Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.C[O:7][C:8]1[C:25]2[C:24]3[C:19](=[CH:20][C:21]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:22]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:23]=3)[C:18]3[C:13](=[CH:14][C:15]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[C:16]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:17]=3)[C:12]=2[C:11]([O:70]C)=[CH:10][CH:9]=1>CCOCC>[CH2:27]([O:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:18]1[C:13](=[CH:14][C:15]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[C:16]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:17]=1)[C:12]1[C:11](=[O:70])[CH:10]=[CH:9][C:8](=[O:7])[C:25]2=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCOc1cc2c3cc(OCCCCCCCCCC)c(OCCCCCCCCCC)cc3c3c(OC)ccc(OC)c3c2cc1OCCCCCCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCOc1cc2c3c(c4cc(OCCCCCCCCCC)c(OCCCCCCCCCC)cc4c2cc1OCCCCCCCCCC)C(=O)C=CC3=O
Yield: 80 %

Procedure:
An aqueous solution (1 mL) of (NH4)2Ce(NO3)6 (0.035 g, 0.064 mmol) was added dropwise to a THF solution (5 mL) of 4a (0.029 g, 0.032 mmol). The reaction mixture immediately turned deep red. After 6 h the reaction mixture was poured into ether and washed with a saturated solution of NaHCO3 and water. The organic layer was dried with MgSO4 and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel (1:1 CH2Cl2/hexane) to afford 5a as a deep red solid in 80% yield (mp 86-87° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[CH2:11]=[O:12].[Mg+2].[Cl-].[Cl-]>C(#N)C>[OH:10][C:3]1[C:4]([CH:11]=[O:12])=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: C=O
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1cc(C)c(C=O)c(O)c1C

Procedure:
To a solution of 2,3,5-trimethylphenol (11.2 g, 82.0 mmoles) in 400 mL of acetonitrile was added paraformaldehyde (17.2 g, 574 mmoles), anhydrous MgCl2 (11.7 g, 123 mmoles), and TEA (43 mL 31 g, 308 mmoles). The mixture was refluxed for 6 h with stirring. After cooling, the mixture was partially concentrated, water added, and the mixture acidified with dilute aqueous HCl. The mixture was extracted with three times with Et2O, the combined organic extracts washed with brine, dried over Na2SO4, filtered, and concentrated. Chromatography of the residue over silica gel using DCM as eluent gave 6-hydroxy-2,4,5-trimethylbenzaldehyde, 8.8 g, as an oil.
Reaction SMILES: [C:1]([S:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].C([O:20][C:21](=[O:29])[CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(Cl)Cl.C(#N)C>[C:1]([S:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:23]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:22][C:21]([OH:29])=[O:20])=[O:9])(=[O:3])[CH3:2]
Reactant: COc1cccc(C(=O)O)c1SC(C)=O
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(C(=O)N(CC(=O)O)C2CCCC2)c1SC(C)=O
Reaction time: 8 h

Procedure:
N,N1 -Dicyclohexylcarbodiimide (10.3 g, 50 mmol) in methylene chloride (80 ml) was added to 2-acetylthio-3-methoxybenzoic acid (11.3 g, 50 mmol) and N-cyclopentylglycine t-butyl ester (10.0 g, 50 mmol) in methylene chloride (300 ml) at 0°-5° C. Overnight stirring was followed by filtration and washing of the filtrate with dilute hydrochloric acid, sodium bicarbonate solution and brine. Drying and concentration gave a gum which was dissolved in acetonitrile (65 ml), combined with sodium iodide (11.2 g, 75 mmol) and heated to 40°-50° C. Chlorotrimethylsilane (8.1 g, 75 mmol) was introduced and the mixture was heated for 30 minutes, then quenched with water. The organic phase was washed with water, aqueous sodium thiosulfate and brine then concentrated. Aqueous sodium bicarbonate was added to the residue and the resulting solution was washed with methylene chloride and ether, then acidified and extracted with ethyl acetate. The organic portion was dried and concentrated and the residue passed through a silica gel column to provide the amorphous product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CCNCC1
Product: Brc1cnc(N2CCCCC2)nc1

