Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: Cc1ccc(-c2nc(N)sc2-c2ccccc2)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(NS(=O)(=O)C(F)(F)F)sc2-c2ccccc2)cc1
Yield: 37.4 %

Procedure:
15.9 g of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 5.0 g of 2-amino-4-(4-methylphenyl)-5-phenylthiazole and 5.2 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 2 hours. Then the reaction mixture was successively washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using chloroform/ethyl acetate as a developer. The crystals thus obtained were recrystallized from n-hexane/isopropyl ether/ethyl acetate to give 2.8 g of 2-trifluoromethanesulfonylamino-4-(4-methylphenyl)-5-phenylthiazole. The melting point of this product was from 186.5° to 188.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.CO>O=[Pt]=O.CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Yield: 80.4 %

Procedure:
To a solution of 40 g of N-(3-nitro-4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide in 900 ml. of MeOH and 100 ml. of EtOAc in a hydrogenation bottle is added 0.5 g PtO2. The bottle is purged with hydrogen then pressurized to 50 psig and shaken until the required amount of H2 was used. The reaction mixture was filtered through celite, washed well with CH2Cl2 and the combined organic phases concentrated in vacuo to yield 29 g of the product. This product was used without further purification in subsequent transformations.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][OH:26].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][CH2:24][CH2:25][OH:26])=[O:15])(=[O:19])=[O:18]
Reactant: OCCCBr
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid), (10) (Aldrich) (0.060 mole), 3-bromo-1-propanol (Aldrich) (0.055 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, (Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give 3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propanol (805). See eg., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, p. 228 (1991).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.N[CH:32]([CH2:57][CH:58]([F:60])[F:59])[C:33](=[O:56])[C:34](=[P:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]#[N:36]>ClCCl>[NH:1]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:60][CH:58]([F:59])[CH2:57][CH2:32][C:33](=[O:56])[C:34](=[P:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:35]#[N:36]
Reactant: N#CC(C(=O)C(N)CC(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: N#CC(C(=O)CCC(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Synthesis of compound 15 (see scheme 7) Boc-Leu-OH (1.16 g, 5 mmol) was dissolved in dichloromethane (50 mL) and EDC (1.05 g, 5.5 mmol) and HOBt (743 mg, 5.5 mmol) were added. The resulting solution was cooled to 0° C. and (±)-4-Amino-6,6-difluoro-3-oxo-2-triphenylphosphoranylidene-hexanenitrile (2.32 g, 5.5 mmol) was added in one portion. The ice bath was removed and the mixture stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed successively with 1 N aqueous HCl, water, saturated aqueous NaHCO3 and brine. Drying (Na2SO4) and evaporation gave 2.7 g (85%) of Boc-Leu-6,6-difluoro-3-oxo-2-triphenylphosphoranylidene-hexanenitrile as a yellowish foam. The foregoing compound (2.7 g, 4.2 mmol) was dissolved in dichloromethane/methanol (40 ml, 7:3, v/v) and cooled to −78° C. Ozone was bubbled through the solution until the blue color remained. The solution was then purged with nitrogen and 12 mL of MeOH were added, the resulting solution was stirred at −78° C. for 30 min. and at room temperature for 2 h. Evaporation gave a light yellow oil, which was dissolved in MeOH (6 mL) and the resulting solution was cooled to 0° C. After addition portionwise of NaBH4 (159 mg, 4.2 mmol) the resulting reaction mixture was stirred at 0° C. for 2 hours, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine and dried (Na2SO4). Evaporation gave a solid which was purified by flash chromatography (PE/ethyl acetate 3:2) to give 832 mg (50%) of the Boc protected dipeptide hydroxyester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.[CH3:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([C:46]([F:49])([F:48])[F:47])[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][C:41]=12)=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:43]1[CH2:44][CH2:45][N:40]2[C:39]([C:46]([F:49])([F:47])[F:48])=[N:38][C:37]([C:35]([NH:34][CH3:33])=[O:36])=[C:41]2[CH2:42]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 61.5 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (598 mg, 2 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (135 mg, 1 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg, 2 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (573 mg, 3 mmol) and N, N-diisopropylethylamine (774 mg, 6 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 13 (650 mg, yield 61.0%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:14]([O:16]CC)=O)[S:13][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:14]([NH:20][NH2:21])=[O:16])[S:13][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCc2cc(C(=O)OCC)sc2CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCN1CCc2cc(C(=O)NN)sc2CC1

