Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCCCS(=O)(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Product: O=C1CCC(c2ccc(S(=O)(=O)CCCNCC(O)COc3ccc(CCOCC4CC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][N:2](C)C.Cl[C:6]1[N:11]=[C:10]([O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([NH2:23])=[CH:15][CH:14]=2)[CH:9]=[CH:8][N:7]=1>CN(C)C=O.[C-]#N.C([N+](CC)(CC)CC)C>[NH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([C:1]#[N:2])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C
Reactant: Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CN(C)C=O
Product: N#Cc1nccc(Oc2ccc(N)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a 0° C. solution of trimethyl amine (20% solution in water, 3.8 mmol) in 2 mL of dimethylformamide was added 4-(2-chloro-pyrimidin-4-yloxy)-naphthalen-1-ylamine (270 mg, 1 mmol). The deep tan solution was warmed to room temperature for 3 h, during which the initially light suspension became a brown suspension. After this time, tetraethylammonium cyanide (156 mg, 1 mmol) was added all at once to provide a deep amber solution. After 1 h, the reaction was quenched with water, extracted with EtOAc and dried over magnesium sulfate. Column chromatography (10-60% EtOAc-hexanes) provided 142 mg (54%) of 4-(4-amino-naphthalen-1-yloxy)-pyrimidine-2-carbonitrile.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>C(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH2:9])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(C(F)(F)F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 68 %

Procedure:
To a stirring solution of 2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-1,3-dione (9 g, 28.0 mmol) in ethanol (90 mL) was added hydrazine hydrate (1.543 g, 30.8 mmol) at RT. Reaction mixture was stirred for 16 h. Reaction mixture was filtered and filtrate was diluted with water and extracted with EtOAC. The organic layer was separated and distilled out to get the titled compound in 68% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH:4]([CH2:5][CH3:6])[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(O)CCCl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(CCCl)O[Si](C)(C)C(C)(C)C

Procedure:
Using the procedure of Example 6A substituting 1-chloro-3-pentanol (50 g, 0.41 moles), tert-butyldimethylsilyl chloride (71, 0.47 moles), imidazole (32.6 g, 0.48 moles), and dimethylformamide (150 ml), there is obtained (3-chloro-1-ethylpropoxy)(1,1-dimethylethyl)dimethylsilane. The crude product is fractionally distilled under vacuum leaving a clear, colorless oil (78 g, 0.33 moles), BP 48° C./0.1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2ccc(O)cc2n1Cc1ccc(Br)cc1
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1nc2ccc(OCc3ccc(C)cn3)cc2n1Cc1ccc(Br)cc1
Reaction time: 12 h

Procedure:
To a 10 mL round-bottomed flask were added a stir bar, ethyl 3-(1-(4-bromobenzyl)-6-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (100 mg, 0.23 mmol), cesium carbonate (227 mg, 0.69 mmol), DMF (2 mL), and 2-(chloromethyl)-5-methylpyridine hydrochloride salt (41 mg, 0.23 mmol). After 12 h, the mixture was partitioned between water (50 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2×20 mL). The combine organic layers were dried with sodium sulfate, filtered, and concentrated to dryness (124 mg, 99%). MS (ESI): mass calcd. for C28H30BrN3O3, 535.15; m/z found, 536.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].O>N1C=CC=CC=1>[CH2:12]([Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:11][CH2:10][C:3]([CH2:2][O:1][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])([CH2:8][O:9][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])[C:4]([O:6][CH3:7])=[O:5])[CH3:13]
Reactant: COC(=O)C(CO)(CO)CO
Reactant: CC[Si](Cl)(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: CC[Si](CC)(CC)OCC(CO[Si](CC)(CC)CC)(CO[Si](CC)(CC)CC)C(=O)OC

