minutes. The mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution successively, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 2-fluoro-3-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-hydroxypropionic acid ethyl ester (100 mg) in a yellow amorphous form. To a mixture of the resulting 2-fluoro-3-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-hydroxypropionic acid ethyl ester (90 mg) and dichloromethane (2 ml) was added Dess Martin reagent (190 mg) at 15 to 30° C. and the mixture was stirred at the same temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution successively, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (80 mg) in a white amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([N:24]1[CH2:32][C:31]2([C:33]([O:35][CH3:36])=[O:34])[CH:26]([C:27](I)=[CH:28][CH2:29][CH:30]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([N:24]1[CH2:32][C:31]2([C:33]([O:35][CH3:36])=[O:34])[CH:26]([C:27]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:28][CH2:29][CH:30]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(C)cc1)=CCC2c1ccccc1OC
Yield: 95 %

Procedure:
A solution of 0.41 g (2.99 mmol) of 4-methylphenylboronic acid in 13 cm3 of methanol and 30 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 1.37 g (2.7 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 0.15 g (0.13 mmol) of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for two hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with 100 cm3 of ethyl acetate, washed with two times 50 cm3 of distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The brown residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture. 1.2 g (93%) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7-(4-methylphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a yellow oil, the characteristics of which were as follows:
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Cl[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1>CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1
Reactant: CNC
Reactant: Nc1ccnc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nccc(N)n1
Temperature: 220 °C
Yield: 91 %

Procedure:
40% Dimethylamine in water (1466 μl, 11.58 mmol) was added into the mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol) in N,N-dimethylformamide (DMF) (1.5 ml). The resulting reaction mixture was heated in a microwave reactor at 220° C. for 30 min. The reaction mixture was purified by RP-HPLC to yield N,N-dimethyl-2,4-pyrimidinediamine (290 mg, 2.099 mmol, 91% yield) as a white solid. MS (ES+) m/z 139.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(Br)c1OC
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(Br)c1OC

Procedure:
1-(5-(3-Bromo-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(3-bromo-4,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.037 g, 10% yield). MS: m/z 513.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Na].[Cl:10][CH2:11][CH2:12][CH2:13]I>O1CCCC1>[CH2:3]([S:8][CH2:13][CH2:12][CH2:11][Cl:10])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCS
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCSCCCCl
Temperature: -78 °C
Yield: 59 %

Procedure:
A suspension of sodium hydride (4.0 g, 100 mmole) in dry tetrahydrofuran (350 mL) under a nitrogen atmosphere was cooled in an ice bath. Pentyl mercaptan (10.8 g, 100 mmole) was added dropwise over 10 minutes. The resulting suspension of sodium alkylmercaptide was added in portions over 30 minutes to a stirred solution of 1-chloro-3-iodopropane (20.44 g, 100 mmole) in tetrahydrofuran (450 mL) that had been cooled to -78° C. The mixture was allowed to warm to ambient temperature overnight, then washed with brine, dried over MgSO4, and concentrated under vacuum. The resultant oil was distilled under water aspirator pressure to yield the desired product (10.67 g, 59% yield), b.p. 113°-119° C. (20 mm Hg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH2:13][C:14]([O:16]C)=O.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>>[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH:23][C:14](=[O:16])[CH2:13][N:3]1[CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:2]1=[O:1])[CH3:19]
Reactant: COC(=O)CN1CC(c2ccccc2)CC1=O
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)CN1CC(c2ccccc2)CC1=O

Procedure:
From 7.0 g. of methyl 2-oxo-4-phenyl-1-pyrrolidineacetate and 5.0 g of 2-(diethylamino)ethylamine, following the procedure of Example 1, there is obtained N-[2-(diethylamino)ethyl]-2-oxo-4-phenyl-1-pyrrolidineacetamide in pure form as an oil, without need for distillation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[K+].S(OC)(O[CH3:32])(=O)=O.O>CN(C)C=O>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH3:32])[CH:13]=[N:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1ccc(N=CNc2ccc(C(=O)OCC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N=CN(C)c2ccc(C(=O)OCC)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of N,N'-bis(4-ethoxycarbonylphenyl)formamidine (6.8 g, 0.02 mol) in 50 ml of dimethylformamide was added 2.0 g of potassium hydroxide and 2 ml (0.02 mole) of dimethyl sulfate. The solution was stirred overnight and heated at 100° for 3 hrs. The reaction mixture was poured into 100 ml of water and the solid which precipated was collected by filtration and dried. The solid was triturated with 150 ml of benzene. The undissolved material was removed by filtration and the filtrate was concentrated to a solid residue. This solid residue was then triturated with 50 ml of chloroform. The remaining solids were removed by filtration. Concentration of the filtrate produced the desired product, mp 89°-91° C. ##STR10##
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:25][NH:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A suspension of 7-bromo-4-chloro-3-nitroquinoline (75.00 g, 260.9 mmol) in 350 mL of dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. The suspension was treated with triethylamine (43.25 mL, 326.1 mmol), which dissolved most of the material. A solution of tert-butyl carbazate (37.93 g, 287.0 mmol) in 250 mL of dichloromethane was added to the reaction mixture over 20 min. The reaction was allowed to slowly come to ambient temperature. After 15 h, the reaction mixture was washed with 5% Na2CO3 solution (2×100 mL) and water (100 mL). The combined aqueous washes were back-extracted with CHCl3 (50 mL). The combined organic portions were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 99.98 g of tert-butyl N′-(7-bromo-3-nitroquinolin-4-yl)hydrazinecarboxylate as a dark red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]#[CH:14]>C(O)C.O.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]#[CH:14]
Reactant: C#CCOc1cc([N+](=O)[O-])ccc1C
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: C#CCOc1cc(N)ccc1C

