Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17](SC)=[C:16](F)[CH:15]=2)[O:3]1.O[O:25][S:26]([O-:28])=O.[K+].CO.[CH2:32]1COCC1.O>>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:26]([CH3:32])(=[O:28])=[O:25])[CH:15]=2)[O:3]1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1F
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)OC(c2cccc(S(C)(=O)=O)c2)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3((2H)-furanone (1.21 g: Example 264) dissolved in 150 ml 1:1:1 methanol/THF/water, was added 2.77 g of OXONE. The mixture was stirred at room temperature for four hours. Then the volatile solvent was removed in vacuo and the resulting solution was diluted with 50 ml water. The aqueous solution was extracted with dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography hexane/ethylacetate=4:1) to afford 520 mg of 2,2-dimethyl-5-{3-(methylsulfonyl)phenyl}-4-phenyl-3(2H)-furanone as a solid. mp: 190-191° C. NMR: δ1.55 (s, 6H), 3.23 (s, 3H), 7.26 (m, 2H), 7.38 (m, 3H), 7.56 (m, 2H), 7.92 (m, 1H). IR (cm−1): 1700, 1427, 1324, 1160, 1147. MS (FAB): 361 (m+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([N:34]2[CH2:38][CH2:37][O:36][C:35]2=[O:39])[CH:29]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1N1CCOC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derived from reduction of intermediate 117, 4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm: 9.48 (1H, dd, J=8.6, 6.5 Hz), 7.41 (2H, m), 7.32 (3H, m), 7.22 (1H, dd, J=9.6, 2.5 Hz), 7.08 (1H, td, J=8.6, 2.7 Hz), 5.21 (2H, s), 4.57 (2H, t, J=7.7 Hz), 4.50 (2H, s), 4.07 (4H, m), 3.99 (2H, m), 1:61 (6H, s). LCMS (M+H)+ m/z 523.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[C:10]1([CH3:20])C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)[Cl:22]>COCCOCCOC.C(O)C>[Cl:22][CH2:10][C:20]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: ClC(Cl)Cl
Reactant: Nc1ncccc1O
Solvent: CCO
Solvent: COCCOCCOC
Solvent: O
Product: ClCc1nc2ncccc2o1
Temperature: 80 °C