Procedure:
To a stirred solution of methyl 3-hydroxy-2,2-bis(hydroxymethyl)propanoate (1 equivalent) in pyridine at rt is added triethylsilyl chloride (3-6 equivalents) and the mixture is stirred at temperatures between rt and 60° C. until the reaction is substantially complete as monitored by LCMS or TLC. Water is added and the mixture is extracted with diethyl ether. The combined extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford methyl 3-(triethylsilyloxy)-2,2-bis((triethylsilyloxy)methyl)propanoate.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:29])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(-c2ccc(Cl)cc2Cl)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(-c2ccc(Cl)cc2Cl)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 85.6 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({cyclohexyl[5-(2,4-dichlorophenyl)-2-methyl-3-furyl]methyl}amino)benzoic acid (458 mg) as well as ethyl 3-(methylamino)propanoate (157 mg) to give the title compound (465 mg, 85%) as an amorphous compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][CH:4]1[CH2:7][CH:6]([C:8]([O:10]CC)=[O:9])[CH2:5]1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[O:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]1
Reactant: CCOC(=O)C1CC(OC(F)(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(OC(F)(F)F)C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a stirred solution of Intermediate 212B (0.10 g, 0.47 mmol) in THF (5 mL) was added NaOH (0.038 g, 0.943 mmol) in water (1 mL) and the mixture was allowed to stir at 60° C. for 4 h. The reaction mixture was quenched with a 1.5 N aqueous solution of HCl and extracted with EtOAc (2×20 mL) The combined organic layers were dried over Na2SO4, filtered and the filtrate evaporated to afford Intermediate 212C as a light brown liquid (30 mg, 35% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.01-12.03 (bs, 1H), 3.34 (m, 2H), 1.04 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([N:7]1[C:13]2[CH:14]=[C:15]([C:18](=[O:22])[CH2:19][CH2:20]Cl)[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5]>ClCCl>[C:4]([N:7]1[C:13]2[CH:14]=[C:15]([C:18](=[O:22])[CH2:19][CH2:20][N:2]([CH3:3])[CH3:1])[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5]
Reactant: CC(=O)N1CCCCc2ccc(C(=O)CCCl)cc21
Reactant: CNC
Solvent: ClCCl
Product: CC(=O)N1CCCCc2ccc(C(=O)CCN(C)C)cc21
Reaction time: 4 h

Procedure:
50% aqueous dimethylamine (27 ml) was added to a solution of 1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-3-chloro-1-propanone (7.10 g, 25.4 mmol) obtained in Reference Example 7 in dichloromethane at room temperature, and then stirred for 4 hours. After the reaction solution was separated, the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=1:1) and crystallized from hexane, whereby the title compound (5.38 g) was obtained as colorless powder with a mp. of 68 to 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH2:19])=[O:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=[O:18])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To solution of (4-bromo-phenoxy)-acetic acid (100 mg, 0.43 mmol), 2-amino isonicotinamide (89.39 mg, 0.65 mmol) and DMAP (106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP (452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1˜2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.083 g, 55% yield).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.C(O)(=[O:12])C>>[N+:1]1([O-:12])[C:9]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[NH:3][CH:2]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: CC(=O)O
Product: [O-][n+]1c[nH]c2ncccc21
Reaction time: 3 h

