Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:36])[CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:21]=1)[C:15]([O:17]C)=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C1COCC1>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:36])[CH2:24][O:25][Si:26]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:35])[CH3:34])[CH:21]=1)[C:15]([OH:17])=[O:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Temperature: 43 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Lithium hydroxide monohydrate (12.14 g, 0.289 mol) in water (100 mL) was added to a solution of methyl 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoate (62 g, 0.131 mol) in THF (300 mL) and warmed to 43° C. The reaction was stirred for 16 hours, the THF removed in vacuo and the resultant mixture acidified to pH 5 with 10% w/v citric acid. This was extracted with ethyl acetate (2×300 mL) and the combined organic layers were dried (MgSO4), filtered and evaporated to afford the title compound (60.2 g).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([N:16]2[CH2:20][CH2:19][C@:18]3([CH2:25][CH2:24][CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21]3)[C:17]2=[O:36])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[Pd]>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([N:16]2[CH2:20][CH2:19][C@:18]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:17]2=[O:36])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1)c1ccccc1

Procedure:
Benzyl (5S)-2-[cis-4-(benzoyloxy)cyclohexyl]-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (0.16 g, 0.00033 mol) in methanol (5 mL, 0.1 mol) was stirred with palladium (20 mg, 0.00002 mol) under an atmosphere of hydrogen for 2 h. The mixture was filtered and the filtrate was concentrated to afford the desired product. LC-MS: 357.2 (M+H)+.
Reaction SMILES: [P:1]([CH2:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1)([OH:4])([OH:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.[OH-].[Na+]>[C:21]([N:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][P:1]([OH:3])([OH:4])=[O:2])[CH2:7][C@@H:8]1[C:12]([OH:14])=[O:13])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 200 mg of cis-4-phosphonomethyl-2-piperidinecarboxylic acid, 96 mg of sodium carbonate in 5 ml of water and 2.31 ml of 1N aqueous sodium hydroxide is added 119 mg of benzoyl chloride. The reaction mixture is stirred at room temperature for 16 hours and the solvent is removed in vacuo. The residue is dissolved in ethanol, the solution is filtered and evaporated to dryness. Crystallization from ethanol/ethyl acetate affords cis-1-benzoyl-4-phosphonomethyl-2-piperidinecarboxylic acid, m.p. 135°-145° dec.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23]Cl)[CH:22]=1.[H-].[Na+]>>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][N:12]2[C@H:8]([C:7]([CH3:15])([CH3:14])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][C:11]2=[O:13])[CH:20]=[N:19][CH:18]=1
Reactant: ClCc1cncc(Br)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a colorless oil. MS: 399.2, 401.2 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]([OH:16])[C:13]([CH3:18])([CH3:17])[C:12]=2[CH:19]=1)#[N:7].C(N(CC)CC)C.O>C(OCC)C>[Cl:1][CH2:2][C:3]([O:16][CH:14]1[C:13]([CH3:17])([CH3:18])[C:12]2[CH:19]=[C:8]([C:6]#[N:7])[CH:9]=[CH:10][C:11]=2[O:15]1)=[O:4]
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)c2cc(C#N)ccc2OC1OC(=O)CCl
Reaction time: 3 h
Yield: 34.2 %