Procedure:
13.0 gm (0.0486 mol) of ethyl 5,6,7,8-tetrahydro-6-propyl-4H-thieno[2,3-d]azepine-2-carboxylate were dissolved in 15 ml of absolute ethyl alcohol, and the solution was refluxed for 3 hours with 14 ml (0.23 mol) of 80% hydrazine hydrate. After cooling, the mixture was concentrated by evaporation in vacuo, and the residue was recrystallized from isopropyl alcohol.
Reaction SMILES: [C:1]([C:9](=[CH:15]OCC)[C:10]([O:12]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([N:25]2[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[OH:12][C:10]1[C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:15][N:30]=[C:29]2[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=[CH:27][C:28]=12
Reactant: Nc1ccnn1-c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of ethyl 2-benzoyl-3-ethoxyacrylate (0.99 g, 4.0 mmol) and 1-phenyl-1H-pyrazol-5-amine (0.64 g, 4.0 mmol) was stirred at 120° C. for 1.5 hr under argon and then cooled. After diphenyl ether (5 g) was added, the mixture was stirred at 240° C. for 2 hr under argon. Flash chromatography and crystallization in heptane and ethyl acetate mixture gave (4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (0.53 g, 1.7 mmol, 42% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:16]([C:19]1[S:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].O>C(COC)OC.O>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:22]3[S:23][C:19]([C:16](=[O:18])[CH3:17])=[CH:20][CH:21]=3)[CH:3]=[CH:4][CH:5]=2)[CH:14]=1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)c1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1ccc(-c2cccc(Nc3cc(C)ccn3)n2)s1
Temperature: 130 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
A suspension of (6-bromopyridin-2-yl)-(4-methylpyridin-2-yl)amine (1.00 g, 3.79 mmol), 5-acetylthiophene-2-boronic acid (644 mg, 3.79 mmol), tetrakis triphenylphosphine palladium (440 mg, 0.38 mmol), sodium hydrogen carbonate (480 mg, 5.68 mmol) in dimethoxyethane-water (12 ml) was heated and stirred in an Ar stream at 130° C. for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over anhydrous magnesium sulfate, the residue obtained by concentration in vacuo was washed with tetrahydrofuran-ethyl acetate (1:1), dried, and the title compound (426 mg, 36%) was obtained.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH:13]([F:24])[CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.F[C:28](F)(F)N1CCN(C(F)CCC(C2C=CC=CC=2)=O)CC1>>[CH3:28][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH:13]([F:24])[CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(F)N1CCN(C(F)(F)F)CC1)c1ccccc1
Reactant: O=C(CCC(F)N1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Product: Cc1ccc(CN2CCN(C(F)CCC(=O)c3ccccc3)CC2)cc1

Procedure:
γ-[4-(p-Fluorobenzyl)piperazino]-4-fluorobutyrophenone γ-[4-(p-Trifluoromethylpiperazino]-4-fluorobutyrophenone
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:28][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CNCCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzyl amine (0.36 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[3-(naphthalen-2-yloxy)-propyl]amine, solid, m.p. 109° C., (yield 0.62 gm, 93.6%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:35][C@H:36]([CH3:48])[C:37]([NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)=[O:38]>ClCCl>[CH3:46][C:44]1[CH:45]=[C:40]([NH:39][C:37](=[O:38])[C@H:36]([NH:35][C:6]([C:5]2[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)=[O:8])[CH3:48])[CH:41]=[C:42]([CH3:47])[CH:43]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cc(C)cc(NC(=O)[C@@H](C)N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)[C@@H](C)NC(=O)c2cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c2)c1