Procedure:
Prepared from 2-chloro-5-bromopyrimidine and piperidine by the method of Example 44 (b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:18][CH2:19][C:20]#[C:21][CH3:22].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11]2[N:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:12]=2[C:13](=[O:15])[CH2:14]1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2F)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a mixture of 5-(2,4-difluorophenyl)cyclohexane-1,3-dione (2.0 g), 1-amino-2-butyne hydrochloride (0.94 g), molecular sieves 4A (4 g) and tetrahydrofuran (40 ml) was added triethylamine (0.90 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 5 hours at 220° C., to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give, the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from isopropylether and hexane to give colorless crystals of 7-(2,4-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.47 g).
Reaction SMILES: [Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([Cl:31])=[CH:29][C:28]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:27][N:26]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1>[Cl:31][C:30]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=2)=[N:26][CH:27]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:29]=1
Reactant: CCCCCCCCOc1cnc(-c2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2ccc(O)cc2)c(Cl)c1
Yield: 80.9 %

Procedure:
4.30 g (8.00 mmol) of 2-(4-tert-butyldiphenylsilyloxyphenyl)-3-chloro-5-octyloxypyridine are stirred at room temperature for 2 hours with 16 ml of a 1-molar tetrabutylammonium fluoride solution in tetrahydrofuran in 50 ml of tetrahydrofuran. Agueous sodium chloride solution is subsequently added, the mixture is extracted with ether, the ether phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness, and the product is purified by chromatography (silica gel/hexane:ethyl acetate 8:2), giving 2.16 g of 3-chloro-2-(4-hydroxyphenyl)-5-octyloxypyridine. ##STR32##
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([O:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:24][CH2:25]2)=[CH:20][C:19]3=[O:40])[CH2:16][CH2:15]1)[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@H:21]([CH2:22][C@@H:23]([O:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:24][CH2:25]2)[CH2:20][C:19]3=[O:40])[CH2:16][CH2:15]1)[CH3:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
Compound 2004 (1.0 g, 1.75 mmol) was dissolved in EtOAc (75 ml) and platinum(IV) oxide (0.012 g, 0.049 mmol) was added. The mixture was placed on a hydrogenation apparatus (atmospheric). The set-up was evacuated to remove the dissolved oxygen and then hydrogen was introduced. The evacuation and introduction of hydrogen process was repeated 2 times. The reaction was stirred under hydrogen at atmospheric pressure for 2.5 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexanes:EtOAc gradient starting with 20:1) giving compound 2005 as a white solid (0.70 g, 71%). 24-t-Butyldimethylsilyloxy-3β-tetrahydropyranyloxy-5α-cholan7β-ol was obtained as a by-product (21%). (Note: This by-product could be converted to the desired ketone 2005 with Collin's reagent in 64% yield.) Compound 2005: 1H NMR (500 MHz, CDCl3) δ: 4.73-4.66 (m, 1H, THP methine H), 3.95-3.85 (m, 1H, THP CH2O), 3.66-3.52 (m, 3H, THP CH2O & C-24 H), 3.50-3.45 (M, 1H, C-3 H), 1.08 (s, 3H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H , t-Bu), 0.64 (s, 3H, C-18 H), 0.04 (s, 6H, TBDMS CH3); IR (CHCl3) 2900, 1685 cm-1 ; MS (CI/isobutane) m/z 575 (M+1, 85%), 491 (M+1-THP, 100%); m.p. 166°-170° C.; Anal. calcd. for C35H62O4Si: C=73.12, H=10.87; Found: C=72.88, H=10.78.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH2:25][CH3:26])[C:21](=[O:27])[N:20](CC2C=CC(OC)=CC=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.BrC1C=C2C(C=CNC2=O)=CC=1OC1CCNCC1>>[CH2:25]([C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][NH:20][C:21]2=[O:27])=[CH:16][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:26]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3)ccc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=c1[nH]ccc2cc(OC3CCNCC3)c(Br)cc12
Product: CCc1cc2c(=O)[nH]ccc2cc1OC1CCNCC1

