Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9](OC1C=CC(S(C)(=O)=O)=CC=1)=[O:10])=[O:4].[CH2:23]1[CH2:28][CH2:27][C:26]([CH2:33][NH2:34])([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)C>[CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([NH:34][CH2:33][C:26]1([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27]1)=[O:10])=[O:4]
Reactant: CC(C)C(=O)OCCOC(=O)Oc1ccc(S(C)(=O)=O)cc1
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)C(=O)OCCOC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A 50 mL, single-neck, round-bottomed flask equipped with a magnetic stir bar and a nitrogen inlet was charged with sulfone D3 (300 mg, 1 mmol) and gabapentin (171 mg, 1 mmol) in acetonitrile (1 mL). To the resulting slurry, saturated aqueous potassium bicarbonate (1 mL) was slowly added over a period of two minutes. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into a separatory funnel, diluted with diethyl ether (20 mL), washed with 5% aqueous sulfuric acid (10 mL), water (10 mL), and brine (100 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum to give a viscous oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E4 as a viscous oil (250 mg, 75% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=6.8 Hz, 6H), 1.35-1.55 (m, 10H), 1.46 (d, J=5.2 Hz, 3H), 2.32 (s, 2H), 2.52 (m, 1H), 3.23 (d, J=6.8 Hz, 2H), 5.27 (t, J=6.4 Hz, 1H, —NH) 6.76 (q, J=5.6 Hz, 1H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][OH:18].O>CO>[OH:18][CH2:17][CH2:16][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2
Reactant: OCCBr
Reactant: O=C1CCc2c(O)cccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CCc2c(cccc2OCCO)N1
Yield: 16.5 %

Procedure:
4.2 Grams of potassium hydroxide were dissolved in 200 ml of methanol, then 10 g of 5-hydroxy-3,4-dihydrocarbostyril were added thereto. Next, 10 g of 2-bromoethanol were added dropwise thereto under refluxing conditions. The reaction mixture was further refluxed for 4 hours, then was concentrated. To the residue thus obtained was added water, and the insoluble matter was collected by filtration, and was washed with water, then recrystallized from methanol to yield 2.1 g of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 176°-178° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[N-:23]=[N+:24]=[N-:25].[Na+].O.[OH-].[Na+]>CN(C)C=O>[N:23]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.0 g, 3.2 mmol) and sodium azide (0.23 g, 3.5 mmol) in N,N-dimethylformamide (5 mL) was heated and stirred at 100° C. for 30 minutes. The solution was cooled to room temperature, and poured into water, and the resulting solution was made basic by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. To a solution of the ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in ethanol (150 mL) was added 10% palladium-carbon (1.2 g, 50% hydrate), and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (basic silica gel, ethyl acetate:methanol=93:7) gave the title compound (900 mg, 96% yield).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:16][CH2:15][C:5]2([CH2:9][NH:8][C@H:7]([C:10]([O:12]CC)=[O:11])[CH2:6]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45].C(N(CC)CC)C>C(Cl)Cl>[F:17][C:2]1([F:1])[CH2:3][CH2:4][C:5]2([CH2:9][N:8]([C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:44]([O:43][CH3:42])=[O:45])[C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]2)[CH2:15][CH2:16]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)[C@@H]1CC2(CCC(F)(F)CC2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CCC(F)(F)CC2)C[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of ethyl (3S)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylate (115), (380 mg, 1.54 mmol) in anhydrous CH2Cl2 (10 mL) was added HATU (614 mg, 1.6 mmol), N-[(methyloxy)carbonyl]-L-valine (283 mg, 1.6 mmol) followed by triethylamine (0.43 mL, 3.1 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. The reaction was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 15-80% hexanes/EtOAc. Appropriate fractions were combined and concentrated in vacuo. The residue was dissolved in THF/water/methanol (5 mL/2.5 mL/2.5 mL) and lithium hydroxide monohydrate was added (119 mg, 2.8 mmol) and the solution stirred at room temperature for 30 min. The reaction was treated with 1N HCl (3.5 mL) and partitioned between EtOAc and water (50 mL each). The aqueous layer was extracted with ethyl acetate (50 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo. The residue was triturated in diethyl ether and concentrated in vacuo to afford the title compound as a white solid (542 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s., 1H) 7.41 (d, J=8.0 Hz, 1H) 4.24 (t, J=8.6 Hz, 1H) 3.95-4.14 (m, 2H) 3.52 (s, 3H) 3.25-3.33 (m, 1H) 2.22 (dd, J=12.3, 8.4 Hz, 1H) 1.79-2.11 (m, 5H) 1.58-1.77 (m, 3H) 1.41-1.59 (m, 2H) 0.93 (dd, J=12.7, 6.6 Hz, 6H). LC-MS ESI (M+H)+=377.23.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH3:13])[CH3:2].O.[NH2:18][NH2:19]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])[NH:19][N:18]=1)=[O:16])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ocnc1C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ocnc2C)[nH]n1
Yield: 50.6 %