Procedure:
Chloroacetyl chloride (3.6 g) was added dropwise to a solution of 5-cyano-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5 g) prepared as in Example 10, and triethylamine (3.2 g) in diethyl ether (50 ml) with stirring and cooling. After 3 hours at room temperature, the mixture was shaken with water and an insoluble solid product was filtered off and dried to give 2.4 g of title compound, mp 138° C.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1Br)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)[CH3:25]>COCCOC>[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:5])=[O:17])[CH3:25]
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Yield: 69.6 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester (2.00 g, 6.55 mmol) in DME (16 ml)/2M Na2CO3 (11.46 ml, 22.93 mmol) was treated with 2-ethylphenylboronic acid (1.96 g, 13.10 mmol), and Pd[PPh3]4 (757 mg, 0.655 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5-20% ethyl acetate/hexanes gradient to afford 1.25 g of colorless oil (t-butyl ester). This material was dissolved in 4N HCl/dioxane (10 ml) and stirred at rt overnight. Concentration under reduced pressure afforded the product as colorless oil (1.08 g, 60%).
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH3:57])[C:3]([O:5][CH:6]([C@:8]12[O:15][C@:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=4)[CH:17]=3)([O:13][CH2:14]1)[C@H:11]([O:33]CC1C=CC=CC=1)[C@@H:10]([O:41]CC1C=CC=CC=1)[C@@H:9]2[O:49]CC1C=CC=CC=1)[CH3:7])=[O:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@:12]23[O:15][C@@:8]([CH:6]([O:5][C:3](=[O:4])[C:2]([CH3:58])([CH3:57])[CH3:1])[CH3:7])([CH2:14][O:13]2)[C@@H:9]([OH:49])[C@H:10]([OH:41])[C@H:11]3[OH:33])=[CH:17][C:18]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)C(C)(C)C)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)C(C)(C)C)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethyl 2,2-dimethyl propanoate 14a (120 mg, 0.15 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.08 mL, 0.72 mmol) and 10% Pd/C (19 mg, 0.02 mmol) in turn at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=4/1 to give the title compound 14 as a white solid (62.3 mg, 77.6%, HPLC: 85.3%). The compound was characterized by the following spectroscopic data: MS(ESI, pos. ion) m/z: 580.3[M+HCOO]−; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.42 (m, 2H), 7.32 (m, 1H), 7.08 (m, 2H), 6.82 (m, 2H), 5.38 (brs, 1H), 5.06 (m, 1H), 4.04 (d, 1H), 3.97 (m, 3H), 3.57 (d, 1H), 3.52 (d, 1H), 3.47 (m, 3H), 1.30 (t, 3H), 1.23 (d, 3H), 1.10 (s, 9H).
Reaction SMILES: O[C@H]1CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C[C@H](C)CCC=C[C@@H]3C[C@@]3(C(=O)NS(C3(C)CC3)(=O)=O)NC(=O)[C@@H]2C1.[CH2:43]([C@H:45]([CH2:81][CH:82]([CH3:87])[CH2:83][CH2:84][CH:85]=C)[C@H:46]([NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[C:47]([N:49]1[CH2:53][C@H:52]([OH:54])[CH2:51][C@H:50]1[C:55](=[O:72])[NH:56][C@:57]1([C:62](=[O:71])[NH:63][S:64]([C:67]2([CH3:70])[CH2:69][CH2:68]2)(=[O:66])=[O:65])[CH2:59][C@H:58]1[CH:60]=C)=[O:48])[CH3:44].O[C@H]1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)CC(C)CCC=C)[C@H](C(=O)N[C@]2(C(=O)NS(C3(C)CC3)(=O)=O)C[C@H]2C=C)C1>>[CH2:43]([C@H:45]1[C@H:46]([NH:73][C:74](=[O:80])[O:75][C:76]([CH3:77])([CH3:78])[CH3:79])[C:47](=[O:48])[N:49]2[CH2:53][C@H:52]([OH:54])[CH2:51][C@H:50]2[C:55](=[O:72])[NH:56][C@:57]2([C:62](=[O:71])[NH:63][S:64]([C:67]3([CH3:70])[CH2:68][CH2:69]3)(=[O:66])=[O:65])[CH2:59][C@H:58]2[CH:60]=[CH:85][CH2:84][CH2:83][C@@H:82]([CH3:87])[CH2:81]1)[CH3:44]
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Agent: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Agent: CC[C@@H]1C[C@H](C)CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: C[C@@H]1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Product: CC[C@@H]1C[C@H](C)CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C