Procedure:
Mcpba (8.7 g, 50 mmol) was added at room temperature to 3H-imidazo[4,5-b]pyridine (5.0 g, 42 mmol) in acetic acid (84 mL, 1469 mmol). The mixture was stirred for 3 hours. The resulting precipitate was filtered and rinsed with Et2O, it gave 4-azabenzimidazole-N-oxide. To 4-azabenzimidazole-N-oxide (2.00 g, 14.8 mmol) phosphorous oxychloride (25.00 mL, 266 mmol) was added at room temperature. The solution was heated to 90° C. for 18 h. The solution was cooled and the rest POCl3 was distilled off in vacuo. The residue was dissolved in CH3CN and quenched with slow addition of ice-water. The mixture was basified to PH 9 with 50% NaOH solution. At room temperature the resulting precipitates were filtered. The collected solid was dissolved in MeOH and insoluble residue was removed by filtration. The filtrates were concentrated and the residue was purified by flash chromatography over silica gel, using 3:7 EtOAc-hexane, gave 7-chloro-3H-imidazo[4,5-b]pyridine (1.20 g, 52.8%). To the mixture of di-tert-butylpyrocarbonate (1193 mg, 5465 μmol), 7-chloro-3H-imidazo[4,5-b]pyridine (0.763 g, 4968 μmol) in acetonitrile (15 mL), 4-(dimethylamino)pyridine (61 mg, 497 μmol) was added. The mixture was stirred at room temperature overnight. Evaporation of the solvent, flash chromatography of the residue over silica gel, using 0% to 25% EtOAc/hexane, gave tert-butyl 7-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylate, Mass Spectrum (ESI) m/e=253.0 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH:9]([CH2:29][OH:30])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:15]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:16].[CH:31]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[CH:42]=1)[CH:38]=O)([CH3:33])[CH3:32].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[OH:8][CH:9]([CH2:29][OH:30])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:15]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:38][C:37]2[CH:40]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[CH:42]=[C:35]([O:34][CH:31]([CH3:33])[CH3:32])[CH:36]=2)[CH2:20][CH2:19]1)=[O:16]
Reactant: COc1cc(OCC(O)CO)cc(C(=O)NC2CCNCC2)c1
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cc(OCC(O)CO)cc(C(=O)NC2CCN(Cc3cc(OC(C)C)cc(OC(C)C)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), crude rac-3-(2,3-dihydroxy-propoxy)-5-methoxy-N-piperidin-4-yl-benzamide trifluoroacetate was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 531.3 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[OH-].[K+].O>CS(C)=O>[C:23]([O:22][C:20](=[O:21])[NH:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 93.1 %

Procedure:
A mixture of N-(4-fluoro-3-nitrophenyl)benzamide (1.00 g, 3.8 mmol), N-Boc-4-hydroxyaniline (0.83 g, 3.8 mmol) and 85% KOH (0.51 g, 7.7 mmol) in DMSO (20 mL) was heated at 80° C. for 1 hour, and then poured into H2O (100 ml) under stirring. The resulting oily crystal was extracted with EtOAc. The extract was washed with H2O (3 times) and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound, which was purified by washing with i-Pr2O to give the desired compound as yellow crystals (1.59 g, 92%).
Reaction SMILES: [Li].[N:2]1([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11]3[CH2:28][CH2:29][CH2:30][C:10]=3[N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>O1CCCC1>[N:2]1([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4([CH2:25][OH:26])[CH2:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[C:11]3[CH2:28][CH2:29][CH2:30][C:10]=3[N:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Agent: [Li]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Reaction time: 10 h

Procedure:
Lithium aluminumhydride (2M solution in tetrahydrofuran, 1.5 mL) was added drop-wise to a solution of 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid (0.61 g, 1.52 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. to 5° C. After addition, the reaction mixture was warmed to a temperature in the range of 15° C. to 40° C. and stirring continued for an additional 10 hours. The reaction was quenched by addition of aqueous sodium hydroxide. The precipitated solid was filtered and washed with ethyl acetate. The combined filtrates were washed with brine, dried over Na2SO4, filtered, and concentrated to yield a white solid. The title compound was afforded following purification by column chromatography (silica gel) as a white solid (0.56 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC=CCC1CSc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: O=C(O)C1CC=CCC1CSc1ccc(F)cc1
Reaction time: 19 h

