Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([C:14]([O:16]C)=[O:15])[CH:5]=1.[OH-].[Na+]>O.C1COCC1>[CH3:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(C)c2c(c1)OCCO2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.65 g (0.28 mol) LiOH in 100 mL water was metered into a solution of 33.60 g (0.16 mol) methyl 8-methyl-2,3-dihydro-1,4-benzodioxin-6-carboxylate in 200 mL THF and the reaction solution was stirred overnight at RT. To complete the reaction 150 mL 6 M NaOH were added and the mixture was stirred for a further 2 h at 50° C. The reaction mixture was evaporated down i.vac, the residue was combined with THF, acidified with conc. HCl while cooling with ice, the precipitate was filtered off, washed with 150 mL water and dried at 60° C. in the circulating air dryer.
Reaction SMILES: [CH3:1][N:2]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27])=[O:9])=[O:4].[C@@H:43]1([NH2:53])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)[C:3](=[O:4])[C:5]1[CH:34]=[CH:33][CH:32]=[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:13][C:12]=2[C:23]2[CH:24]=[C:25]([C:26](=[O:27])[NH:53][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:29]=[CH:30][N:31]=2)=[O:9])[CH:6]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of 550 mg of 2-(2-(3-(methyl(2-morpholinoethyl)carbamoyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid, 142 mg of (S)-1,2,3,4-tetrahydronaphthalen-1-amine, and 497 mg of diisopropylethylamine in 6 mL of DMF was treated with 366 mg of HATU. After stirring for 2 h the product was isolated by reverse phase HPLC, eluting with 0.05% TFA in a water/acetonitrile gradient. The procedure gave 220 mg of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[CH3:55][NH:56][O:57][CH3:58]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:25])[N:56]([O:57][CH3:58])[CH3:55])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A solution of 5 g (13.6 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 20-5620 in 150 ml CH2Cl2 was treated with 10.5 ml (95.2 mmol) N-methylmorpholine, 0.37 g (2.72 mmol) 1-hydroxybenzotriazole, 6.26 g (32.64 mmol) EDCI and 2.92 g (29.92 mmol) N,O-dimethylhydroxylamine hydrochloride. The reaction was stirred over night at room temperature and partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaCl and dried over Na2SO4. Purification by flash-chromatography on silica gel (Hexane/EtOAc 1:1) gave 3.6 g (62%) of (2S,4R)-4-(4-methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 411 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27][O:28]C(=O)C)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:32])[N:11]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:10]2=[O:41])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[N:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[C:10](=[O:41])[N:11]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH:12]([CH3:32])[C:13]3=[CH:18][N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOC(C)=O)c4)ncc3C2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCO)c4)ncc3C2C)cc1

Procedure:
Acetic acid (±)-2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl ester (10 g; 1.81 mmol) (from Example 3c supra) was dissolved in a mixture of methanol (17 mL) and water (7 mL) and treated with potassium carbonate (1.00 g; 7.26 mmol) at room temperature for 19 hours. The reaction mixture was partitioned between ethyl acetate and water-brine mixture. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (Biotage 40M; ethyl acetate) to give (±)-3-[7-[3-(2-hydroxy-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile. (Yield 0.67 g; 72.9%). A small amount of additional material bumped over into the solvent trap during concentration. This material was recovered and crystallized from ethyl acetate. (Yield 0.09 g; 9.9%). Melting Point: 195–200° C. HR-MS(ES+) m/z Calculated for C29H26N6O3 ([M+H]+): 507.2139. Found: 507.2145. HR-MS(ES+) m/z Calculated for C29H26N6O3 ([M+Na]+): 529.9158. Found: 529.1963.
Reaction SMILES: [N+](C1C=CC(C([O:10][C:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[CH:29][C:30]([Cl:34])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[Li+].[OH-].O>C1COCC1>[Cl:34][C:30]1[CH:29]=[C:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:27]2[C:32](=[CH:33][C:24]([CH2:23][N:21]3[CH:22]=[C:18]([C@@:11]([OH:10])([CH2:12][CH3:13])[C:14]([F:17])([F:15])[F:16])[N:19]=[N:20]3)=[CH:25][CH:26]=2)[N:31]=1
Reactant: CCC(OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 1-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (300 mg, 0.49 mmol) and LiOH 2M/H2O (1.25 mL, 2.5 mmol) in THF (5 mL) was stirred at rt 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound. MS (+ESI): 465 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33][C:34](C3OC=CC=3)=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=C=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33][C:34]([NH:41][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccco3)cc(-c3cccc(Cl)c3)c2c1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)Nc3ccccc3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
A mixture of (±)-2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.000210 mol) (see Example B8) and isocyanato-benzene (0.000630 mol; 3 equiv) in THF (1 ml) was stirred for 5 hours at 60° C. Water (a few drops) was added. The solvent was evaporated. The residue was HPLC purified. The product fractions were collected and the solvent was evaporated, yielding 0.071 g (56.77%) of (±)-N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinolinyl]-N′-phenylurea, MS (ESI) m/z: 594 596 598.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CO>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1ccc(CNCCCOc2ccc(-c3csc4ccccc34)cc2)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, benzylamine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=98%, [M+H]+=374.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[CH3:15][C:16](N(C)C)=[O:17]>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([O:17][C:16]2[CH:13]=[CH:12][C:11]([CH:1]=[O:4])=[CH:10][CH:15]=2)=[N:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(=O)N(C)C
Agent: [K+]
Product: O=Cc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7,4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acectic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][OH:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>CN(C=O)C.O>[S:17](=[O:20])(=[O:19])([O:11][CH2:10][CH:7]1[O:6][C:5]2[CH:12]=[C:13]([Cl:14])[C:2]([Cl:1])=[CH:3][C:4]=2[O:9][CH2:8]1)[NH2:18]
Reactant: OC[C@H]1COc2cc(Cl)c(Cl)cc2O1
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)OCC1COc2cc(Cl)c(Cl)cc2O1
Reaction time: 0.5 h

