Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10](/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC)([OH:18])[C:9]([CH3:34])=[CH:8]2)[O:3]1.[CH:35]1(/[C:38](/I)=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1.[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.O1CCCC1>[CH:35]1(/[C:38](/[CH:20]=[CH:19]/[C:10]2([OH:18])[C:11]([CH3:17])([C:13]([F:16])([F:14])[F:15])[CH2:12][C:4]3([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]3)[CH:8]=[C:9]2[CH3:34])=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)(CCCC)CCCC
Reactant: CCOC(=O)/C=C(\I)C1CC1
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Under argon, 2,3,7,9-tetramethyl-8-[(E)-2-(tributylstannyl)vinyl]-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (150 mg, 0.25 mmol) and ethyl (2Z)-3-cyclopropyl-3-iodoacrylate (67 mg, 0.25 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. tetrahydrofuran (4 ml), dichlorobis(acetonitrile)palladium(II) (3 mg, 0.01 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z,4E)-3-cyclopropyl-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]penta-2,4-dienoate (40 mg, 36% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.80/7.78 (d, 1H), 6.40/6.38 (d, 1H), 5.62/5.60 (s, 1H), 5.52/5.44 (s, 1H), 4.28/3.63 (m, 2H), 4.18 (q, 2H), 2.52/2.41 (d, 1H), 2.03/1.94 (d, 1H), 2.00 (br. s, 1H, OH), 1.72/1.69 (s, 3H), 1.62/1.55 (m, 1H), 1.40-1.34 (m, 3H), 1.29-1.17 (m, 6H), 0.92 (t, 3H), 0.83 (m, 2H), 0.58 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCN1CCCC1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN3CCCC3)cccc2c1Nc1ccccc1C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry dimethylformamide (100 ml) at 100° , 1-(3-chloropropyl)pyrrolidine hydrochloride (3.6 g, 20 mmol) added, and stirring continued for 1 hour. The mixture was diluted with water and extracted with ether, and the ether extracts dried and evaporated. Chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and recrystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(1-pyrrolidinyl)propoxy)quinoline (0.35 g, 8.5 %), m.p. 101°-103°.
Reaction SMILES: C([NH:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(=O)CC.Cl>C(O)C>[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20]
Reactant: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: Nc1c([N+](=O)[O-])cnn1-c1ncc(Cl)cc1Cl
Yield: 92.4 %

Procedure:
5 g (0.015 mole) of 5-propionamido-1-(3,5-dichloropyrid-2-yl)-4-nitro-pyrazole and 10 ml of concentrated hydrochloric acid are heated under reflux in 15 ml of ethanol for 4 hours, the solvent is distilled off in vacuo, the residue is taken up in 400 ml of methylene chloride and the mixture is neutralized with sodium bicarbonate solution, washed with sodium chloride solution, dried over sodium sulphate and freed from the solvent in vacuo. 3.8 g (92% of theory) of 5-amino-1-(3,5-dichloropyrid-2-yl)-4-nitropyrazole of melting point 194° C. are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([O:31][CH2:32][CH2:33][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)[CH3:29]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Compound A2 (0.13 mmol, 50 mg), and 1-bromo-2-ethoxy-ethane (0.65 mmol, 99 mg) were dissolved in DMF (1 mL) and triethylamine (0.91 mmol, 127 μL). The reaction was heated in a microwave at 80° C. for 20 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by prep-TLC provided Compound A12 as a yellow solid (20 mg, 33%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.06 (s, 1H), 8.29 (s, 1H), 7.84 (d, 2H), 7.74 (d, 2H), 5.39 (s broad, 1H), 3.53 (m, 2H), 3.39 (q, 2H), 2.86 (s, 3H), 2.77 (m, 2H), 2.65 (m, 3H), 2.04 (m, 2H), 1.92 (m, 3H), 1.09 (m 3H). LCMS (ESI), m/z 466.3 (M+H+, 100%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15]I>O1CCCC1>[C:1]1([C:7]2[S:8][CH2:9][C:10]([CH3:15])([C:12]([OH:14])=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CSC(c2ccccc2)=N1
Reactant: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CSC(c2ccccc2)=N1