Procedure:
As described above 1-methyl-4-nitro-2-(2-propynyloxy)benzene was made, mp 75°-77° C. This compound, (26 g) was reduced using iron in ethanol and water to give 4-methyl-3-(2-propynyloxy)benzenamine isolated as the hydrochloride salt mp >250° C. This amine salt was converted to the isocyanate analogue using phosgene in ethyl acetate as solvent, i.e. 4-isocyanato-4-methyl- 2-(2-propynyloxy)benzene, bp 78°-80° C./0.05 mm. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (19.6 g) was converted to its sodium salt using sodium hydride (4.6 g., 60%) in THF (100 ml). This solution was chilled to -62° C. and treated with a solution of the isocyanate (20 g) in THF (15 ml) over 2 minutes. The reaction warmed to -48° C. before cooling again. After stirring to ambient temperature and overnight the solvent was removed, water (250 ml) added, filtered to remove the precipitate and acidified whereupon a second precipitate was obtained. This solid was collected on a filter washed with water and re-extracted into aqueous sodium bicarbonate. After filtering the clear filtrate was acidified and the resulting cream precipitate was collected on a filter, washed with water and dried to give 3-[4-methyl-3-(2-propynyloxy)phenyl]-6- (trifluoromethyl)-2,4-(1H,3H)-pyrimidinedione, mp 202°-204° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15]([SH:17])[CH3:16].[OH-].[K+]>C(O)C.C(OCC)(=O)C>[CH2:15]([S:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:16]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCSCCCCCCCCCCC(=O)O
Yield: 8.2 %

Procedure:
11-Bromoundecanoic acid (1 g, 3.77 mmol, Aldrich) was added to a solution of ethanethiol (0.279 mL, 3.77 mmol, Aldrich) and potassium hydroxide (0.486 g, 8.66 mmol) in absolute ethanol (40 mL) and refluxed for 5 hr under a nitrogen atmosphere. After cooling and acidification with HCl, solvent was removed under reduced pressure to give a white solid. The solid was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by silica column chromatography using increasing concentrations of ethyl acetate in hexane for elution. The product eluted at 25% ethyl acetate/hexane. Solvent was removed under reduced pressure to yield 11-(ethylthio)-undecanoic acid (76 mg, 8%), mp 58-61°C.; 1H NMR (300 MHz, CDCl3) δ1.24 (t, 3H, J=7.4, CH3), 1.20-1.40 (bm, 12H, methylene envelope), 1.48-1.67 (bm, 4H, S--CH2 --CH2COO--CH2 --CH2), 2.33 (t, 2H, J=7.5, CH2 --COOH), 2.49 (t, 2H, J=7.4, S--CH2 --CH2), 2.51 (q, 2H, J=7.4, S--CH2 --CH3), 10.5 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3) δ14.88, 24.70, 25.98, 28.97, 29.08, 29.24*, 29.38, 29.48, 29.69, 31.73, 34.11, 180.05; MS, m/z 246 (M+, 50), 217 (COOH(CH2)10S+, 7), 199 (100), 181 (7), 167 (7), 149 (6), 117 (7), 101 (9), 97 (9), 87 (14), 83 (18), 75 (54), 69 (29), 62 (18), 55 (37).
Reaction SMILES: [CH2:1]([C:16]([OH:18])=[O:17])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].O[CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C1(C)C=CC=CC=1>[CH2:1]([C:16]([O:18][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:33])[CH3:34])[CH3:28])[CH3:23])=[O:17])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)CC=C(C)CCC=C(C)CCC=C(C)C
Yield: 78.7 %