Procedure:
(2S)-6,7 dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethanol (2.0 g, 8.5 mmol), prepared according to the procedure described in Example 11 above, in DMF (20 mL) was cooled in an ice bath. Then, 95% sodium hydride (0.28 g, 11 mmol) was added under argon and the reaction mixture was stirred 30 min. Sulfamoyl chloride (1.97 g, 17 mmol) was added and the reaction mixture was stirred with ice bath cooling. After 1 h, the reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate. The combined ethyl acetate was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil, which was purified by flash column chromatography (ethyl acetate/heptane 1:1) to yield a white solid. The white solid was recrystallized from benzene to yield the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[NH:12][C:13]([CH:15]3[CH2:18][N:17]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=4)[CH2:16]3)=[N:14][C:10]=2[CH:9]=1.ClCCl.O>O1CCOCC1>[Cl:25][C:24]1[C:19]([N:17]2[CH2:18][CH:15]([C:13]3[NH:12][C:11]4[CH:27]=[CH:28][C:8]([Cl:7])=[CH:9][C:10]=4[N:14]=3)[CH2:16]2)=[N:20][C:21]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:22][CH:23]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2[nH]c(C3CN(c4nc(Cl)ncc4Cl)C3)nc2c1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccc2[nH]c(C3CN(c4nc(N5CCOCC5)ncc4Cl)C3)nc2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 72.2 %

Procedure:
A mixture of morpholine (0.062 mL, 0.711 mmol) and 5-chloro-2-(1-(2,5-dichloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.063 g, 0.18 mmol) in dioxane (1 mL) was heated to 60° C. under argon and stirred for 6 h. The mixture was cooled to RT, dichloromethane and water were added, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 4-(5-Chloro-4-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-2-yl)morpholine (0.052 g, 0.13 mmol, 72%) as a white solid. [M+1] 405. IC50 (uM) 0.1554.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.IC.[CH3:25]C([O-])(C)C.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:7](=[O:18])[C:6]3([CH3:25])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CCOC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.9 %

Procedure:
2-Chloro-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (320 mg, 0.985 mmol) and iodomethane (0.307 ml, 4.93 mmol) were frozen in DMSO (2 ml). Sodium 2-methylpropan-2-olate (284 mg, 2.96 mmol) was added and covered by a layer of DMSO. The mixture was allowed to warm to room temperature and stir for 1 hour, then was diluted with water then extracted twice with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 390 mg of 2-chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a tan oil. [M+H] found 339.
Reaction SMILES: [CH:1]1([C:7]([CH3:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]([F:18])([F:17])[C:12](OCC)=[O:13].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:10][C:11]([F:18])([F:17])[C:12](=[O:13])[CH2:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(CC(=O)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclohexylmethylketone (2.75 g, 21.8 mmol) in DME (200 mL) was added ethyl trifluoroacetate (7.79 ml, 65.4 mmol) and sodium methoxide (7.71 g, 131 mmol), and the resulting reaction mixture was stirred at room temperature overnight. EtOAc (500 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over MgSO4, and concentrated in vacuo to give the title compound in quantitative yield. This was used for the next coupling step without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[C:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:40][CH2:39][CH2:38][O:37]3)[CH2:34]2)[CH2:30]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:37][CH2:38][CH2:39][O:40]3)[CH2:34]2)[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C(CCCCOCc1ccccc1)=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: c1ccccc1
Product: C1=C(CCCCCOCc2ccccc2)C[C@H]2CC3(C[C@@H]12)OCCO3
Reaction time: 2.5 h
Yield: 102.2 %