Procedure:
Cysteine, benzonitrile, and 5 equivalents of triethylamine were refluxed in ethanol for 6-8 hours to obtain a 66-70% yield of 2-phenylthiazoline-4-carboxylic acid. The 2-phenylthiazoline-4 carboxylic acid was reacted with 2.05 equivalents of base and 1 equivalent of methyl iodide in tetrahydrofuran at 0° C. to form 2-phenyl-4-methylthiazoline-4 carboxylic acid. The 2-phenyl-4-methylthiazoline-4 carboxylic acid can be resolved and isolated as the (S)-enantiomer using emulsion crystallization, and subsequently hydrolyzed with hydrochloric acid, thereby obtaining (S)-2-methylcysteine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:17])[C:9]=1[O:10]COCCOC)[CH:5]=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[C:23](=[CH:5]/[C:4]2[CH:7]=[C:8]([CH3:17])[C:9]([OH:10])=[C:2]([CH3:1])[CH:3]=2)/[C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COCCOCOc1c(C)cc(C=O)cc1C
Product: COc1ccc(/C(C#N)=C/c2cc(C)c(O)c(C)c2)cc1OC
Yield: 57.8 %

Procedure:
The hydroxyl group of 3,5-dimethyl-4-hydroxybenzaldehyde (2.3 g) was protected by use of 2-methoxyethoxymethyl chloride (3.4 g) in accordance with (production process 1), to thereby produce 3,5-dimethyl-4-methoxyethoxymethoxybenzaldehyde (2.7 g, yield: 62%). The thus-produced 3,5-dimethyl-4-methoxyethoxymethoxybenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.5 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.5 g, yield: 57%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([Br:20])[CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:20][C:18]1[CH:17]=[C:11]([CH:10]=[C:9]([NH:8][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(N)cc(Br)c1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Br)cc(NC(=O)CCCCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
4-Chlorobutyryl chloride (636 mg, 505 μl, 4.5 mmol) was added to a solution of ethyl 3-amino-5-bromobenzoate (1.0 g, 4.1 mmol) and triethylamine (455 mg, 630 ul, 4.5 mmol) in dichloromethane (25 ml) at 0° C. After complete addition the reaction mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate (50 ml). The solution was washed with 2M HCl, saturated NaHCO3, water and brine. The organic phase was dried and evaporated to give the title compound as a pale yellow solid (1.35 g, 94%)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H]3CCN(CCC)C3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[CH3:30][O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36](C2C=CC=C(N)C=2)[CH2:35]1)=[O:33].FC(F)(F)OC1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:30][O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:28])([F:1])[F:29])[CH:5]=3)(=[O:11])=[O:12])[CH:15]=2)[CH2:35]1)=[O:33]
Reactant: COC(=O)N1CCC(c2cccc(N)c2)C1
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)cc2)C1
Agent: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Product: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)C1

