Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:60])([CH3:59])[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([C:53]([O:55]C)=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:30][CH2:29][CH2:28][O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].O.C(N(CC)CC)C.[Br-].[Li+]>C(#N)C>[C:1]([Si:5]([CH3:59])([CH3:60])[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([C:53]([OH:55])=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:30][CH2:29][CH2:28][O:27]1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
No. 5327507 (Compound C; 1.09 g, 1.27 mmol) was dissolved in acetonitrile (10.9 mL), and then water (0.109 mL), triethylamine (1.06 mL, 7.61 mmol), and lithium bromide (2.91 g, 33.5 mmol) were added at room temperature. The reaction solution was stirred at 50° C. for 3.5 hours, then cooled to room temperature, quenched by the addition of 1 M hydrochloric acid (30 mL), and then extracted with ethyl acetate (100 mL). The organic layer was washed twice with water (100 mL) and then with a saturated aqueous solution of sodium chloride (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.08 g (purity 71%, ESI (LC/MS positive mode) m/z 845 (M+H); Rt 3.32 min.) of Compound I, tert-butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-carboxy-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH:22]=O)[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20](/[CH:22]=[N:25]/[OH:26])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(C=O)c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(/C=N/O)c2)CC1

Procedure:
To the solution of tert-butyl 4-(3-bromo-5-formylphenoxy)piperidine-1-carboxylate (205 mg, 0.533 mmol) in ethanol (1.9 mL) and water (0.6 mL), hydroxylamine hydrochloride (40.8 mg, 0.587 mmol) and sodium acetate (61.3 mg, 0.747 mmol) were added sequentially, then the resulting solution was refluxed for 1 hour. The most organic solvent was removed in vacuo and the solution was diluted with water. The resultant precipitate was collected and dried under vacuum to give the desired product as white solid. LCMS (M+H)+: 399.1, 401.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(C)=O
Product: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc21
Yield: 82.2 %

Procedure:
A suspension of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol (13.1) (500.0 mg, 1.60 mmol) and 2-Iodoxybenzoic acid (45%)(1488.0 mg, 2.39 mmol) in 10 mL acetone was heated at reflux for 3 h. Solvent was removed under reduced pressure. The residue was diluted with water; pH was adjusted to around 10 with 10% NaOH aqueous solution. The precipitates were collected by filtration and washed with water three times. The solid was dissolved in DCM, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (410.0 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 8.42 (m, 1H), 8.32 (m, 1H), 8.27 (d, 1H), 7.95 (dd, 1H), 7.815 (d, 1H), 7.66 (d, 1H), 4.12 (s, 2H). LCMS (method A): [MH]+=312, tR=4.64 min.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:27][C@H:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)C=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:27][C@@H:26]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)NC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: [S-]c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
0.45 g (3.41 mmol) of sodium thiophenolate was added to a solution of 1.23 g (3.08 mmol) of (4R)-1-t-butoxycarbonyl-4-(p-toluenesulfonyloxy)-N-t-butyl-L-prolinamide [prepared as described in Preparation 6(a)] in 10 ml of a 2:1 by volume mixture of dimethylformamide and ethyl acetate, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was poured into a 10% w/v aqueous solution of sodium hydrogen-carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 1.0 g of the title compound as a colorless powder, melting at 119°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.[N:33]#[C:34]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O>[NH2:33][C:34]1[O:28][C:27]([C:26]2[CH:31]=[CH:32][C:23]([C:22]3[CH:21]=[N:20][N:17]4[CH:18]=[CH:19][C:14]([N:9]5[C@@H:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)[CH2:12][O:11][C:10]5=[O:13])=[N:15][C:16]=34)=[CH:24][CH:25]=2)=[N:29][N:30]=1
Reactant: NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cc5)nc34)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a suspension of (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (0.040 g, 0.0925 mmol) in dioxane (4 mL) was added cyanic bromide (0.0216 g, 0.204 mmol) followed by a solution of NaHCO3 (0.00933 g, 0.111 mmol) in water (0.9 mL). The resulting mixture was stirred at ambient temperature overnight, then diluted with EtOAc. The organic layer was washed with brine and water, dried (phase separator silicone treated filter paper) and concentrated. The crude material was purified on silica gel (2-5% MeOH in DCM) to provide (S)-3-(3-(4-(5-amino-1,3,4-oxadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (0.0066 g, 16% yield). LCMS (APCI+) m/z 458 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)[CH:38]=1>C(#N)C>[O:1]=[C:2]1[CH2:7][N:6]([CH2:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)[CH:38]=2)[CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:10]=1.[ClH:35]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3=O)ccn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)C(=O)C3)ccn2)cc(OC)c1OC
Product: Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Oxo-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperazine (62 mg) was dissolved in acetonitrile (5 mL), and to the solution potassium carbonate (24 mg), potassium iodide (29 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (51 mg) were added, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant oil was purified by preparative TLC on silica gel (chloroform:methanol=25:1) to obtain the title compound as a hydrochloride.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:30])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:17](=[O:19])[CH3:18].[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>CCCCCC.O1CCCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:18][C:17](=[O:19])[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)=[CH:15][N:14]([CH3:13])[CH3:30]
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C=C(C(=O)CC(=O)C(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 3.9 g. portion of diisopropylamine was dissolved in 200 ml. of dry tetrahydrofuran, and to the solution was added 16 ml. of 2.4-molar butyllithium solution in hexane. The mixture was stirred for 30 minutes and chilled to about -70°. To the mixture was added 10 g. of 1-dimethylamino-2-(3-trifluoromethylphenyl)-1-butene-3-one suspended in 50 ml. of tetrahydrofuran. The temperature rose to about -60°, and the mixture was stirred for 50 minutes and chilled. To the mixture was then added over a period of 1 minute a 4.7 g. portion of pivaloyl chloride. The temperature of the reaction mixture was then about -70°. The mixture was allowed to warm slowly to ambient temperature while it was stirred for 16 hours. The mixture was then diluted with 200 ml. of diethyl ether, and was washed successively with 1 N hydrochloric acid, 1 N sodium hydroxide, and saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate, and was evaporated to dryness under vacuum to obtain 9.1 g. of a dark oil. The oil was chromatographed over a 300 g. silica gel column with 1:10 ethyl acetate:dichloromethane as the eluting solvent. The product-containing portions were combined and evaporated under vacuum to dryness to obtain 1.3 g. of the product, which was identified by nmr analysis, which showed (CDCl3) δ1.03 (s, 9H); 2.78 (s, 6H); 5.03 (s, >1H); 7.53 (broad s, 4H); 7.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][NH2:13])=O)=[CH:5][CH:4]=1.Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[N:16]3[N:17]=[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=[CH:20][C:15]3=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)NN)cc1
Reactant: Clc1ccc(-c2cccs2)nn1
Product: COc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from 4-methoxy-phenylacetic acid hydrazide (1.39 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.32 mmol) as a pale orange solid. 1H NMR (CD3OD) δ 8.17 (1H, d, J=9.8 Hz), 7.92 (1H, dd, J=3.8 Hz, 1.2 Hz), 7.88 (1H, d, J=9.9 Hz), 7.74 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.40 (2H, d, J=8.8 Hz), 7.23 (1H, dd, J=5.0 Hz, 3.8 Hz), 6.88 (2H, d, J=8.9 Hz,), 4.51 (s, 2H), 3.75 (3H, s). ESI-MS (m/z): Calcd for C17H14N4OS: 322.1; found 323.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:16])([CH2:14][OH:15])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C>CCOCC.O>[CH2:24]([O:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:16])([CH2:14][OH:15])[CH2:6][CH2:5]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CO)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CO)O2

