Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[NH:25]C(=O)OC(C)(C)C)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[CH:14]=2)[N:9]=1)=[O:7].C(OCC)(=O)C.Cl.C(OCC)C>C(OCC)(=O)C>[NH2:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[NH:18][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[CH:14]=2)[N:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[N:17]=1
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
To a suspension of 2.24 g of tert-butyl {(1R,2S)-2-[(2-{[(2-methoxyethyl)amino]carbonyl}-6-methylquinazolin-4-yl)amino]cyclohexyl}carbamate in 10 ml of ethyl acetate, 10 ml of a 4 N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 48 hours. To the reaction solution, 20 ml of diethyl ether was added, and the mixture was stirred for 30 minutes. Then, the deposited substance was collected by filtration, washed with diethyl ether and dried under reduced pressure. The resulting powder was purified by Fuji Silysia NH silica gel column chromatography (chloroform:methanol=20:1), whereby 1.61 g of a desired compound was obtained as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 85.3 %

Procedure:
A solution of 3,17β-dihydroxyestra-1,3,5(10)-triene (4.73 g, 17.4 mmol) in DMF (10 mL) was added slowly to a stirred and cooled mixture of 60% NaH (1.1 g, 27.5 mmol) in DMF (10 mL). After addition was complete, the cooling bath was removed and the mixture stirred at room temperature for 1 hour until all of the NaH had reacted. Benzyl bromide (2.9 mL, 27.8 mmol) was added in a stream and the solution stirred at room temperature for 20 hours. After concentrating under reduced pressure, the residue was partitioned between EtOAc and 10% citric acid. The aqueous layer was extracted with EtOAc again and the organic extracts combined, washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The residue was triturated with Et2O-hexane to give 5.38 g (85%) of the above-titled product, mp=97°-100°.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1>>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([CH2:12][CH:10]4[CH2:11][N:8]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C1C=COCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C4CCOCC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 2H-pyran-4(3 H)-one underwent reductive amination with 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine to give 503. 517.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C@H:16]([OH:19])[CH2:17][OH:18])[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C@H:16]([OH:19])[CH2:17][OH:18])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@H](O)CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCO
Product: OC[C@@H](O)[C@@H]1OCCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 160.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-[(1R)-1,2-dihydroxyethyl]-1,4-oxazepane-4-carboxylate (170 mg) obtained in Example 45, step M) in ethanol (5 ml) was added 12 mol/kg hydrogen chloride-ethanol solution (5 mL), and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was crystallized from water-ethanol-diethyl ether to give the title compound (115 mg) as colorless crystals.
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][CH2:9][CH2:10][O:11]C.Cl[C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[C:15]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]>C(O)CO>[OH:8][CH2:9][CH2:10][O:11][C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:17]=[C:16]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[C:15]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]
Reactant: COCCOC
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(Cl)c1Oc1ccccc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCO
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Temperature: 85 °C

Procedure:
To a solution of potassium tert.-butoxide (366.5 mg) in ethylene glycol (5 ml) was added 1,2-dimethoxy ethane (5 ml) and ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (420 mg). The reaction mixture was heated to 85° C. for 7 days, concentrated in vacuo, poured onto water, acidified by 2N HCl, and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The precipitated product was washed with diethyl ether, filtered and dried at HV to give ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (400 mg). LC-MS: tR: 3.45, [M+H]+: 448.24.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:19])=[CH:3][C:4]=2[N:5]=1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 100 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g, 0.0046 mol—Preparation 2), 3-aminophenylboronic acid (0.67 g, 0.0051 mol), sodium carbonate (0.98 g, 0.0092 mol) toluene (30 mL), ethanol (10 mL) and water (5 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.14 g, 0.0002 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to provide the title compound (1.1 g, 70%). 1H NMR (300 MHz, DMSO-d6): δ 9.02 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.01-6.99 (m, 2H), 6.68-6.17 (m, 1H), 5.33 (br s, 2H), 4.52 (br s, 4H), 3.79 (t, J=4.8 Hz, 4H). LC-MS (ESI): Calculated mass: 341.1; Observed mass [M+H]+: 342.1. (RT=0.73 min).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:41](O)C>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:36])([CH3:37])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH2:35][CH3:41])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1

Procedure:
Prepared analogously to Example 7 by reacting methyl 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate with sodium hydroxide in ethanol.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: ClCc1ccccn1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccccn1