Procedure:
This compound was obtained following the same synthetic procedure as described for 3-trifluoromethoxy-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide by reacting 1-(Methoxycarbonyl)-3-(3-aminophenyl)-pyrrolidine as obtained in example b.1 with commercially available 3-trifluoromethoxy-benzenesulfonyl chloride.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.N12CCC(CC1)CN2>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1COCCN1
Agent: C1CN2CCC1CN2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOCC3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A mixture of 2.83 g (0.01 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.9 g (0.01 mol) of morpholine and 2.3 g of diazabicyclo[2.2.2]octane (0.02 mol) in 35 ml of dimethyl sulphoxide is heated to 140° C. for 5 hours. The solvent is distilled off in vacuo, 50 ml of water are added to the residue, the mixture is acidified with semiconcentrated hydrochloric acid, and, when the mixture is cold, the product is filtered off under suction, washed with water, dried in vacuo and recrystallised from glycol monomethyl ether. 2.4 g of 1-cyclopropyl-6,8-difluoro-7-(morpholin4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 257°-260° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 4-(5-Bromo-pyridin-2-yloxy)-benzaldehyde (RH3-A02640-038) (3.501 g, 12.6 mmol) in 1,2-dichloroethane (61 mL) is added isoamylamine (1.65 mL, 14.2 mmol), NaBH(OAc)3 (4.00 g, 18.9 mmol), and acetic acid (1.10 mL, 19.2 mmol). The reaction is stirred overnight. The reaction mixture is then washed with saturated NaHCO3 (2×100 mL), dried over MgSO4, filtered, and concentrated. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 25% of ethyl acetate to 100% of ethyl acetate to give [4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (2.18 g, 50%) as a yellow oil. 1NMR (400 MHz, CDCl3) δ ppm: 8.21 (d, J=3.1 Hz, 1H), 7.75 (dd, J=2.6, 8.7 Hz, 1H), 7.37-7.34 (m, 2H), 7.09-7.05 (m, 2H), 6.82 (d, J=9.1 Hz, 1H), 2.49 (s, 2H), 2.66 (dd, J=7.6, 7.6 Hz, 2H), 1.67-1.61 (m, 1H), 1.44-1.38 (m, 2H), 1.15 (s br, 1H), 0.90 (d, J=6.6 Hz, 6H); MS (ES): [M+H]+ found 261.7. Step 3 N-(6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-pyridin-3-yl)-acetamide
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)[CH:2]=[CH2:3].Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>>[CH2:24]([O:26][N:27]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH3:25]
Reactant: C=CCC(COCCCNC(C)C)CC(=O)c1ccccc1
Reactant: CCON
Agent: Cl
Product: C=CCC(COCCCNC(C)C)CC(=NOCC)c1ccccc1

Procedure:
The procedure described in Example 88 was repeated using 3-allyl-4-(3-[N-isopropylamino]propoxy)butyrophenone and ethoxyamine hydrochloride to give 3-allyl-4-(3-[N-isopropylamino)propoxy)-butyrophenone O-ethyloxime as a solid, m.p. 124°-126° C.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[P:26]([O-:38])([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]>>[P:26]([O:38][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:28][CH2:29][CH2:30][CH2:31][CH3:32])([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:27]
Reactant: CCCCOP(=O)([O-])OCCCC
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CCCCOP(=O)(OCCCC)OC1(N=O)CCCCC1

Procedure:
Dibutyl 1-nitrosocyclohexyl phosphate was prepared from cyclohexanone oxime, lead tetraacetate and dibutyl phosphate using conditions of General Method 3. 1H NMR (400 MHz, chloroform-d) δ 4.12-4.21 (1H, m), 4.00 (3H, q, 6.7 Hz), 1.61-1.79 (6H, m), 1.36-1.48 (5H, m), 1.25-1.35 (4H, m), 0.86-0.97 (9H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:24])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](OC)=[O:21])=[CH:15][CH:14]=2)[N:10]=1.[OH:25][CH:26]([C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:24])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:25][CH:26]([C:33](=[O:40])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:21])=[CH:15][CH:14]=2)[N:10]=1
Reactant: COC(=O)CCC(O)C(=O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
A mixture of methyl [4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]acetate (1.00 g), methyl 4-hydroxy-5-oxo-5-phenylpentanoate (709 mg), WSC (734 mg), 4-(N,N-dimethylamino)pyridine (77.9 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 6 hrs. The reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.56 g, yield %) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC(O)=O)[C:12](=[O:13])[CH:11]=C1.C([O:29]C(Cl)=O)C(C)C>C(N(CC)CC)C>[OH:29][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH3:11])=[CH:19][CH:18]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.50 g. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.309 g. of p-hydroxyacetophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3), followed by ethyl acetate-hexane (7:3). The residue obtained by concentration of selected fractions, 0.500 g., an oil, is the title compound, having Rf 0.4 (TLC on silica gel in ethyl acetate-hexane (1:1)).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=1)=[O:28]>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[CH3:26])=[CH:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: CC(=O)Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 4-bromoacetanilide (278 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (26 mg, 5.3%). MS (ISP) 489.3 [(M+H)+]; mp 238° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2[CH:19]=O)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Li+].[S:29]1[CH:33]([C:34](=[O:44])[CH2:35]P(=O)(OCC)OCC)[CH:32]=[C:31]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:30]12>C(Cl)Cl.C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2/[CH:19]=[CH:35]/[C:34]([C:33]2[S:29][C:30]3[CH:48]=[CH:47][CH:46]=[CH:45][C:31]=3[CH:32]=2)=[O:44])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CC(=O)C1C=C2C=CC=CC2S1)OCC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: -20 °C