Procedure:
2-Amino-3-pyridinol (1.1 g, Chemical Abstracts #16867-03-1) and chloromethyltrimethylorthoformate (2.27 g) were combined in diglyme (in 21 mL) and heated at 80° C. for 6 hours. The mixture was treated with p-toluenesulfonic acid hydrate (4 mg) and heated at 80° C. for an additional 48 hours. The mixture was allowed to cool to room temperature and diluted with chloroform (40 mL) and ethanol (10 mL). The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in methanol and filtered again. The resulting filtrate was concentrated under reduced pressure to provide the title compound and then dissolved in acetonitrile (35 mL) and used as a solution in the next step. 1H NMR (CDCl3, 300 MHz) δ 4.82 (2H, s), 7.38 (dd, 1H, J=8.7, 5.4 Hz), 7.89 (dd, 1H, J=8.7, 1.5 Hz), 8.62 (dd, 1H, J=5.4, 1.5 Hz). MS (DCI/NH3) m/z 169 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].C(N(CC)CC)C>C(O)C>[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
5.0 gm (0.017 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.0 gm (0.02 mol) of triethylamine were refluxed in 250 ml of ethanol for 30 minutes. Subsequently, the reaction mixture was evaporated in vacuo, and the residue was stirred with water. After suction-filtering and drying, 5-acryloyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was obtained with a quantitative yield. Recrystallization from ethanol.
Reaction SMILES: [OH:1][N:2]=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C(=O)N(Cl)C(=O)C1.[CH2:24]([O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:25]#[CH:26].C(=O)(O)[O-].[Na+]>C1COCC1.CCN(CC)CC.CN(C=O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:24][C:25]2[O:1][N:2]=[C:3]([C@@H:4]3[CH2:8][CH2:7][CH2:6][N:5]3[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:26]=2)[CH:29]=1
Reactant: C#CCOc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=NO
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc(COc2cccnc2)on1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a DMF (60 mL) solution of the compound (8.57 g) obtained in Example 2-(1), NCS (5.341 g) was added in small portions at 0° C. and the mixture was stirred at room temperature for an hour. The reaction mixture was cooled to 0° C. and after adding a solution of 3-(prop-2-yn-1-yloxy)pyridine (2.663 g) in THF (5 mL) and a solution of Et3N (5.6 mL) in THF (15 mL), the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate (200 mL), followed by extraction with AcOEt (200 mL). The resulting organic layer was washed with brine (200 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (3.81 g, pale yellow solid.)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:13]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Br)(=O)C([Br:41])=O>ClCCl>[CH2:1]([O:8][C@@H:9]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:13]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][CH:10]1[Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C[C@H]1OCc1ccccc1
Reactant: O=C(Br)C(=O)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: BrC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Deoxy-2,4,6-tri-O-benzyl-glucopyranose (2.2 g) was dissolved in dichloromethane (20 mL) and dry DMF (880 μL) was added. The reaction solution was cooled at 0° C. and oxalyl bromide (500 μL) was added and the resulting solution stirred at 0° to 5° C. for 1 hour. The solution was then diluted with dichloromethane (100 mL) and washed with water (3×100 mL), dried over sodium sulfate, filtered and evaporated to dryness to obtain 3-deoxy-2,4,6-tri-O-benzyl-glucopyranosyl bromide (compound 13).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([N:27]2[CH2:28][CH2:29][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25][CH2:26]2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (350 mg, 0.906 mmol), 1-tert-butoxycarbonyl-4-piperidone(198 mg, 0.996 mmol), sodium triacetoxyborohydride (288 mg, 1.358 mmol) and glacial acetic acid(60 ul, 0.996 mmol) were mixed with 5 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until the pH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography to give 254 mg of 1-[1-(1-tert-butoxycarbonyl-4-piperidyl)-4-piperidyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 1.39(m, 13H), 1.75(m, 2H), 1.91(m, 2H), 2.17(m, 2H), 2.35(m, 2H), 2.72(m, 2H), 3.0 (m, 2H), 3.63(m, 1H), 3.98(m, 2H), 4.63(m, 1H), 7.16(m, 5H), 7.44(m, 2H), 7.67(d, J=8.60 Hz, 2H), 8.23(s, 1H); LC/MS (MH+=484).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH2:20])=[O:10])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added in toluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3 ml, 361 mmol) was added dropwise at room temperature, and the mixture was heated at 45° C. for 2 hours. The obtained reaction mixture was added dropwise to 25% aqueous ammonia (325 ml) while keeping the mixture at 5-20° C. The mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with 20 water and isopropyl ether and dried under reduced pressure to give 4-(trifluoromethyl)cinnamamide (60.76 g, yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[O:29][C:30]([C:33]([F:36])([F:34])[F:35])=[N:31][N:32]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Product: Cl
Product: Fc1ccc(COc2ccc(Nc3ncnc4ccc(-c5nnc(C(F)(F)F)o5)cc34)cc2)cc1

Procedure:
The title compound was prepared according to Procedure A from 4-(4-fluoro-benzyloxy)aniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.81(1H,bs), 9.53(1H,s), 8.91(1H,s), 8.67(1H,dd), 8.13(1H, d), 7.63(2H,d), 7.54(2H,dd), 7.25(2H,dd), 7.15(2H,d), 5.15(2H,s); m/z (M+1+) 482.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].N1CCCCC1.C(OCC)(=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)C(OCC)OCC
Yield: 102 %