Procedure:
2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Freshly prepared sodium methoxide (5 g., 0.22 mole of sodium dissolved in 150 ml. of methanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then filtered. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Cl[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>C(O)(C)C>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: NCCCCCSc1nc2ccccc2[nH]1
Reactant: Clc1nc2ccccc2s1
Solvent: CC(C)O
Product: c1ccc2[nH]c(SCCCCCNc3nc4ccccc4s3)nc2c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
0.6 g of the compound obtained in Example 17c and 0.34 g of 2-chloro-benzothiazole were refluxed for 23 hours in 15 ml of isopropanol. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.32 g of the title compound (yield: 43%).
Reaction SMILES: COCC[O:5][C:6](=[O:82])[C:7]1[CH:19]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[C:30]([S:34]([NH:37][C:38]2[CH:39]=[C:40]([C:51]([O:53]CCOC)=[O:52])[CH:41]=[C:42]([CH:50]=2)[C:43]([O:45]CCOC)=[O:44])(=[O:36])=[O:35])=[CH:29][C:28]([S:58]([NH:61][C:62]2[CH:63]=[C:64]([C:75]([O:77]CCOC)=[O:76])[CH:65]=[C:66]([CH:74]=2)[C:67]([O:69]CCOC)=[O:68])(=[O:60])=[O:59])=[CH:27]3)(=[O:23])=[O:22])[CH:17]=[C:9]([C:10]([O:12]CCOC)=[O:11])[CH:8]=1.Cl>[OH-].[Na+]>[C:30]1([S:34]([NH:37][C:38]2[CH:39]=[C:40]([C:51]([OH:53])=[O:52])[CH:41]=[C:42]([CH:50]=2)[C:43]([OH:45])=[O:44])(=[O:35])=[O:36])[C:31]2[C:26](=[CH:25][C:24]([S:21]([NH:20][C:18]3[CH:17]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=[C:7]([CH:19]=3)[C:6]([OH:82])=[O:5])(=[O:22])=[O:23])=[CH:33][CH:32]=2)[CH:27]=[C:28]([S:58]([NH:61][C:62]2[CH:63]=[C:64]([C:75]([OH:77])=[O:76])[CH:65]=[C:66]([CH:74]=2)[C:67]([OH:69])=[O:68])(=[O:59])=[O:60])[CH:29]=1
Reactant: COCCOC(=O)c1cc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cc(C(=O)OCCOC)cc(C(=O)OCCOC)c4)cc(S(=O)(=O)Nc4cc(C(=O)OCCOC)cc(C(=O)OCCOC)c4)cc3c2)cc(C(=O)OCCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cc(C(=O)O)cc(C(=O)O)c4)cc(S(=O)(=O)Nc4cc(C(=O)O)cc(C(=O)O)c4)cc3c2)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of 12.06 g of the product of Example 3 and 60 ml of 2N sodium hydroxide is stirred for one hour. The resulting yellow solution is acidified with 65 ml of 2N hydrochloric acid to give a colorless gum which solidifies on standing. The mixture is filtered and the separated product is washed with water until the washings are neutral. The material is dried in vacuo, then is pulverized, and dried again to give 8.36 g of the product of the Example as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C@H:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.[CH3:36][O:37][CH:38]([O:43][CH3:44])[CH2:39][C:40](O)=[O:41].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C@H:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH3:13])[C:40](=[O:41])[CH2:39][CH:38]([O:43][CH3:44])[O:37][CH3:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CNCCCC(=O)OC(C)(C)C)Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: COC(CC(=O)O)OC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: COC(CC(=O)N(CCCC(=O)OC(C)(C)C)C[C@@H](C)Nc1ccc(C(F)(F)F)c(Cl)c1)OC
Temperature: 25 °C

Procedure:
A solution of 1.25 g (3.20 mmol) of 4-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl ester (22% ee) in 25 ml CH2Cl2 was treated with a solution of 1.00 g (3.80 mmol) of 2-chloro-1-methylpyridinium iodide and 0.51 g (3.80 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 5 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.89 ml (7.90 mmol) of tributylamine. The reaction was naturally warmed to RT over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.68 g (quantitative) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as light brown oil. MS: 511.22 (MH+, Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(F)cc2F)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 2,4-difluorophenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:16])[CH:13]([OH:15])[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:16])[CH:13]([CH3:14])[OH:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)C(C)O
Agent: [Pd]
Product: CC(O)C(C)Cc1ccc(C(C)(C)C)cc1