Procedure:
A mixture of 2,4-diketo4-(4-methyloxazol-5-yl)butyric acid ethyl ester (8.50 g), hydrazine hydrate (1.88 g), and ethanol (100 ml) was refluxed for 3 hours and concentrated. The residue was chromatographed (silica gel, Hex/EtOAc 1/1) to yield 4.20 g of 3-ethoxycarbonyl-5-(4-methyloxazol-5-yl)pyrazole as tan solids, mp 131°-133° C. (methanol/isopropyl ether). NMR: 1.42 (t, 3H), 2.48 (s, 3H), 4.44 (q, 2H), 7.05 (s, 1H, 4-pyrazolyl H), 7.85 (s, 1H, 2-oxazolyl H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.I[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:13]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: CCCI
Reactant: COC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cccnc1C(=O)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of methyl 3-hydroxypicolinate (0.472 g, 3.08 mmol) in N,N-dimethylformamide (6 ml) were added 1-iodopropane (0.33 ml, 3.38 mmol) and potassium carbonate (0.519 g, 3.76 mmol), and the mixture was stirred at 80° C. for 3 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 3-propyloxypicolinate (0.418 g, 2.14 mmol, yield 69%). This was dissolved in methanol (5 ml), 1N-aqueous sodium hydroxide m solution (5 ml) was added at room temperature, and the mixture was stirred at 60° C. for 3.5 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 5%-aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 3-propyloxypicolinic acid (0.248 g, 1.37 mmol, yield 64%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH3:29])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(C(C)c3ccccc3)C2=O)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and (1-bromoethyl)benzene, to give the desired product as a white foam (67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C:29]([CH2:34][O:35][CH3:36])([CH2:31][O:32][CH3:33])[C:28]3=[N:37][N:38]=[N:39][N:27]3[C:26]=2[CH:40]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[CH3:33][O:32][CH2:31][C:29]1([CH2:34][O:35][CH3:36])[C:28]2=[N:37][N:38]=[N:39][N:27]2[C:26]2[CH:40]=[C:22]([NH:21][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[CH2:17][C@H:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)[CH:23]=[CH:24][C:25]=2[O:30]1
Reactant: COCC1(COC)Oc2ccc(N)cc2-n2nnnc21
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COCC1(COC)Oc2ccc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)cc2-n2nnnc21
Temperature: 100 °C

Procedure:
A mixture of (7R,8aS)-N-(2-choro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (36 mg, 0.12 mmol, 1 equiv), 8-amino-4,4-bis(methoxymethyl)-4H-tetrazolo[5,1-c]-[1,4]-benzoxazine (40 mg, 0.14 mmol, 1.2 equiv) and pTsOH.H2O (46 mg, 0.24 mmol, 2.0 equiv) in isopropanol (1.0 mL) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed and the residue was purified by column chromatography using a mixture of DCM/2N NH3 in MeOH (95:5) to give the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:17]([C:21]1[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]2[O:28][C:27](=[O:29])[CH:26](O)[C:25]=2[CH:31]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCCl.O>[C:17]([C:21]1[CH:22]=[C:23]([C:32]([CH3:34])([CH3:35])[CH3:33])[C:24]2[O:28][C:27](=[O:29])[CH:26]([C:7]3[C:2]([CH3:1])=[C:3]([CH3:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=3[CH3:8])[C:25]=2[CH:31]=1)([CH3:19])([CH3:18])[CH3:20]
Reactant: Cc1cc(C)c(C)c(C)c1C
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: Cc1c(C)c(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c(C)c1C
Yield: 89.3 %

Procedure:
11.5 g (77.5 mmol) of pentamethylbenzene and 10 ml (85.0 mmol) of tin tetrachloride are added to a solution of 19.7 g (75.0 mmol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 50 ml of 1,2-dichloroethane and the reaction mixture is refluxed for 1 hour. The reaction mixture is diluted with water and extracted three times with toluene. The organic phases are combined, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 26.3 g (89%) of 5,7-di-tert-butyl-3-(2,3,4,5,6-pentamethylphenyl)-3H-benzofuran-2-one, m.p. 185°-190° C. (compound (111), Table 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: Cc1cc(-n2nc(C(=O)N3CCNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
50 mg (0.11 mmol) of the compound of Example 48A is reacted analogously to the synthesis of the compound of Example 1 with 12 mg (0.12 mmol) of 2-oxopiperazine. 51 mg (86% of theory) of the title compound is obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.00 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 352 mg (72%) colorless powder.
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[C:15](=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)([CH3:17])[CH3:16]>O>[CH:6]1([C:15]([CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)([CH3:17])[CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CC(C)=C1C=Cc2ccccc21
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: O
Product: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
18.8 cm3 (47.0 mmol) of n-butyllithium were added at 0° C. to a solution of 5.93 g (47.0 mmol) of indene (industrial, 91% pure) filtered over Al2O3. After the mixture had been stirred at room temperature for 15 minutes, the solution was slowly added dropwise to a solution of 7.40 g (47.0 mmol) of 1-isopropylideneindene. After the mixture had been stirred at room temperature for 2 hours, 50 cm3 of water were added and the mixture was extracted with diethyl ether. The yellow organic phase was dried over MgSO4. The residue which remained after the solvent had been stripped off was chromatographed on silica gel 60. 1.5 g (13%) of the product (2 isomers) could be isolated with hexane/methylene chloride (10:1).
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[C:12]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[C:6]([F:11])[CH:5]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Br)cc1F
Reaction time: 48 h