Procedure:
To the solution of 4-chloro-3,5-dinitrobenzoic acid (1.058 g, 4.29 mmol) and EEDQ (1.062 g, 4.29 mmol) in dichloromethane (25 ml) is added (2R)-2-amino-N-(3,5-dimethylphenyl)propanamide, prepared in Example 5 (0.825 g, 4.29 mmol) in dichloromethane (25 ml). After 16 h of mixing at room temperature the product is recovered on a G-4 filter and washed with dichloromethane (30 ml). The product is dried at 50° C. for 4 h. 1.026 g (56%) of yellowish powder are obtained, mp 202°–204° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].FC(F)(F)S(O)(=O)=O.ClC(Cl)(Cl)C(=N)O[CH2:68][CH:69]=[CH2:70]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:70][CH:69]=[CH2:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (400 mg in 6 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (209 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (9 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 6 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (320 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(#N)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[N:13]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(-c2ccc(=O)n(CCOc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)-(1H)-pyridin-2-one (1 eq, 0.30 mmol, 60 mg) in THF (3 mL) was added K2CO3 (10 eq, 3.00 mmol, 0.41 g). The reaction was stirred at room temperature for 30 minutes then 1-(2-bromoethoxy)benzene (3 eq, 0.90 mmol, 0.18 g) was added. The reaction was stirred at 60° C. for 12 hours. After concentration of the solvent, acetonitrile (3 mL) was added followed by K2CO3 (10 eq, 3.00 mmol, 0.41 g) and 1-(2-bromoethoxy)benzene (10 eq, 3.00 mmol, 0.60 g) then the reaction was microwaved for 5 minutes at 180° C. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt (80/20) as the eluent to afford 5-(4-methoxyphenyl)-1-(2-phenoxyethyl)pyridin-2(1H)-one (0.13 mmol, 42 mg, 44%) as a yellow oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:27]([C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])[C@@:39]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)([CH3:50])[C@@:40]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)([CH3:42])[N:41]=2)=[C:33]([O:66][CH2:67][CH3:68])[CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]([C:58]([N:60]3[CH2:65][CH2:64][N:63]([C:5](=[O:7])[CH2:4][CH2:3][S:2][CH3:1])[CH2:62][CH2:61]3)=[O:59])[C@@:39]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)([CH3:50])[C@@:40]([C:43]3[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=3)([CH3:42])[N:41]=2)=[C:33]([O:66][CH2:67][CH3:68])[CH:32]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CSCCC(=O)O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCSC)CC1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 3-(methylthio)propionic acid (30.8 mg, 0.256 mmole, Lancaster) in dimethylformamide (10 mL) were added successively 1-hydroxybenzotriazole (46.3 mg, 0.342 mmole, Chem-Impex), N,N,N′,N′-tetramethyl-O-(1H-Benzotriazol-1-yl)uranium hexafluorophosphate (130.0 mg, 0.343 mmole, Aldrich) and diisopropylethylamine (111.0 mg, 0.857 mmole). The mixture was stirred for 15 min before [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (104.4 mg, 0.171 mmole) was added. The reaction mixture was allowed to stir for 1 h before concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, brine, dried and concentrated. The crude residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in methylene chloride) to give the title compound (108.7 mg, 89% yield). HR-MS (ES, m/z) calculated for C37H46Cl2N5O3S [(M+H)+] 710.2693, observed 710.2691.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:10][CH2:9]1.C=O.[C:25]([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][N:12]2[CH3:25])[CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)NCC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Reaction time: 0.25 h

Procedure:
A mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.5 g, prepared as described in Example RC10), 37-40% aqueous formaldehyde solution (2.9 ml), sodium cyanoborohydride (0.75 g) and acetonitrile (100 ml) was stirred for 15 minutes. Glacial acetic acid was added to neutralise the solution and stirring was continued for a further 45 minutes. The mixture was basified with aqueous sodium hydroxide solution, then extracted with ethyl acetate. The extracts yielded 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>O1CCCC1>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:11][C:4]=12
Reactant: FC(F)(F)c1ccnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(F)(F)F)ccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
4-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (1.5 g, 8 mmol) was suspended in tetrahydrofuran (20 mL) and cooled to 0° C. Sodium hydride (390 mg, 9.7 mmol) was added in small portions and the mixture was stirred at 0° C. for 1 h. Triisopropylsilyl chloride (2.6 mL, 12 mmol) was added and the mixture was stirred at 23° C. for 12 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with water (5 mL). The mixture was applied to a Varian chemelut cartridge and eluted with ethyl acetate. Purification by flash silica gel chromatography using a gradient of dichloromethane in hexanes afforded 4-Trifluoromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2.5 g, 7.3 mmol, 90% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J=5 Hz, 1H), 7.76 (d, J=4 Hz, 1H), 7.44 (d, J=5.5 Hz, 1H), 6.74 (m, 1H), 1.88 (septet, J=7.5 Hz, 3H), 1.05 (d, J=7.5 Hz, 18H). MS: m/z 343.2 (M+H+).