Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[C:15](=O)[CH2:16]Cl>CO>[ClH:12].[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[C:15]1[CH2:16][S:11][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][N:10]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: NNC(=S)Nc1ccccc1
Solvent: CO
Product: Cl
Product: Clc1ccc(C2=NN=C(Nc3ccccc3)SC2)c(Cl)c1
Yield: 116.3 %

Procedure:
4.54 g (0.03 mole) of 4-phenyl-thiosemicarbazide and 6.70 g (0.03 mole) of 2,4-dichlorophenacyl chloride are reacted in 200 ml of methanol using the conditions of Example 2. Recrystallization of the solid is from methanol/ethyl acetate, yielding 6.5 g of 5-(2,4-dichlorophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 186° C. The solid was subsequently dried under high vacuum at 65° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:37]>O1CCCC1.CO.C(OCC)(=O)C>[ClH:37].[ClH:37].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCNCC3)ns2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
To a solution of tert-butyl 4-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate (87.0 mg, 0.169 mmol) in tetrahydrofuran (5 ml) and methanol (3 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (8 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 50.0 mg (65.6%) of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N+:25]#[C-:26])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][CH:9]=1.[O:27]=[C:28]([CH3:42])/[CH:29]=[N:30]/[CH:31]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1>CN(C=O)C>[C:28]([C:29]1[N:30]([CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]2)[CH:26]=[N:25][C:14]=1[C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)(=[O:27])[CH3:42]
Reactant: CC(=O)/C=N/C1CN(C(=O)OC(C)(C)C)C1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (15.0 g, 108 mmol) was added to a solution of 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2, see Organic Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. 10, p. 692) (12.5 g, 43.2 mmol) and tert-butyl 3-{[(1E)-2-oxopropylidene]amino}azetidine-1-carboxylate (C1) (10 g, 44 mmol) in DMF (150 mL). The mixture was stirred for 16 hours at room temperature, then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was washed with water (3×500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Eluant: 1:1 petroleum ether: ethyl acetate) to give the product as a solid. Yield: 11 g, 31 mmol, 72%.
Reaction SMILES: O(Cl)Cl.[Zr:4].[P:5](=[O:9])([OH:8])([OH:7])[OH:6]>>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Zr+4:4].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Zr+4:4].[Zr+4:4]
Reactant: O=P(O)(O)O
Reactant: [Zr]
Agent: ClOCl
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]

Procedure:
Zirconium oxychloride and concentrated phosphoric acid were allowed to react with heating in the presence of excess phosphoric acid followed by filtration and washing with water to produce zirconium phospate. This zirconium phosphate was half-neutralized with NaOH to obtain a neutral form of zirconium phosphate. This compound was thoroughly washed with water and then calcined at 200° C. The resultant zirconium phosphate of neutral form was indicated by ZrNaH(PO4)2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=C[C:7](C=O)=[CH:6][C:5]=1[CH:12]=[O:13])(C)C.B(F)(F)F.CC[O:20][CH2:21][CH3:22].[C:23]([O-:26])(=O)[CH3:24].[Na+]>C(O)(=O)C>[OH:26][C:23]1[CH:24]=[C:12]([OH:13])[C:5]([CH:4]([CH3:9])[CH3:1])=[CH:6][C:7]=1[C:21](=[O:20])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)c1ccc(C=O)cc1C=O
Reactant: CCOCC
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C(C)C)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Isopropyl-benzene-1,3-dial (5.8 g) and boron trifluoride etherate (28.7 ml) were introduced into a 250 ml single neck RB flask equipped with a reflux condenser and an inlet for nitrogen atmosphere stirred at room temperature for 10 minutes. Acetic acid (4.55 ml) was added to the reaction mixture and stirred at 90° C. for 16 hours. On completion, 10% sodium acetate (300 ml) was added to the reaction mixture which was stirred at room temperature for 4 hours. The reaction mixture was then extracted with ethyl acetate (300 ml) and washed with saturated sodium bicarbonate (100 ml) and the organic layer was dried over sodium sulphate. The reaction was monitored by TLC (10% EtOAc/n-hexane, product Rf˜0.5). The solvent was removed under reduced pressure to give a residue, which was further purified by column chromatography (SiO2, 10% EtOAc/n-hexane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.B(Cl)([C@H]1[C@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.CCCCCC.[OH-].