Procedure:
1.50 g of p-toluenesulfonic acid and 2.9 ml of ethylene glycol were added to 17.8 g of 3-(5-benzyloxypentylidene)- 7,7-ethylenedioxy-cis-bicyclo[3,3,0]octane (prepared as described in Preparation 3) in 300 ml of benzene, and the mixture was heated, with stirring, for 2.5 hours whilst removing water as an azeotropic mixture. Upon completion of the reaction, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the reaction mixture under reduced pressure, to give 18.20 g of the title compound as an oil. This mixture was used for the subsequent reaction of Preparation 5 without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.O>CN(C=O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccc(NC(=O)c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a solution of Example 238b (2.5 g, 8.5 mmol) in DMF (50 mL) was added CsCO3 (5.5 g, 17.0 mmol), and 4-aminothiophenol (1.0 g, 8.5 mmol). The mixture was heated at 80° C. for 16 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (60:30:10) to give the desired product (1.5 g, 46%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-benzyloxyaniline (3.0 g), allyl bromide (1.27 mL), potassium carbonate (4.2 g) and dimethylformamide (15 mL) was heated at 80° C. for 3 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC. The product with the molecular weight of 239.32 (C16H17NO); MS (ESI):240 ([M+H]+), was obtained in this way.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=4[CH:17]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2CO1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[O:17]1[CH2:18][CH2:19][N:14]([C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCOCC2)CCCCCCCCCC1
Yield: 59.8 %

Procedure:
A two liter three-necked flask was charged with 366 grams (2.0 moles) cyclododecanone, 348 grams (4.0 moles) morpholine, 600 ml toluene and 3.0 grams (0.0158 moles) para-toluene sulfonic acid catalyst. A magnetic stir bar was added along with a few carbon boiling chips. A Dean-Stark water trap and condenser were then attached and the mixture brought to reflux with stirring. After 46 hours reflux, 75 ml. of aqueous phase had been collected. The mixture was then cooled and the excess toluene and morpholine removed at reduced pressure (25-50 mm Hg). The residue was then distilled under vacuum (0.6 mm Hg) to yield 300.5 grams of a viscous clear oil, 1-morpholino-1-cyclododecene, b.p. 135°-150° C., 60% yield.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7]N(C)C(Cl)=O.C[C:14]1[CH:22]=[N+:21]([O-])[CH:20]=[CH:19][C:15]=1[C:16]([O-:18])=[O:17]>C(Cl)Cl>[C:5]([C:20]1[CH:19]=[C:15]([CH:14]=[CH:22][N:21]=1)[C:16]([O:18][CH3:7])=[O:17])#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: CN(C)C(=O)Cl
Reactant: Cc1c[n+]([O-])ccc1C(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.5 %

Procedure:
Trimethylsilyl cyanide (3.8 g, 0.0386 mol) and dimethylcarbamyl chloride (5.0 g, 0.0483 mol) were added to a solution of methylisonicotinate N-oxide (5.0 g, 0.0322 mol) in dry CH2Cl2 (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h and then quenched with 10% K2CO3 solution. The organic product was extracted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica 230-400 mesh, eluent 1-2% MeOH in CH2Cl2) to afford methyl 2-cyanoisonicotinate (1.75 g, yield 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.97-8.95 (d, J=5.0 Hz, 1H), 8.41 (m, 1H), 8.15-8.13 (dd, J=4.8 Hz, 1.6 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].Cl[CH2:20][O:21][CH2:22]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:20][O:21][CH3:22])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: ClCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., to a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (6.85 g, 23 mmol) in dimethylformamide (100 mL) was added portionswise sodium hydride (60% in mineral oil, 1.01 g, 25.3 mmol), the mixture was stirred at 0° C. for further 30 minutes. Chloromethyl ether (2.02 g, 25.3 mmol) was slowly added in drops and when the addition finished, the mixture was stirred at room temperature for further 3 hours. Water (150 mL) was added, the mixture was extracted for two times with ethyl acetate, the combined organic phases were washed with saturated brine for one time and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20:1) to afford the target compound.