Procedure:
A mixture of farnesyl carboxylic acid (5.0 g), farnesol (4.44 g) and triethylamine (4.85 g) was added dropwise at room temperature to a stirred solution of 2-chloro-1-methylpyridinium iodide (5.61 g) in 40 ml of toluene. After complete addition, the reaction mixture was heated on boiled water bath for three hours. After cooling, the mixture was washed with water and dried (Na2SO4). The solvent was removed in vacuo and gave a pale yellow oil. This material was purified by silica gel chromatography by using n-hexane and gave 7.15 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].I[CH:33](C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH:28]([CH3:33])[CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CC(C)I
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OC(C)C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting 2-iodopropane (20 equivalents iodide and sodium hydride with portion-wise addition) provided the title compound as a light yellow syrup. IR (liq.) 2971, 2935, 1564, 1552, 1497, 1471, 1392, 1379, 1368, 1206, 1177, 1140, 1123, 1101, 1061 cm−1; OAMS supporting ions at: ESI+ 470.2; MS (EI) m/z 469 (M+); HRMS (FAB) calcd for C26H29CL2N3O+H1 470.1766, found 470.1773. [α]25D=−93 (c 0.33, methylene chloride); Anal. Calcd for C26H29Cl2N3O: C, 66.38; H, 6.21; N, 8.93. Found: C, 66.53; H, 6.19; N, 8.89.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1.N1C=CC=CC=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.Cl>CN(C=O)C>[CH:20]1([C:23]([N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([OH:13])[C:10]=3[CH2:11][CH2:12][C@@H:3]2[CH3:2])=[O:24])[CH2:22][CH2:21]1
Reactant: C[C@H]1CCc2c(O)cccc2N1
Reactant: O=C(Cl)C1CC1
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]1CCc2c(O)cccc2N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A 1000-mL round bottomed flask fitted with a nitrogen inlet, overhead stirrer, addition funnel, and thermocouple, was charged with (S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide (20 g, 82 mmol), followed by anhydrous DMF (109 mL), and pyridine (19.8 mL, 246 mmol). Cyclopropanecarbonyl chloride (7.43 mL, 82 mmol) was added dropwise over 30 minutes while holding temperature below 20° C. with a cool water bath. Following completion of the addition, the reaction mixture was stirred for 1.5 h at ambient temperature. The pot was cooled to 0° C. in an ice bath and 0.29 M aqueous HCl solution (315 mL) was added dropwise over 15 minutes. The slurry was stirred for 90 minutes in the ice bath before being filtered. The pot and filter cake were washed with 25 mL of ice water. The filter cake was dried under nitrogen on a Buchner funnel to afford (2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (17.16 g, 91%) as an off-white powder. MS (ES, m/z): 232 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Br:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[OH-].[Na+].Cl>CO.CCOC(C)=O>[Br:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(C)c(Br)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1Br
Reaction time: 12 h
Yield: 47 %

Procedure:
4-Bromo-5-methyl-3-nitrobenzoic acid methyl ester ((Example 294: step a (11.6 g, 42.3 mmol) was dissolved in MeOH (400 mL) at rt and 2N NaOH (43 mL) was added dropwise over 30 min via addition funnel. The solution was stirred for 12 hr during which, precipitate appeared, and sm disappeared (TLC shows only baseline spot in 30% EtOAc). The pH was adjusted to ˜2 with conc HCl and the methanol was removed in vacuo. EtOAc (300 mL) was added to the aqueous slurry and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL) and then discarded. TLC analysis of the combined organic extracts showed two products (40% EtOAc in Hexanes, 4% AcOH). The combined organic extracts were washed with a 3:1 solution of 0.5N NaH2PO4/0.5N NaOAc (˜30×50 mL portions) until removal of the o-nitrobenzoic acid (lower spot on TLC, 40% EtOAc in Hex, 4% AcOH) was complete. The organic layer was then washed with brine and dried over sodium sulfate. Concentration of the solution yielded 5.4 g (47%) of a white solid. 1H NMR (CD3OD) δ 8.10 (m, 2H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:22][CH2:21]1>C(O)(C)C>[OH:19][CH:17]([CH2:16][O:15][C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:18][N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:24][CH2:25]1
Reactant: c1ccc(COc2ncccc2OCC2CO2)cc1
Reactant: O=C1NCCN1C1CCNCC1
Solvent: CC(C)O
Product: O=C1NCCN1C1CCN(CC(O)COc2cccnc2OCc2ccccc2)CC1
Reaction time: 16.5 h

Procedure:
4.8 g of 2-benzyloxy-3-(2,3-epoxypropoxy)-pyridine and 3.0 g of 1-(4-piperidyl)-imidazolidin-2-one are dissolved in 50 ml of isopropanol and the solution is stirred for 15-18 hours at 20-30°. The crystals which have precipitated out are filtered off with suction and washed with ether and yield 1-{1-[2-hydroxy-3-(2-benzyloxy-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one with a melting point of 145°-147°.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[N:35][C:34]([O:33][CH3:32])=[N:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cn1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-methoxypyrimidine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (11%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[N:11][C:10]([O:16][CH3:17])=[CH:9][CH:8]=2.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[CH2:18]([O:25][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[N:11][C:10]([O:16][CH3:17])=[CH:9][CH:8]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc2ncc(Cl)c(C#N)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(OCc3ccccc3)c(C#N)c2n1
Temperature: -30 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
Sodium hydride (70 mg, 1.73 mmol, 2.0 eq) is added at −30° C. to a stirred solution of 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile (190 mg, 0.87 mmol, 1.0 eq) and benzyl alcohol (187 mg, 1.73 mmol, 2.0 eq) in tetrahydrofuran (12 mL). After 2 hours stirring at −30° C., the reaction mixture is concentrated and extracted with ethyl acetate (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-carbonitrile as a light yellow solid (160 mg, 64% yield).