Procedure:
A mixture of 0.55 g. (2.33 mmol) of (S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol, 790 mg. (5.72 mmol) of anhydrous K2CO3, 0.68 ml. (748 mg; 5.93 mmol) of benzyl chloride (distilled from and stored over K2CO3) and 4.5 ml. of DMF was stirred for 22 hrs. at room temperature then poured into H2O and worked up with ether in the usual manner. There was obtained 0.89 g. of a yellow oily product which was chromatographed on silica gel (35 g.). Elution with 19:1 and 9:1 benzene-ethyl acetate gae 724 mg. (97.1%) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol as a colorless solid, mp 66°-69.5°; [α]25D-2.35° (c 1.2, CHCl3).
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][CH:12]=[CH2:13]>>[CH3:10][O:11][CH:12]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)[CH3:13].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: C=COC
Reactant: C#Cc1ccc(O)cc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)OC)cc1

Procedure:
Using 8 g of poly(p-hydroxystyrene) obtained according to (1) of Preparation Example 6 and 2.2 g of methylvinyl ether, the procedure of (3) of Preparation Example 1 was carried out for reaction and after-treatments to give 8.6 g of poly(p-1-methoxyethoxystyrene/p-hydroxystyrene) as faintly brown-tinted powdery crystal. P-1-methoxyethoxystyrene unit/p-hydroxystyrene unit molar ratio in the polymer≈4:6 (1H NMR). Mw≈18,000; Mw/Mn=1.89 (GPC with polystyrene calibration).
Reaction SMILES: CO.[CH:3]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:44])=[CH:11][C:12](=[O:43])[N:13]3[CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([N:24]([CH2:32][C:33]4[CH:42]=[CH:41][C:36]5[O:37][CH2:38][CH2:39][O:40][C:35]=5[CH:34]=4)C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[ClH:45].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:45].[CH:3]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10]([CH3:44])=[CH:11][C:12](=[O:43])[N:13]3[CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][C:33]4[CH:42]=[CH:41][C:36]5[O:37][CH2:38][CH2:39][O:40][C:35]=5[CH:34]=4)[CH2:20][CH2:19]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C3CC3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(C3CC3)ccc12
Reaction time: 1.5 h