Procedure:
A reactor equipped with a mechanical stirrer, under nitrogen, was charged with a mixture consisting of (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate in DCM and a mixture consisting of lithium chloride (1 molar equivalent) in THF. Diethyl 2-(2,7a-dihydrobenzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) was added neat and rinsed with DCM. Some lithium chloride precipitated from solution when the THF and DCM mixtures were combined. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and further stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) was added neat via addition funnel and the temperature was maintained at −5° C. for 19 hours. The temperature was adjusted to 0° C. and the reaction mixture was treated with 5% aqueous citric acid. The layers were separated and the organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 27; 1H NMR (CDCl3) δ 8.10-8.15 (m, 2H), 8.05 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.75 (m, 4H), 7.38-7.60 (m, 5H), 6.98-7.17 (m, 2H), 5.45-5.55 (m, 1H), 5.18-5.25 (m, 1H), 2.93-3.15 (m, 3H), 2.55-2.77 (m, 2H), 2.38-2.47 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:8]1[O:10][CH2:9]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: C1CNCCN1
Product: COc1ccc(OCC(O)CN2CCNCC2)cc1
Yield: 50.7 %

Procedure:
Following the procedure of part A of Example 1, 9.56 g of piperazine is allowed to react with 10 g of p-methoxyphenyl glycidyl ether to obtain 7.5 g of N-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-piperazine.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:43]=[CH:44][CH:45]=1)[O:24][C:25]1[CH:32]=[C:31]([B:33]2[O:37]C(C)(C)[C:35](C)(C)[O:34]2)[C:28](C=O)=[C:27]([CH3:42])[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:35]1[O:34][B:33]([OH:37])[C:31]2[CH:32]=[C:25]([O:24][C:23]3[CH:43]=[CH:44][CH:45]=[C:21]([O:20][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:22]=3)[CH:26]=[C:27]([CH3:42])[C:28]1=2)[CH3:12]
Reactant: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCc4ccccc4)c3)cc(C)c21
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a suspension of zinc dust (1.03 g, 15.75 mmol) in THF (15 mL) was added trimethylsilyl chloride (1.2 mL, 9.45 mmol) at 40° C. The mixture was heated to 55° C. and stirred for 15 minutes. After cooling down to 37° C., ethyl bromoacetate (1.74 mL, 15.75 mmol) was slowly added to the reaction mixture at 37-40° C. After addition, the resulting mixture was cooled to room temperature over 30 minutes. This solution was added to a solution of 4-(3-benzyloxy-phenoxy)-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.4 g, 3.75 mmol) in THF (50 mL) at −78° C. The mixture was allowed to warm to room temperature over 3 hours, quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane:EtOAc 50:50) to give [6-(3-benzyloxy-phenoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.93 g, 68%). 1H NMR (400 MHz, DMSO): δ 9.22 (s, 1H), 7.41-7.24 (m, 6H), 7.07 (s, 1H), 6.95 (s, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J=6.8 Hz, 1H), 5.48 (d, J=7.2 Hz, 1H), 5.05 (s, 2H), 4.02 (q, J=7.2 Hz, 2H), 3.10 (dd, J=2.4, 15.6 Hz, 1H), 2.30-2.27 (m, 1H), 2.26 (s, 3H), 1.11 (t, J=6.8 Hz, 3H). MS (ESI) m/z=433 [M+H]+.