Procedure:
A mixture of 2-chloro-5-nitrobenzaldehyde (3.73 g), ethyl 4,4-diethoxyacetoacetate (4.365 g) and piperidine (272.5 mg) in benzene (10 ml) was refluxed under azeotropic dehydration for 1.5 hours. To the mixture was added ethyl acetate, and the resultant mixture was washed three times with water and then with an aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a reddish brown oil (7.87 g) of ethyl 2-(2-chloro-5-nitrobenzylidene)-4,4-diethoxyacetoacetate. The mixture of thus obtained reddish brown oil and ethyl 3-aminocrotonate (3.48 g) was heated with stirring at 105° to 107° C. in an oil bath for 4.5 hours. The resultant mixture was extracted with ethyl acetate, and the extract was washed with water three times and then with an aqueous solution of sodium chloride, and dried over magnesium sulfate. After removal of the solvent from the extract, the obtained residue (10.87 g) was subjected to column chromatography on silica gel with an eluent (a mixture of 20 parts of chloroform and one part of ethyl acetate by volume). The fractions were checked with thin-layer chromatography and crystals (6.02 g) were obtained by removing the solvent from the fraction containing the designated substance. The crystals were recrystallized from a mixture of diethyl ether and n-hexane to give crystals of diethyl 2-methyl-4-(2-chloro-5-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 117° to 118° C.
Reaction SMILES: [CH3:1][C:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[CH:9]1)[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.C1C=CC2[N:42]([OH:43])N=NC=2C=1.[O:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1NO>C(Cl)Cl.O>[CH3:1][C:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[CH:9]1)[C:3]([NH:42][O:43][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][O:44]1)=[O:5]
Reactant: On1nnc2ccccc21
Reactant: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)O)S(C)(=O)=O
Reactant: ONC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoic acid (304.6 mg, 0.945 mmol, 1 eq) in DCM (10 mL) was added TEA (172 mg, 1.70 mmol, 0.237 mL, 1.80 eq), EDCI (254 mg, 1.32 mmol, 1.4 eq), HOBT (260 mg 1.70 mmol, 1.80 eq) and O— tetrahydro-2-H-pyran-2-ylhydroxylamine (166 mg, 1.42 mmol, 1.5 eq). The reaction was allowed stir at RT overnight. The reaction mixture was diluted with DCM and water. The aqueous layer was extracted several times with DCM and the combined organic layers were dried (MgSO4), filtered and concentrated. The crude product mixture was absorbed onto silica gel and purified by flash chromatrography on silica gel eluting with an EtOAc-heptane gradient to give 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (24 mg, 6% yield). LC-MS M+H+422.6.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:18]([CH:15]1[CH2:14][CH2:13][N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:17][CH2:16]1)[C:1](=[O:3])[CH3:2]
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
0.2 mole of acetyl chloride is slowly added to a solution containing 0.2 mole of N-[1-(benzyl)-4-piperidyl]-N-methylamine, 0.2 mole of triethylamine and 500 cm3 of methylene chloride. The mixture is left in contact for 2 hours, evaporated, taken up in ether and then washed with water. After evaporation, an oil which corresponds to the expected compound is obtained:
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:12])[CH:3]=1.S(Cl)([Cl:15])=O>ClCCl>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(C)cc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)c(C)cc1Br

Procedure:
10.3 g (45 mmol) of 4-bromo-2,5-dimethylbenzoic acid are dissolved in 250 ml of dichloromethane and after the addition of 9.9 ml of (135 mmol) of thionyl chloride refluxed for two hours. Then the mixture is evaporated to dryness.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:34])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](Cl)(=[O:31])=[O:30])=[C:13]1[CH3:33])[CH3:8]>N1C=CC=CC=1.O>[CH2:7]([O:9][C:10](=[O:34])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:31])=[O:30])=[C:13]1[CH3:33])[CH3:8]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Reactant: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCCC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a stirred solution of piperidine (0.36 mL, 3.6 mmol) in pyridine (50 mL) was added 2-(3-(2-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester (1.53 g, 3.6 mmol), and the resulting solution stirred at room temperature for 18 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated copper sulfate solution (×3), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 2-(5-fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-1H-indol-1-yl)acetic acid ethyl ester (1.23 g, 2.60 mmol, 72%) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:11](=O)[CH2:10][C:9]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[CH2:13]2)[CH2:8]1.O>O1CCCC1.C1C=CC=CC=1>[NH:7]1[CH2:11][CH2:10][C:9]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([OH:21])[CH2:13]2)[CH2:8]1
Reactant: O=C1CC2(CN1)CC(=O)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: OC1CC2(CCNC2)c2ccccc21
Reaction time: 20 h