Procedure:
The same procedure was used as described for of tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate but tert-butyl ((2S,3R)-3-ethyl-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-5-methyl-1-oxonon-8-en-2-yl)carbamate was used as a starting material instead of tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.32 (s, 1H) 7.01 (d, J=9.54 Hz, 1H) 5.38 (m, 2H) 5.08 (m, 1H) 4.40 (br. s., 1H) 4.20 (t, J=7.78 Hz, 1H) 4.00 (m, 1H) 3.67 (m, 2H) 2.85 (q, J=7.53 Hz, 3H) 2.22 (d, J=8.03 Hz, 1H) 1.84 (m, 4H) 1.29 (m, 22H) 0.84 (m, 6H) 0.48 (m, 2H). MS: MS m/z 625.4 (M++1).
Reaction SMILES: [F:1][C:2]1([F:38])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH:3]1[CH2:15][NH:16][C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH2:35][CH2:36][OH:37])[CH3:34])=[CH:29][CH:28]=2)[N:18]=1.Cl.CC(=O)OCC>CC(=O)OCC>[F:38][C:2]1([F:1])[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:15][NH:16][C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:34])[CH2:35][CH2:36][OH:37])=[CH:29][CH:28]=2)[N:18]=1
Reactant: CN(CCO)c1ccc(-c2cc3nccnc3c(NCC3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CCO)c1ccc(-c2cc3nccnc3c(NCC3CNCCC3(F)F)n2)cc1
Yield: 65.3 %

Procedure:
A solution of tert-butyl 4,4-difluoro-3-((7-(4-((2-hydroxyethyl)(methyl)amino)phenyl) pyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate (25 mg, 0.05 mmol) and 2 mL of HCl-EA (5.0 N) in 4 mL of EA was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo, and the residue was added to 5 mL of MeOH and 0.5 mL of NH3.H2O. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:10-5:1) to give 14 mg of title compound. MS (m/z)=429 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(=O)C(C)(OC)C(=O)Cl
Reactant: Cc1cc(Br)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(OC)C(=O)Nc1ccc(Br)cc1C
Yield: 25 %

Procedure:
4-Bromo-2-methylaniline (2.83 grams, 0.02 mole) and ethyl 2-(chlorocarbonyl)-2-methoxypropionate (4.12 grams, 0.02 mole), prepared in Part C, were reacted in the presence of triethylamine (1.54 grams, (0.02 mole) in 200 milliliters of methylene chloride in a manner similar to that described in Example I to give 1.73 grams (0.005 mole) of ethyl 3-[(4-bromo-2-methyl-phenyl)amino]-2-methoxy-2-methyl-3-oxopropanoate having a melting point of 99° C.-103° C.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[NH:41][C:17]4=[N:18][CH:19]=[CH:20][C:21]([C:22]5[C:23]([C:29]6[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])=[CH:31][CH:30]=6)=[N:24][N:25]([CH2:27][CH3:28])[CH:26]=5)=[C:16]4[CH:15]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=O)C>C(O)C>[CH2:27]([N:25]1[CH:26]=[C:22]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:41][C:14]([C:8]4[CH:7]=[C:6]5[C:11]([CH2:12][CH2:13][NH:4][CH2:5]5)=[CH:10][CH:9]=4)=[CH:15][C:16]=23)[C:23]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])=[CH:31][CH:30]=2)=[N:24]1)[CH3:28]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc5c(c4)CN(C(C)=O)CC5)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: CCO
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc5c(c4)CNCC5)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described in Example 11 using N′-(4-{4-[2-(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea in ethanol at 100° C. provided the title compound. ESMS [M+H]+: 507.4
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:18]C)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:18])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)(C)C)cc1-c1ccc(C)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2cc(C(C)(C)C)ccc2O)nc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a solution of 2-(5-(tert-butyl)-2-methoxyphenyl)-5-methylpyridine (1.216 g, 4.76 mmol) in dry dichloromethane (50 mL) at 0° C. under nitrogen was added dropwise a solution of boron tribromide in dichloromethane (1.0 M, 9.52 mL, 9.52 mmol) and the reaction mixture stirred at 0° C. to room temperature for 5 hours. The reaction mixture was then re-cooled to 0° C., methanol (50 mL) added dropwise and the mixture then stirred at 40° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, the residue re-dissolved in methanol (100 mL) and re-concentrated to afford a pink solid. Saturated aqueous sodium hydrogen carbonate solution (80 mL) was added and the resulting suspension extracted with ethyl acetate (80 mL). The organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 15% ethyl acetate in hexanes to give 4-(tert-butyl)-2-(5-methylpyridin-2-yl)phenol (1.062 g, 92% yield) as a yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[CH2:5]2.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:17]1([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C:6]2([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]2)[CH2:5]3)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C2(Cc3ccc(NS(=O)(=O)c4cccc5ccccc45)cc3C2)N1