Procedure:
To 1 mL of methanol solution containing 95 mg of tert-butyl (1-(2-(7-cyclopropyl-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 45 mg of 7-cyclopropyl-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:17])[C:10]([CH3:16])=[C:11](B(O)O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[C:18](=[O:21])([O-])[OH:19].[Na+].[CH:23]([OH:26])([CH3:25])[CH3:24]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:17])[C:10]([CH3:16])=[C:11]([C:24]3[CH:3]=[CH:1][C:2]([C:18]([OH:19])=[O:21])=[CH:25][C:23]=3[O:26][CH2:11][CH2:12][CH2:7][CH2:5][OH:6])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)O
Reactant: O=C([O-])O
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cc1OCCCCO
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Intermediate 23 (318 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (252 mg) and tetrakis(triphenylphosphine) palladium (0) (45 mg) were combined in isopropanol and aqueous sodium hydrogen carbonate solution (1M, 2.7 ml) added. The reaction was stirred under nitrogen at 90° C. for 6 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate/chloroform (1:1) and water. The organic phase was dried using a hydrophobic filter, the solvent evaporated under vacuum. The residue was dissolved in methanol (10 ml), aqueous sodium hydroxide solution (2M, 10 ml) added and the reaction stirred at 20° C. for 18 hours. The solvents were evaporated and residue partitioned between ethyl acetate/chloroform (1:1) and water. The aqueous layer was acidified to pH1 using concentrated hydrochloric acid and extracted with ethyl acetate/chloroform (1:1). The organic phase was dried using a hydrophobic filter and evaporated, and the residue purified using SPE (5 g, Si), eluting with a methanol/chloroform gradient (1-10%). The solvents were evaporated from the product fraction in vacuo to give 5′-[(cyclopropylamino)carbonyl]-3′-fluoro-2-[(4-hydroxybutyl)oxy]-2′-methyl-4-biphenylcarboxylic acid as a cream solid (140 mg).
Reaction SMILES: N[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.CC1C=CC(S(O[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:37](C=O)C>>[NH2:37][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:8][CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: NC1(O)C=CC=CC1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-aminophenol (1) (207 mg, 1.9 mmol), 2-(tert-butoxycarbonylamino)ethyl 4-methylbenzenesulfonate (2) (500 mg, 1.9 mmol), and cesium carbonate (770 mg, 2.2 mmol) in DMF (6 ml) was stirred at room temperature under argon for 15 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (40 to 60% EtOAc-hexanes gradient) gave tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) as colorless oil. Yield (220 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 6.92 (t, J=5.2 Hz, 1H), 6.85 (t, J=8.0 Hz, 1H), 6.08-6.12 (m, 2H), 6.02-6.04 (m, 1H), 4.99 (bs, 2H), 3.79 (t, J=6.0 Hz, 2H), 3.21 (q, J=6.0 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH2:58])=[CH:52][CH:51]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:58][CH2:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCc2ccc(OC)cc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-(4-methoxy-phenyl)-ethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H53Cl2N6O4 [(M+H)+] 799.35, observed 799.3501.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[CH3:19][CH:20](Br)[CH2:21][CH3:22].O>O1CCCC1.CN(C=O)C>[CH3:19][CH:20]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:17][CH:18]=1)[CH2:21][CH3:22]
Reactant: CCC(C)Br
Reactant: CCOC(=O)NCCOc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)NCCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To pre-washed sodium hydride (0.106 g, 4.4 mmol) in 5 ml of tetrahydrofuran (THF) and 5 ml of DMF at RT is added ethyl N-[2-(4-hydroxyphenoxy)ethyl]carbamate (1.0 g, 4.4 mmol) in 5 ml of THF. The mixture is stirred at RT for 1.5 hours and is then cooled to -5°. 1-Methylpropyl bromide (0.72 g, 5.3 mmol) in 2 ml of THF is added to the mixture, followed by addition of 5 ml of DMF. The reaction mixture is allowed to warm slowly to RT, and is then heated at 60° for 18 hours. The reaction is cooled to RT and poured into water, and the mixture is extracted with ether (3X). The combined ether layers are washed with water until neutral, followed with brine, and dried over calcium sulfate. The solvent is removed in vacuo and purification by prep. TLC yields ethyl N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}carbamate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:17][C:18]([C:20]1[CH:28]=[CH:27][C:25]([OH:26])=[C:22]([O:23][CH3:24])[CH:21]=1)=[O:19].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][O:26][C:25]1[CH:27]=[CH:28][C:20]([C:18](=[O:19])[CH3:17])=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a N2 purged flask was added 2,4-bis-trifluoromethyl benzyl bromide (2.21 g, 7.20 mmol), acetovanillone (1.32 g, 7.92 mmol), and DMF (15 mL). To the reaction solution was added fine mesh K2CO3 (3 equiv, 21.6 mmol). The reaction was allowed to stir at 70° C. for 1 h, then at 60° C. for 14 h. The reaction solution was then diluted with EtOAc (150 mL), filtered through a Buchner funnel, washed with sat'd NH4Cl (70 mL×2) washed with sat NaCl (50 mL), dried over Na2SO4, and then filtered and concentrated in vacuo to provide a crude product (2.8 g, 99% yield).