Procedure:
4-[7-Ethyl-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (319) is deprotected following the method described for 7-bromo-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (17). Final purification by preparative HPLC delivers the title compound as trifluoroacetate. Rt=0.92 min (Method A). Detected mass: 273.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:42])([C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)=[CH:26][N:27]=1)[CH2:9][O:10][P:11]([O:18]C(C)(C)C)([O:13]C(C)(C)C)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[NH2:7][C:8]([C:23]1[NH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:33]=2)=[CH:26][N:27]=1)([CH3:42])[CH2:9][O:10][P:11](=[O:12])([OH:18])[OH:13]
Reactant: CCCCCCCCc1ccc(-c2cnc(C(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OC(C)(C)C)[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCc1ccc(-c2cnc(C(C)(N)COP(=O)(O)O)[nH]2)cc1
Reaction time: 4 h

Procedure:
To a stirring solution of 8 (22 mg, 0.035 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL) and stirring was continued 4 hours. Solvent and excess trifluoroacetic acid were removed in vacuo to afford a brown oil. The oil was diluted with ether and concentrated in vacuo 5 times on a rotary evaporator to afford a white solid which was placed in a fritted funnel and washed with cold ether producing VPC24287 (13 mg, 91%) as a powdery white solid. Rf=0 (4:1 CHCl3/methanol).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]([F:42])([F:41])[C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17].[I-].[K+].C(N(C(C)C)CC)(C)C>C(#N)C>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:41])[F:42])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: O=C(CBr)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A mixture of phenacyl bromide (0.88 g), (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (2 g), potassium iodide (catalytical), diisopropyl-ethylamine (0.77 mL), and acetonitrile (20 mL) was stirred at room temperature overnight. After cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichloromethane and NaOH (2N). The layers were separated, the organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 97/3) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-phenyl-2-ethanon-1-yl)piperazine 2.16 g (85%). MH+ 574, Rf 0.44 (CH2Cl2/MeOH 97/3).
Reaction SMILES: [OH:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][OH:34])[CH:26]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([N:19]3[CH2:24]COC[CH2:20]3)=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.S(=O)(=O)(O)O>>[OH:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][OH:34])[CH:26]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([N:19]([CH3:20])[CH3:24])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: O=C(COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(O)c(CCO)c1)CC2)N1CCOCC1
Agent: O=S(=O)(O)O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(O)c(CCO)c1)CC2

Procedure:
Using (-)-4-[2-[(2S)-2-[[(2R)-2-hydroxy-2-(4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetyl]morpholine (Compound 18) and sulfuric acid, the following salt was obtained in the same manner as that described in Example 7.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:19])([CH3:18])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:22]=1[C:23]#[N:24]>>[NH2:20][C:21]1[C:22]([C:23]#[N:24])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:1][CH2:2][C:3]([CH3:19])([CH3:18])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)=[O:7]
Reactant: N#Cc1c(N)cccc1F
Reactant: COc1ccc(CNC(=O)NCC(C)(C)CO)cc1
Product: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(N)c2C#N)cc1
Yield: 60 %

Procedure:
Prepared as in Example 215b (Method B) from 1-(3-hydroxy-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 252c) and 2-amino-6-fluorobenzonitrile in 60% yield. MS 383 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][Br:8].[C:13](Cl)(=[O:16])[CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][Br:8])(=[O:16])[CH2:14][CH3:15]
Reactant: O=C(CBr)Nc1cccc(O)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Oc1cccc(NC(=O)CBr)c1
Reaction time: 0.33 h