Procedure:
To a stirred solution of 50 mg (0.23 mmol) (±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 6) in THF (3 mL) was added 1-naphthalenesulfonyl chloride (53 mg, 0.24 mmol) and triethylamine (0.034 mL, 0.24 mmol). After 30 min the reaction mixture was concentrated to dryness. The residue was dissolved in DMF and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=408 (M+1). HRMS: m/z=408.1019; calculated m/z=408.1013 for C21H17N3O4S.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([F:26])[C:24]=1F.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C.CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc(O)cc21
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Yield: 52.6 %

Procedure:
Ethyl 2-(6-hydroxyindazol-1-yl)propionate (30 mgs) was dissolved in 0.72 cm3 of a mixture of dry methyl isobutyl ketone (6cm3) and 1 drop of dry DMF. 3-chloro-4,5-difluorobenzotrifluoride (42 mg) and dry potassium carbonate (27mg) were added. The mixture was stirred and heated under reflux for 7 hours, additional dry potassium carbonate being added after 3 hours. After cooling, the solvents were removed under vacuum and diethyl ether added to the residue, the mixture filtered and the inorganic portion washed thoroughly with diethyl ether. The combined ethereal filtrate was concentrated under vacuum and the residue purified by chromatography (SiO2 ; hexane:t-butylmethylether,4:1) to give compound 1, ethyl 2-[6-(2-chloro- 4-trifluoromethyl-6-fluorophenoxy) indazol-1-yl]propionate (29 mg). M+ =430.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](I)[C:20]=1[Cl:26]>>[Cl:18][C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Clc1cccc(I)c1Cl
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cccc(Cl)c3Cl)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,2-dichloro-3-iodobenzene according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 7.83 (s, 1H), 7.17 (m, 2H), 7.06 (d, J=8.7 Hz, 1H), 7.03 (m, 2H), 6.94 (dd, J=8.3, 1.4 Hz, 1H), 3.28 (s, 3H), 1.97 (m, 4H), 0.81 (t, J=7.3 Hz, 6H); MS (ESI) m/z [M+H]+(379/381/383); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.80; H, 4.96; N, 7.13.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([N:13]([C:21]1[N:31]=[CH:30][C:29]2[C:28]3[S:32][CH:33]=[CH:34][C:27]=3[CH2:26][CH2:25][O:24][C:23]=2[CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:33]1[S:32][C:28]2[C:29]3[CH:30]=[N:31][C:21]([N:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:22][C:23]=3[O:24][CH2:25][CH2:26][C:27]=2[CH:34]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sccc1CCO2)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(Br)cc1CCO2)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of N-bromosuccinimide (59 mg, 0.33 mmol) in 1 ml of dimethylformamide was added dropwise to a solution of tert-butyl tert-butyl(4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate (120 mg, 0.32 mmol) in 2 ml of dimethylformamide (DMF). The reaction mixture was stirred for 18 hours, concentrated in vacuum and partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuum to give tert-butyl 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl(tert-butyl)carbamate which was used in the next step without further purification. MS: (ESI+) 453.2
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:26]([Cl:38])[CH:25]=1>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[C:26]([Cl:38])[CH:25]=3)=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Clc1cc(Br)ccc1OCCN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(Cl)c3)nc2)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere 0.14 mL (1.00 mmol) triethylamine, 11 mg (0.02 mmol) Pd(PPh3)2Cl2 and 2.9 mg (0.015 mmol) CuI are added successively to a solution of 71 mg (0.33 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 100 mg (0.33 mmol) 1-[2-(4-bromo-2-chloro-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF. The mixture is stirred for 10 min at 100° C. and at 200 Watt in the microwave. The reaction solution is diluted with 30 mL EtOAc, washed twice with semisaturated NaCl solution and the organic phase is dried over MgSO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography with HPLC-MS.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH3:30])=[O:5])C>Br>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:21])([F:20])[F:22])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH3:30])([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1ccnc1C
Agent: Br
Product: Cc1nccn1Cc1c(C(=O)O)nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of 2-ethoxycarbonyl-1-(2-methyl-1-imidazolyl)methyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 7) (300 mg, 0.72 mmol) in hydrobromic acid (48% in water) (20 ml) was stirred at 80° C. for 16 h. The precipitate was collected and washed with ether. M.p. >250° C.