[Na+]>O1CCCC1>[OH:13][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@@H]([C@H]1C)C3(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1ccc(O)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-hydroxyphenylpyruvic acid 9.01 g (50.0 mmol) in tetrahydrofuran 120 ml, triethylamine 7.0 ml (50.0 mmol) was added and the mixture was stirred at −20° C. for 0.5 hr. A solution of (−)-B-chlorodiisopinocamphenylborane in 60% hexane 41.2 ml (70.0 mmol) was added to the reaction mixture dropwisely and the mixture was warmed to room temperature and stirred for 6 hrs. 1N sodium hydroxide solution 200 ml was added to the reaction mixture and the mixture was washed with ethyl ether 200 ml. 3N hydrochloride aq. 80 ml was added to the aqueous phase and the mixture was extracted with ethyl acetate 200 ml. The organic phase was washed with brine 200 ml and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and n-hexane:ethyl acetate=60:40 50 ml was added to the residue and the precipitate was corrected by filtration to obtain (R)-2-hydroxy-3-(4-hydroxyphenyl)propanoic acid 5.53 g (yield 61%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[S:11]([N:21]1[C:25]2=[N:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=[C:24]2[CH:23]=[CH:22]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[C:32]([N:39]1[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45](O)=[O:46])[CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[S:11]([N:21]1[C:25]2=[N:26][CH:27]=[C:28]([CH2:30][NH:31][C:45]([C@@H:41]3[CH2:42][CH2:43][CH2:44][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:40]3)=[O:46])[N:29]=[C:24]2[CH:23]=[CH:22]1)([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:12])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
DIEA (7.7 mL, 44.3 mmol) was added to a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (5 g, 14.7 mmol) in DCM (78 mL) and the reaction was stirred at ambient temperature for about 10 min followed by the addition of (R)-N-Boc-piperidine-3-carboxylic acid (3.38 g, 14.7 mmol, CNH-Technologies) and HATU (5.61 g, 14.7 mmol). The mixture was stirred for about 1 h, then water (30 mL) was added, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford crude (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (7.58 g, 94%): LC/MS (Table 1, Method b) Rt=2.30 min; MS m/z: 514 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N:19]1([C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:31][NH:30][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:33][CH:32]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(-n2cccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(-n3cccn3)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (134 mg, 0.50 mmol) and 4-(1H-pyrazol-1-yl)benzohydrazide (101 mg, 0.50 mmol) in anhydrous THF (10 mL) was added 1-Hydroxybenzotriazole monohydrate (77 mg, 0.50 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (192 mg, 1.00 mmol) at −45° C. followed by triethylamine (0.14 mL, 1.00 mmol). The reaction mixture warmed to room temperature and stirred for 48 h, then quenched with 5% aq. citric acid (30 mL). The solution was extracted with EtOAc (30 mL). The organic extract was washed with 5% aq. Citric acid (2×20 mL), sat. aq. NaHCO3 (3×20 mL), H2O (2×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (164 mg, 73%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.85 (br s, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.89 (d, J=8.6 Hz, 2H), 7.80-7.72 (m, 3H), 7.37 (dd, J=3.7, 8.2 Hz, 1H), 6.54-6.50 (m, 1H), 6.45 (dd, J=5.7, 8.6 Hz, 1H), 5.25 (d, J=6.3 Hz, 1H), 4.71 (br s, 1H), 4.53-4.45 (m, 1H), 2.32 (s, 3H), 1.36 (d, J=6.3 Hz, 3H).
Reaction SMILES: O.FC(F)(F)C(O)=[O:5].[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([C:25]#[CH:26])[CH:16]=2)=[O:11].[OH-].[Na+]>O1CCOCC1>[C:25]([C:17]1[CH:16]=[C:15]2[C:20]([C:21]([C:22]([NH2:24])=[O:23])=[C:13]([NH:12][C:10]([NH2:9])=[O:11])[NH:14]2)=[CH:19][CH:18]=1)(=[O:5])[CH3:26]
Reactant: C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
Water (6 μl L, 0.25 mmol) and trifluoroacetic acid (150 μL, 2.0 mmol) were added to a solution of 2-aminocarbonylamino-6-ethynylindole-3-carboxamide (Compound 10-1, 20 mg, 0.083 mmol) in 1,4-dioxane (2 mL), the mixture was stirred at 95° C. for 5 hours. 1 N Sodium hydroxide aqueous solution (2 mL) was added to the reaction mixture under ice-cooling, and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (2 mL) and dried under reduced pressure to give the title compound (12 mg) as a colorless solid (yield 57%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:19][C:30](=[O:31])[CH2:29][Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1NC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)CCl)c1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cool solution of (2-amino-6-methoxyphenyl)carbamic acid benzyl ester (9.5 g; 34.9 mmol) and triethylamine (5.8 ml; 42 mmol) in anhydrous THF (90 ml), chloroacetylchloride (3.3 ml; 42 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hours, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous HCl and diluted aqueous Na2 CO3 then it was dried and evaporated. The crude residue was crystallized with n-hexane to give the title compound as a white solid. 10.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.[F:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][CH2:38][N:37]5[CH2:32][CH2:31][CH2:40][CH:35]([F:34])[CH2:36]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: FC1CCCNC1
