Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccnc(OCCO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(OCCO)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 84.6 %

Procedure:
Intermediate 67d (74 mg, 0.16 mmol) and Intermediate B (62 mg, 0.16 mmol) were suspended in 1,4-dioxane (5 mL) and DIPEA (32 mg, 42 μL, 0.25 mmol) added and the reaction heated to 60° C. for 18 h. The reaction was cooled, concentrated in vacuo and subjected to FCC, eluting with 0-5% 2M NH3 in MeOH/DCM, to afford the title compound (92 mg, 83%). LCMS (Method 3) Rt 3.51 min, 680.4 [MH+].
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:51])[CH2:45][C@@H:46]1[CH2:50][CH2:49][CH2:48][O:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:51])[CH2:45][C@@H:46]2[CH2:50][CH2:49][CH2:48][O:47]2)=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 27.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:26]([O-])=O.C1COCC1>CO.[Pd]>[NH2:26][C:4]1[CH:5]=[C:6]([S:9]([N:12]([CH3:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(S(=O)(=O)N(C)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(C)c2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 4 h

Procedure:
A solution of Example 52A (00 mg) in methanol:THF (1 mL:1 mL) was treated with 10% palladium on carbon, stirred under hydrogen (1 atm) for 4 hours, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% methanol/dichloromethane to provide 31 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13](=[O:15])[CH3:14])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:16][C:17](=[O:19])[CH3:18])[CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:19])[CH3:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([O:12][C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: COC(=O)c1c(OC(C)=O)cc(C)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(OC(C)=O)cc(CBr)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.6 %

Procedure:
Methyl 4-methyl-2,6-diacetoxybenzoate (14.9 grams, 56.0 mmoles) was dissolved in carbon tetrachloride (200 mL), and N-bromosuccinimide (11.1 grams, 62.2 mmoles) and benzoyl peroxide (0.2 grams, 0.8 mmoles) were added. The mixture was refluxed under nitrogen. After 3.5 hours, an additional portion (0.2 grams) of N-bromosuccinimide was added. Reflux was continued for an additional hour. The reaction mixture was cooled to room temperature and then in ice for 1 hour, and the solid removed by filtration. The filtrate was evaporated to dryness. Hexanes (250 mL) was added to the residue, and the mixture was boiled until dissolution was obtained. The hexanes solution was concentrated to about 75 mL when a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. White crystals formed slowly, and the mixture was chilled in ice for 2 hours to complete crystallization. The solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 11.9 grams (62% yield) of methyl 4-bromomethyl-2,6-diacetoxy-benzoate (m.p. 93°-95° C., open capillary, uncorrected). The product was contaminated with a small amount of methyl 2,6-diacetoxy-4-dibromomethylbenzoate, which did not interfere with subsequent reactions.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:22][CH2:21][C:15]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].FC(F)(F)C(C1C=CC(N2CCC3(CCN(S(C4C=CC=CC=4C(F)(F)F)(=O)=O)CC3)C2=O)=CC=1)O.I[C:62]1[CH:67]=[CH:66][C:65]([C:68]([OH:71])([CH3:70])[CH3:69])=[CH:64][CH:63]=1>>[OH:71][C:68]([C:65]1[CH:66]=[CH:67][C:62]([N:18]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:22][N:12]([S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:23])[F:24])(=[O:11])=[O:10])[CH2:13][CH2:14]3)[C:19]2=[O:20])=[CH:63][CH:64]=1)([CH3:70])[CH3:69]
Reactant: CC(C)(O)c1ccc(I)cc1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Agent: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Product: CC(C)(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(2-trifluoromethyl-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 166 A) and 2-(4-iodo-phenyl)-propan-2-ol (synthesis: Brown et al.; JACS; 79; 1957, p 1906). Light yellow solid. MS (ESI): 497.17 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[C:9](=[O:23])[NH:10][C@H:11]2[CH2:17][CH2:16][C@@H:15]([CH3:18])[N:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C@@H:12]2[OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]1([CH2:7][C@H:8]([NH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[C:9](=[O:23])[NH:10][C@H:11]2[CH2:17][CH2:16][C@@H:15]([CH3:18])[N:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCN1C[C@H](O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)c2ccco2)CC[C@H]1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN1CC(=O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)c2ccco2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Sulfur trioxide-pyridine complex (0.0.35 g, 2.2 mmol) was added to a solution of Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide (0.19 g, 0.44 mmol) in DMSO (4.0 ml) and triethylamine (0.61 ml, 4.4 mmol) was stirred at RT for 1 h. The reaction mixture was diluted with water, then was extracted with EtOAc. Then, the organic layer was was extracted with brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (3% methanol/methylene chloride) gave the title compound (0.15 mg, 79%): 1H NMR: 7.44(s, 1H), 7.11(d, 1H), 7.04(d, 1H), 6.92(d, 1H), 6.49(d, 1H), 5.29(m, 1H), 4.69(m, 1H), 3.40(d, 1H), 3.08(m, 2H), 2.51(m, 2H), 1.88-0.81(m, 29H); Electrospray mass spec: M+H+=432.2.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[C:3]#[N:4].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C.O>[F:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[F:13])[O:6][CH2:5][C:2]([CH3:15])([NH2:1])[CH2:3][NH2:4]
Reactant: CC(N)(C#N)COc1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(N)(CN)COc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
300 mg (1.41 mmol) of rac-2-amino-3-(3,4-difluorophenoxy)-2-methylpropanonitrile were initially charged in 14.4 ml of abs. THF, and 0.92 ml (0.92 mmol) of a 1 N lithium aluminium hydride solution in diethyl ether was added under argon at 0° C. The reaction solution was stirred at 0° C. for 30 min, then allowed to warm up gradually to room temperature and stirred overnight. The reaction mixture was admixed cautiously with 140 μl of water, 140 μl of 2 N aqueous sodium hydroxide solution and 280 μl of water, the precipitate was filtered off and washed with THF and methanol, the filtrate was concentrated and the residue was purified by means of silica gel chromatography (eluent:dichloromethane/2 N ammonia in methanol=20/1). 87 mg of the target compound were obtained (24% of theory, about 84% purity).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CO>O>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1n[nH]cc1-c1ccc(Cc2ccccc2)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl)-2-carbamoylpyrazole (1.00 g), sodium hydroxide (1.00 g), methanol (40 ml) and water (40 ml) was stirred under heating reflux for 3.5 hours, and ice-water was added. The mixture was extracted with chloroform, washed with water, dried over Glauber's salt, and concentrated under reduced pressure to give the title compound (0.77 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:12]=[N+:13]=[N-:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccccc1[N+](=O)[O-]