Procedure:
The anilide, 3'-hydroxy bromoacetanilide, 6.9 g. and propionyl chloride (3.1 g., 0.033 mole) are combined in 120 ml. of methylene chloride as a solvent. Pyridine (2.6 g., 0.033 mole) is added dropwise. A slightly exothermic reaction takes place during the addition. Stirring is continued at room temperature for 20 minutes. A clear solution is obtained. The material is washed sucessively with water, dilute hydrochloric acid and again with water. The organic layer is dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting material is recrystallized from a mixture of ethylacetate and ether. There is obtained 6.5 g. of the title compound, m.p. 85°-88° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:34](B(O)O)=[CH:33][CH:32]=[N:31]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:34]([C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[C:12]2[N:8]([CH:9]=[C:10]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:11]=2)[CH2:7][CH2:6][O:5]3)=[CH:33][CH:32]=[N:31]1
Reactant: OB(O)c1ccnn1C1CCCCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCCCO3)cc1OCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of 12-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (2.00 g, 5.34 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (1.58 g, 8.01 mmol), Pd(dppf)Cl2 (437 mg, 0.535 mmol), Na2CO3 (1.70 g, 16.0 mmol) in DME/EtOH/H2O (15/3/3 mL) was stirred at 100° C. for 1 hr under microwave irradiation. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and evaporated to give crude product, which was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:5) to afford 12-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (2.2 g, 90% yield) as white solid. LCMS (ESI) m/z: 446.3 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.C1OCCOCCOCCOCCOCCOC1>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)(=[O:7])=[O:8])[CH2:28][CH2:27]1)=[O:19])[CH3:2]
Reactant: BrCCBr
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 65 °C
Yield: 163 %

Procedure:
To a mixture of 1.69 g (5.69 mmol) of (4-trifluoromethyl-benzenesulfonyl)-acetic acid ethyl ester (prepared according step 1 and 2 of Method A), 1.59 g (11.5 mmol) of potassium carbonate, 100 mg 18-crown-6 and 100 mg tetrabutylammonium bromide in acetone (40 mL) were added 0.49 mL (5.69 mmol) of 1,2-dibromoethane. The reaction was heated in a sealed tube to 65° C. for 18 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluent heptanes, 0-20% ethyl acetate) to afford 2.99 g of 1-(4-trifluoromethyl-benzenesulfonyl)-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:8]1[CH:9]=[C:2]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1
Reactant: O=Cc1cc(Cl)cc(Br)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C=O)c2)cn1
Temperature: 25 °C

Procedure:
3-bromo-5-chlorobenzaldehyde (502 mg, 2.3 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (794 mg, 2.3 mmol), Pd(dppf)Cl2 (84 mg, 0.1 mmol), and K2CO3 (632 mg, 4.6 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and the resulting mixture was heated to 70° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:27].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][C:16]([Br:27])=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Br-]
Reactant: Cc1ccc(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)c(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a stirred solution of (R)-2-Benzyl-7-methyl-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (190 mg, 0.59 mmol) in dry CH2Cl2:methanol (4:2 mL), tetrabutylammonium tribromide (331 mg, 0.68 mmol) was added. The reaction was stirred for 1 h under Argon added more tetrabutylammonium tribromide (45 mg, 0.09 mmol). After 20 min removed solvent in rotavap and then diluted with dichloromethane (100 mL), washed with 5% Na2S2O3 (10 mL), saturated NaHCO3 (10 mL) and brine (15 mL). The organic layer was dried over MgSO4, and conc in vacuo and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to yield 86 mg (36%) of the product as a faint brown oil. MS (ESI) 401, 403 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
4-Methoxy-3-hydroxy-benzaldehyde (1.0 mg, 7.5 mmoles) is dissolved in DMF (20 mL). Cesium carbonate (2.45 g, 7.5 mmoles) and 1-fluoro-4-nitro-benzene (1.75 mL, 7.5 mmoles) are added and the resulting mixture is stirred at room temperature for 20 hours. The reaction mixture is then quenched by addition of 1N HCl and extracted with AcOEt. The organic layer is dried over Na2SO4 and the solvent is evaporated. The crude mixture is purified by chromatography on SiO2 (eluent:hexane:AcOEt=9:1) to yield 2.0 g of the pure title compound.