Procedure:
17.1 g of lithium aluminium hydride in 300 cc of absolute tetrahydrofuran and 600 cc of absolute benzene are placed in a Soxhlet apparatus. 30 g of the spiro[indan-1,3'-pyrrolidin]-3,5'-dione to be reduced are placed in the Soxhlet apparatus in a Soxhlet capsule. Boiling at reflux is then effected for 20 hours, whereby the entire product is dissolved. The reaction mixture is subsequently cooled and carefully decomposed with 25 cc of water in 25 cc of tetrahydrofuran, the precipitate is filtered off and the filtrate concentrated. Spiro[indan-1,3'-pyrrolidin]-3 -ol is obtained as light yellow oil and is converted into its hydrogen fumarate by reacting with a solution of 17 g of fumaric acid in 400 cc of ethanol. M.P. 155°-158° (from ethanol/ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:17]([O:16][C:14]([NH:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Reactant: CN1CCNCC1
Product: COC(=O)c1cc(NC(=O)OC(C)(C)C)c(Cl)c(N2CCN(C)CC2)c1

Procedure:
Methyl 3-((tert-butoxycarbonyl)amino)-4-chloro-5-(4-methylpiperazin-1-yl)benzoate was prepared starting from methyl 3-bromo-5-((tert-butoxycarbonyl)amino)-4-chlorobenzoate (Intermediate 3) and 1-methylpiperazine according to procedure for example 1A
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].O(Cl)Cl.[P+5].CO[CH:16](OC)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:7][O:8][CH:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:6][C@H:3]1[CH2:4][OH:5]
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CC(C)(CO)[C@@H](O)CO
Agent: ClOCl
Agent: [P+5]
Solvent: ClCCl
Product: COc1ccc(C2OCC(C)(C)[C@H](CO)O2)cc1
Yield: 66.1 %

Procedure:
Following the general procedure for the transacetalization reaction of Description 6, 21.4 g (160.0 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 400 mL of dichloromethane (DCM) in the presence of 932 μL (1.53 g, 10.0 mmol) of phosphorus(V) oxychloride (POCl3) with 45.6 g (250.0 mmol) of para-anisaldehyde dimethyl acetal. Two-fold purification by silica gel column chromatography using tert-butyl methyl ether (MTBE) and hexane (Hxn) mixtures as eluent (MTBE/Hxn=3:7→MTBE/Hxn=2:3→MTBE/Hxn=1:1→MTBE/Hxn=2:1→MTBE/Hxn=3:1) provided 26.7 g (66% yield) of the title compound (8a) as a pale-yellow liquid. Rf=0.26 (MTBE/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.01-2.05 (m, 1H), 3.59-3.3.63 (m, 1H), 3.66-3.73 (m, 4H), 3.82 (s, 3H), 5.48 (s, 1H), 6.88-6.94 (m, 2H), 7.42-7.46 (m, 2H) ppm. MS (ESI) m/z: 253.1 (M+H)+. The analytical data for the compound was consistent with that given in the literature (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122). Similar yields were obtained using camphorsulfonic acid (CSA) as the acidic catalyst.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:23](=[O:25])[CH3:24])[C:12]([O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:13][CH:14]=2)[CH:9]=1.[OH:27][C:28]1[C:33]([CH2:34][CH2:35][CH3:36])=[C:32]([OH:37])[CH:31]=[CH:30][C:29]=1[C:38](=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:23](=[O:25])[CH3:24])[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:37][C:32]3[CH:31]=[CH:30][C:29]([C:38](=[O:40])[CH3:39])=[C:28]([OH:27])[C:33]=3[CH2:34][CH2:35][CH3:36])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: COC(=O)CCCOc1ccc2ccc(OCCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 63.1 %

Procedure:
A mixture of 1.8 g of 4-[[8-acetyl-7-(3-bromopropoxy)-2-naphthlenyl]oxy]butanoic acid methyl ester, 1 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.9 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone and 6 ml of anhydrous dimethylformamide was stirred at reflux for 15 hours. The mixture was filtered and the filtrate was concentrated in vacuo to an oil which was dissolved in ethylacetate and washed with water, 1N sodium hydroxide solution and sodium chloride solution. The oil resulting from the ethyl acetate extract was purified by flash column chromotography to yield 1.44 g (63%) of 4-[[8-Acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester as an oil.