Procedure:
2-Nitrobenzylchloride dissolved in ethanol is heated at reflux with a 10% molar excess of sodium azide for from six to eight hours. Insoluble salts are removed by filtration, the ethanol removed, and the resultant oil is dissolved in diethyl ether. Additional insoluble material is removed by filtration and 2-nitrobenzylazide is obtained as a pale yellow oil by removal of the diethyl ether.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:27]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(Cl)c(Cl)c4)ccc3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-dichlorobenzoyl chloride (0.34 g, 1.6 mmol) and TEA (0.32 g, 3.2 mmol) in THF (25 mL) was heated to 40° C. with stirring under N2, for 2.5 hours. The mixture was filtered, and the filtered solid was loaded onto a silica gel column, which was run using with a methylene chloride-methanol gradient. The product eluted at 93:7 methylene chloride-methanol, 0.42 g, in 58% yield; mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.36 (99.65%); 1H NMR (DMSO-d6) δ 1.96-2.03 (m, 1H), 2.31-2.43 (m, 1H), 2.56-2.62 (m, 1H), 2.85-2.97 (m, 1H), 4.30 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H), 5.11 (dd, J=13.4 Hz, J=5.0 Hz, 1H), 7.45-7.55 (m, 2H), 7.70 (d, J=7.8, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.88 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 9.33 (t, J=6.0 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.9, 47.1, 51.6, 122.2, 123.0, 127.2, 127.6, 129.2, 130.4, 130.7, 131.3, 134.1, 134.4, 142.4, 143.4, 164.0, 167.9, 171.0, 172.8; Anal. Calcd for C21H17Cl2N3O4+0.25H2O: C, 55.95; H, 3.91; N, 9.32. Found: C, 55.98; H, 3.55; N, 9.32.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].[CH2:32]([O:39][CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.Cl.O>[CH2:32]([O:39][CH:40]1[CH2:45][CH2:44][CH:43]([CH:2]=[O:3])[CH2:42][CH2:41]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(OCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=CC1CCC(OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred suspension of methoxymethyl triphenylphosphonium chloride (13.8 g, 40 mmol) in dry THF (80 ml) is added dropwise a solution of lithium diisopropylamide (24.4 ml, 44 mmol, 1.8 M in hexane/THF/ethylbenzene), at 0-5° C. The resulting reaction mixture is stirred for 30 minutes and then cooled to −78° C. At this temperature, a solution of 4-benzyloxy-cyclohexanone (6.1 g, mmol) in tetrahydrofuran (30 ml) is added over a period of 30 minutes. Once the addition is completed the reaction mixture is stirred at −78° C. for 1 hour and then allowed to warm to room temperature and stirred overnight. The reaction mixture is then diluted to pH=2 with a 2N aqueous solution of hydrochloric acid and stirred for 3 hours at room temperature. The reaction was diluted with water and extracted with ethyl acetate (2×100 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography to give 4-benzyloxy-cyclohexanecarbaldehyde (5.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13](=[O:23])[C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)=[O:19])=[CH:16][CH:15]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCC)cc3)cc2)cc1