Procedure:
65 g of 3-(p-tert.butyl-phenyl)-1,2-dimethyl-allyl alcohol are dissolved in 650 ml of alcohol and treated with 6 g of 5% palladium/carbon while gassing with nitrogen. The mixture is hydrogenated until the hydrogen uptake has been completed. Subsequently, the catalyst is removed by filtration and the alcohol filtrate is evaporated. By distillation there is obtained pure 3-(p-tert.butyl-phenyl)-1,2-dimethyl-propanol of boiling point 110° C./0.03 Torr.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O>[N+:16]([C:6]1[CH:5]=[C:4]([CH2:3][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O-:18])=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cc(CCBr)ccc1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
4-(Bromoethyl)-2-nitro-1-phenylbenzene (584.3 mg, 2.0 mmol) and potassium phthalimide (555.0 mg, 3.0 mmol) were dissolved in N,N-dimethylformamide (8 mL) and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 2-[(3-nitro-4-phenylphenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione (600.8 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:51][C:52](=[O:64])[CH2:53][C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])C>C(Cl)Cl>[C:52]([CH2:53][C@H:54]([NH:63][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])([OH:64])=[O:51]
Reactant: CCOC(=O)C[C@H](N)Cc1ccccc1Cl
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.8 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (160 mg, 790 μmol, 1.0 eq.), DIPEA (439 μL, 3.2 eq.) and HATU (300 mg, 788 μmol, 1.0 eq.) were combined in DCM (20 mL) and stirred for 5 minutes at room temperature. (R)-3-amino-4-(2-chloro-phenyl)-butyric acid ethyl ester (200 mg, 827 μmol, 1.1 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated NH4Cl, and the product was extracted with DCM, dried and evaporated. THF (20 mL) and 10 M aqueous NaOH (315 μL) was added and the mixture was stirred for 1 hour. The crude material was dissolved in AcOH (1.5 mL) and purified using preparative HPLC to yield the title compound (25 mg, 95% purity). MS m/z [M+H]+ calc'd for C21H22ClNO5, 404.12. found 404.4.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9](=[O:14])[CH2:8][CH2:7]2>C(O)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([OH:14])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC1CCc2cc(F)ccc2C1
Yield: 80 %

Procedure:
Sodium borohydride (1.67 g) was added in portions to a solution of 6-fluoro-2-tetralone (6.56 g) in dry ethanol (30 ml) with stirring, keeping the temperature below 25° C. The mixture was then stirred at room temperature for 3 hours. The mixture was then diluted with a little ethyl acetate and concentrated to an oily residue. Dilute sulphuric acid was added dropwise until effervescence no longer occurred. The mixture was extracted with ether and the extract washed, dried, and concentrated to give an oil. This was distilled (b.p. 75-77/0.1 Torr) to give 6-fluorotetralin-2-ol (5.31 g) containing a trace of the tetralone starting material.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[N:16]([CH2:20][CH:21]([OH:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[N:16]([CH2:20][C:21](=[O:38])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cccc2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.14 g (11.2 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.121 g (0.282 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate in 10 ml absolute DMSO. Having stirred for 16 hours, the batch is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 98:2) and yields the product as a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17]([OH:19])=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17](=[O:19])[NH:24][CH2:23][CH:20]3[CH2:22][CH2:21]3)[C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Reactant: NCC1CC1
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)NCC3CC3)c2C1
Yield: 78 %

Procedure:
In a manner similar to general method 1, 280 mg (1.0 mmol) of 6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester were reacted with 90 μL of cyclopropylmethylamine to yield 260 mg (78% of theoretical) of 3-(cyclopropylmethyl-carbamoyl)-6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester, which were obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][NH:30][C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH:26]=[CH:25][CH:24]=1>>[C:33]([CH2:32][C:31]([NH:30][CH2:29][C:27]1[N:28]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][CH:26]=1)=[O:35])#[N:34]
Reactant: N#CCC(=O)NCc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CNC(=O)CC#N)n3)s2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) and N-[(6-bromopyridin-2-yl)methyl]-2-cyanoacetamide (0.96 g, 0.38 mmol) as starting materials.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([O:23]CC(=O)C)[CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:23][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:15]=2[N:14]=[C:13]([CH3:12])[CH:22]=[CH:21]3)=[CH:6][CH:7]=1
Reactant: CC(=O)COc1cccc2ccc(C)nc12
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: Cc1ccc2cccc(OCC(=O)c3ccc(Cl)cc3)c2n1
Yield: 64 %

Procedure:
8-(2-(p-Chlorophenyl)-2-oxoethoxy)-2-methylquinoline (12a) was prepared from 2-bromo-4'-chloroacetophenone by the same procedure as 10a in 64% yield. mp: 112°-113° C.; 1H-NMR (CDCl3): δ2.77 (s, 3H, 2-CH3), 5.56 (s, 2H, OCH2), 6.94-8.12 (m, 8H, Ar--H), 7.31 (d, 1H, 3-H), 8.00 (d, 1H, 4-H).