Procedure:
Methyl iodide (182.1 mL, 1.319 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2-fluorophenol (210 g, 1.099 mol; see step (i) above) and K2CO3 (303.92 g, 2.19 mol) in dry acetone (1.7 L). Stirring was continued at 60° C. for two days under a nitrogen atmosphere before the reaction mixture was filtered and the solvent was concentrated under reduced pressure. This provided 4-bromo-2-fluoro-1-methoxybenzene (225 g) as a liquid, which was employed directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>COCCOC.CCOCC>[CH3:24][O:19][C:18](=[O:20])[CH2:17][C@@H:16]([OH:21])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 450 mg (1.52 mmoles) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid in 1,2-dimethoxyethane, while being cooled in ice, was added dropwise 7 ml (4.56 mmoles) of a solution of diazomethane in ether. The mixture was stirred for 30 minutes. The reaction mixture was evaporated to dryness to yield 461 mg (98% yield) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid methyl ester; [α]D21 +1°.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:8](=[O:23])[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][NH:22][C:34](=[O:36])[CH3:35])=[CH:17][CH:18]=3)=[CH:12]2)=[C:4]([F:26])[CH:3]=1
Reactant: NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
According to Scheme 19 Step 3: To a solution of 1-(4-chloro-2-fluorobenzyl)-5-(4-(2-aminoethoxy)phenyl)pyridin-2(1H)-one (1 eq, 0.18 mmol, 0.07 g) in CH2Cl2 (5 mL) at 0° C. were added Et3N (6 eq, 1.10 mmol, 0.15 mL) and 30 min. later acetyl chloride (1.5 eq, 0.27 mmol, 19 μL) and. The reaction mixture was stirred 1 hour at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 70/30) to afford N-(2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)ethyl)acetamide (0.08 mmol, 0.04 g, 47%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][C:3]=1[N+:16]([O-])=O.C(O)C.[Na+].[SH-]>O>[NH2:16][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH2:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: C=C(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CCO
Product: C=C(c1ccccc1)c1ccc(N)c(N)c1
Yield: 83 %

Procedure:
1-(4-Amino-3-nitrophenyl)-1-phenylethylene (7.7 g., 0.032 mole) was dissolved in refluxing ethanol (450 ml.). To this was added, dropwise, a solution of sodium sulfhydrate (38.5 g., 0.45 mole) in water (110 ml.). The resulting solution was refluxed overnight. The reaction mixture was diluted with water (1 l.), cooled and filtered yielding 1-(3,4-diaminophenyl)-1-phenylethylene: 5.6 g., 83% yield, m.p. 109°-110°.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1.[C:32]([O:36][C:37](=[O:46])[CH2:38][O:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:35])([CH3:34])[CH3:33].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:32]([O:36][C:37]([CH2:38][O:39][CH:40]1[CH2:41][CH2:42][N:43]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:44][CH2:45]1)=[O:46])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (13.27 mmol) sodium triacetoxyborohydride were added batchwise to a mixture of 2.58 g (11.06 mmol) benzyl 4-oxo-piperidine-1-carboxylate and 2.80 g (12.36 mmol) tert-butyl(piperidin-4-yloxy)-acetate in 30 mL THF and the reaction mixture was stirred overnight at RT. It was combined with 50 mL 1 M NaOH, the mixture was stirred for 1 h at RT, combined with EtOAc, the organic phase was separated off and dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by chromatography (Alox, DCM/MeOH 100:1).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.O.C([O-])(=O)C.[Na+].[CH3:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[CH3:23]>C(#N)C>[CH3:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(CNc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
To a 1-liter (1) 3-necked round-bottomed flask equipped with an overhead stirrer, reflux condenser and dropping funnel and containing a stirred mixture of 52.0 g (0.30 mole) of sulfanilic acid in 225 ml of warm (~65° C.) water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The temperature of the resulting yellow solution was stabilized at about 70° C. and a solution of 33.8 g (0.20 mole) of 4-(1-methylethyl)benzyl chloride in 75 ml of acetonitrile was added over 70 minutes. The solution was then refluxed for an additional 31/2 hrs, and 95 ml of acetonitrile was removed by distillation over a 30 minute period, during which time 50 ml of concentrated hydrochloric acid (con. HCl) was added dropwise. The resulting mixture was filtered hot (~80° C.) and the collected solids were slurried in 300 ml of boiling methanol for 15 min. and then vacuum filtered. The slurrying and vacuum filtration process was repeated first with 300 ml of warm (65° C.) water and then again with 300 ml of boiling methanol. Air-drying of the collected solids gave 12.51 g (20.5% yield) of purified 4-(((4-(1-methylethyl)phenyl)methyl)amino)benzenesulfonic acid as a white powder, having a melting point greater than 275° C.