Procedure:
The procedure of Example 5 is conducted except that ethyl p-hydroxybenzoate and terephthalic dichloride are substituted. The reaction product is recrystallized from ethyl acetate-chloroform (1:1) to yield di(p-ethoxycarbonylphenyl)terephthalate, m.p. 187°-189° C., as white crystals.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[N:17]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH2:26]([N:17]1[CH:18]([C:22]([F:23])([F:24])[F:25])[CH2:19][CH2:20][CH2:21][CH:16]1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:43])=[O:3])[CH:11]=[C:12]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=2)[CH:13]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccccc2)c1
Temperature: 78 °C

Procedure:
To a solution of 2-[5-(1-Benzyl-6-trifluoromethyl-piperidin-2-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester, compound 8a (38 mg, 0.062 mmol), in EtOH (3 mL) was added 2M KOH (310 μl, 0.62 mmol). The reaction was heated to 78° C. for 1.5 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, followed by salt exchange with aqueous 1N HCl gave the product as a light yellow solid. (18.6 mg, 52%) 1H NMR (300 MHz, MeOD) δ ppm 0.81-0.88 (m, 6 H) 1.42 (dd, J=13.38, 6.59 Hz, 1 H) 1.55 (dd, J=13.56, 7.16 Hz, 2 H) 1.63-1.76 (m, 4 H) 1.82-1.97 (m, 2 H) 3.39-3.49 (m, 1 H) 3.61 (td, J=7.82, 2.83 Hz, 1 H) 3.68-3.77 (m, 3 H) 6.96-7.09 (m, 5 H) 7.29-7.37 (m, 2 H) 7.43 (s, 1 H) 7.58-7.66 (m, 4 H) Calcd for C32H33F6NO2 (M+H) 577.60, Found 578.4.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[O:19]([C:20]1[CH:21]=[CH:22][C:23]([C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of aluminum chloride (29.3 g) and dichloromethane (250 ml), ethyl chloroglyoxylate (22.3 ml) was added dropwise at 0° C. After stirring for 30 minutes, diphenyl ether (63.5 ml) was added dropwise over 30 minutes at 0° C. followed by stirring for 2 hours, the reaction mixture was poured onto ice (250 g) and stirred for 1 hour at room temperature. The dichloromethane layer was separated, washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl 4-phenoxyphenylglyoxylate (38.0 g, yield 70%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:10, v/v).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29]Cl)[N:21]=2)=[CH:4][CH:3]=1.[C:31]([O:35][P:36]([O-:43])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:34])([CH3:33])[CH3:32]>CC#N>[C:39]([O:38][P:36](=[O:37])([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])[O:43][CH2:29][N:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([CH2:19][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[C:15]([Cl:17])[CH:16]=3)[C:6]=2[F:18])=[N:21]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CCl)c4ncccc34)c2F)c1
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCn1nc(Cc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)c2cccnc21)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
step 2—To a mixture of 16 (1.28 g, 2.54 mmol), di-tert-butylphosphate (1.06 g, 5.08 mmol), in MeCN (70 mL) was added Ag2O (0.59 g, 2.54 mmol) and the resulting mixture was stirred for 1 d at RT. The resulting mixture was filtered through CELITE®, the filtrate was evaporated and the crude product purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 1% MeOH) to afford 1.1 g of phosphoric acid 3-[4-bromo-3-(3-chloro-5-cyano-phenoxy)-2-fluoro-benzyl]-pyrazolo[3,4-b]pyridin-1-ylmethyl ester di-tert-butyl ester (18)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:32])[CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (0.96 g, 2.26 mmol; see step (a) above) and 3-chlorophenylboronic acid (0.70 g, 4.52 mmol). Yield 100 mg (39%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[C:16]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[N:37](=[CH:45][CH2:46]Cl)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Cl.O>CN(C=O)C.C(OCC)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:46][CH2:45][N:37]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:24][CH:23]=1)=[C:16]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Reactant: ClCC=NCCCCCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2ccc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Add sodium hydride (324 mg, 8.0 mmol) into a solution of 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenol (1.18 g, 2.7 mmol) in DMF (10 mL) and stir for 20 minutes at room temperature. Add 2-(hexamethyleneimino)ethyl chloride hydrogen chloride (1.07 g, 5.4 mmol) and stir at room temperature for 12 hours. Add H2O (10 mL) and diethyl ether (100 mL). Separate layers and wash the aqueous layer with diethyl ether (2×50 mL). Combine organic layers, dry with magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0% to 10%), to obtain 1.0 g of the title compound (66%): mass spectrum (ion spray) m/z=562.3 (M+H).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-amino-propionic acid ethyl ester instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 359 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.27 (1H, s) 8.17 (1H, t, J=5.37 Hz) 8.02 (1H, d, J=5.47 Hz) 7.78 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.47 Hz) 7.32 (1H, d, J=3.32 Hz) 6.81 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.42, 1.66 Hz) 4.03 (2H, q, J=7.03 Hz) 3.43-3.53 (2H, m) 2.55 (2H, t, J=7.03 Hz) 1.15 (3H, t, J=7.03 Hz)