Procedure:
A solution of methyl(1R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylate (656 mg, 2.34 mmol) in methanol (1.0 ml) and ethylene glycol dimethyl ether (5.0 ml) was treated with a 2 M aqueous solution of lithium hydroxide (6.0 ml). After stirring for 19 h, the reaction mixture was adjusted to pH 2 with a 2 M aqueous solution of hydrochloric acid and partitioned between water and ethyl acetate. After separating the organic phase, the aqueous phase was extracted with an additional portion of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent on a rotary evaporator provided (1R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylic acid as a golden-yellow syrup.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:21][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: Sc1ccccn1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCSc2ccccn2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 2-mercaptopyridine.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH:17]=[O:18])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2].CC(=CC)C.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:16])([C:17]([OH:26])=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C=O)CC2
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2.3 g of 6-nitro-2-formyl-2,5,7,8-tetramethylchroman was dissolved in 150 ml of t-butanol and 23 g of 2-methyl-2-butene was added at room temperature. An aqueous solution prepared by dissolving 5.8 g of sodium chlorite and 7.6 g of sodium dihydrogen phosphate dehydrate in 60 ml of water was added dropwise at room temperature, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction solution was poured into water and then extracted with ether. The organic layer was partitioned with an aqueous 5% sodium hydrogen carbonate solution and the ether layer was discarded. The pH of the aqueous layer was adjusted to 4 with 10% hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the resulting crystal was washed with hexane to obtain 1.6 g of the objective product.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1cccc(CBr)c1OCC
Product: CCCc1c(OCc2cccc(C(=O)OCC)c2OCC)ccc(C(C)=O)c1O

Procedure:
1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with 3-(bromomethyl)-2-ethoxybenzoic acid ethyl ester according to the procedure of Example 69 and the product was purified by HPLC to give 3--[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid ethyl ester, the title compound, m.p. 59°-62° in 90% yield.
Reaction SMILES: [ClH:1].C([N:6]([N+:13]1[N-:14][O:15][C:16](=[NH:18])[CH:17]=1)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(C)(C)C.C(OC(C)C)(=O)C>Cl>[ClH:1].[CH:7]1([NH:6][N+:13]2[N-:14][O:15][C:16](=[NH:18])[CH:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)N(C1CCCCC1)[n+]1cc(=N)o[n-]1
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: N=c1c[n+](NC2CCCCC2)[n-]o1
Reaction time: 24 h

Procedure:
A solution of 4 g of 3-(tert.-butyl-N-cyclohexyl-amino)sydnonimine hydrochloride in 30 ml of concentrated ethanolic hydrochloric acid is left to stand at room temperature for one day and then concentrated in a rotary evaporator. The residue is purified by column chromatography (silica gel, CH2Cl2 :MeOH=9:1) and the residue obtained after concentration of the corresponding fractions is stirred with isopropyl acetate and filtered off with suction. Yield: 2.5 g melting point: 90° C. (decomp.)
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[Br:14]N1C(=O)CCC1=O.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:14][CH:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(Br)C2=O
Temperature: 60 °C
Yield: 86.2 %

Procedure:
5-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.0 g, 5.8 mmol), 1-bromopyrrolidine-2,5-dione (1.04 g, 5.8 mmol) and 4-methylbenzenesulfonic acid hydrate (0.111 g, 0.58 mmol) were ground in a porcelain mortar. The resulting powder was placed in a vial, and heated at 60° C. for 12 mins. The mixture became a muddy liquid at 60° C. After cooling to room temperature, the mixture was dissolved in CH2Cl2 (80 mL). The solution was washed with saturated NaHCO3, water, brine, and dried (MgSO4). Solvent was evaporated off to give racemic 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.25 g, 5.0 mmol, 86% yield) as a yellow solid: LCMS=249.98 [M+H]+.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(OC(C)(C)C)=O)CC1.[CH:30]1([C:33]2[C:34]([O:47][CH2:48][C:49]3([CH3:57])[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([O:40]C(C)(C)C)=[O:39])[CH2:32][CH2:31]1>>[CH:30]1([C:33]2[C:34]([O:47][CH2:48][C:49]3([CH3:57])[CH2:50][CH2:51][C:52]([F:56])([F:55])[CH2:53][CH2:54]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([OH:40])=[O:39])[CH2:31][CH2:32]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(F)(F)CC1
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 4, and making variations as required to replace tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoate, the title compound was obtained as a colorless solid (2.74 g, 86%): MS (ES+) m/z 343.2 (M+1).