Reactant: ClCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCCC(F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(3-fluoropiperidin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and 3-fluoropiperidine following General Procedure G.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:20]([OH:21])[C@@H:19]([CH2:22][OH:23])[O:18][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:6]1[OH:24])[CH:2]=[CH2:3].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CO>CN(C)C=O>[CH2:1]([O:4][C@H:5]1[C@@H:20]([OH:21])[C@@H:19]([CH:22]([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[OH:23])[O:18][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C@@H:6]1[OH:24])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](OCCCCCC(=O)OC)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCO[C@H]1[C@@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O[C@@H](OCCCCCC(=O)OC)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound 2 of Example 2 (10.85 g) was dissolved in dry dimethylformamide (DMF, 120 mL) containing imidazole (1.63 g) and 4 Å molecular sieves and cooled in an ice bath. To this, t-butyldimethylsilyl chloride (tBDMS chloride, 3.6 g) was added and stirred at this temperature for 10 min and then at room temperature 1 h. Another portion of imidazole (1.05 g) and tBDMS chloride (2.34 g) were added to the ice cold solution and stirred for 1 h. Methanol (1 mL) was added and the reaction mixture was evaporated to dryness. The residue was dissolved in CH2Cl2 and washed with water, 1M ice cold HCl and saturated NaHCO3 solution. The solution was dried over anhydrous magnesium sulfate, filtered and evaporated. 1H n.m.r. of the crude product (12.0 g of colorless solid) showed it to be essentially pure titled compound. [α]D25 -3.2±2° (c 1.03, CHCl3). 1H n.m.r.(CDCl3 +D2O<5%) ∂: 5.95 (m, 1 H, --CH=C), 5.33 and 5.23 (m, 2 H, C=CH2), 4.24 (m, 3 H, H-1, J1,2 =Hz, O--CH2 --C=), 4.06 (d, H-4), 3.9-3.8 (m, 3 H, H-6a,b, OCH2 --C), 3.73 (dd, H-2), 3.67 (s, COOCH3), 3.52 (m, OCH2 --C), 3.44 (m, H-5), 3.35 (dd, H-3),2.32 (t, CH2COO), 1.65 and 1.40 (6 H, hydrogens of pentyl group), 0.89 (s, t-butyl group), 0.09 (d, CH3 --Si--CH3). 13C n.m.r. (CDCl3) ∂: 173.9, 134.8, 117.4, 103.2, 80.7, 75.0, 71.2, 71.0, 69.3, 66.3, 62.2, 51.3, 33.9, 29.2, 25.9, 25.6, 24.6, 18.3, -5.34, -5.39. Anal. Calcd for C22H2842O8Si: C, 57.14; H, 9.09. Found: C, 56.30; H 9.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.[CH2:13]([Br:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O.CCOCC>[Br-:20].[CH2:13]([N+:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2cnccc2c1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1ccc2c[n+](Cc3ccccc3)ccc2c1
Product: [Br-]

Procedure:
6-Methoxyisoquinoline (1.6 g) and benzyl bromide (2 ml) in acetone (75 ml) were heated under reflux for 1 hour. The mixture was diluted with ether and cooled to 0°. The solid was filtered off and recrystallised from methanol/ether, and had m.p. 155°-158°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH2:24]>C(#N)C>[CH2:24]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 8: Enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol) and 3-bromo-1-propene (0.23 mL, 2.78 mmol). Refluxed for 2 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 5:1). Yield: 0.33 g. [α]D=−26.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 120° C.; MS m/z (relative intensity, 70 eV) (239 (M+, 25), 198 (48), 141 (35), 127 (23), 83 (bp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([N:37]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:36])[CH2:27]1>>[CH:44]1([N:37]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[C:35](=[O:36])[CH2:34][C@H:28]2[CH2:27][C@@H:26]([CH2:25][CH2:24][N:23]3[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:31][C:30]([CH3:33])([CH3:32])[O:29]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(C2CCCCC2)C2CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(C2CCCCC2)C2CCCCC2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the tiotle compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dicyclohexylacetamide.
Reaction SMILES: [F:1][C:2]1[C:7]([Li])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].FC1C(F)=C(F)C(F)=C(F)C=1.C([Li])CCC.[C:29](=[O:31])=[O:30]>>[F:1][C:2]1[C:7]([C:29]([OH:31])=[O:30])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: [Li]c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C=O
Agent: Fc1cc(F)c(F)c(F)c1F
Agent: [Li]CCCC
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Up to now, several synthetic reactions for pentafluorophenyl alkali metal salt are known. For example, a method of producing pentafluorophenyllithium through bromine-metal exchange reaction using relatively expensive bromopentafluorobenzene as a starting raw material for a source of pentafluorophenyl group and butyllithium is already known. For example, in Synthesis of Fluoroorganic Compounds, p. 190, Springer-Verlag (1985), pentafluorophenyllithium is prepared in diethylether-hexane at -70° C. and is reacted with sulfur dioxide to give lithium pentafluorophenylsulfenate with 94% yield. Also, a method of producing pentafluorophenyllithium through hydrogen-metal exchange reaction using pentafluorobenzene as a starting raw material for a source of pentafluorophenyl group and butyllithium is already known. For example, in J. Org. Chem., 29, 2385 (1964), pentafluorophenyllithium prepared from pentafluorobenzene and butyllithium is reacted with carbon dioxide gas to give pentafluorobenzoic acid wherein the reaction yield is unknown, but the purification yield, depending on reaction solvent system, is 68% in diethylether-hexane system, 80.9% in diethylether type and 82% in diethylether-tetrahydrofuran system respectively.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[C:18]([O-])([O-])=O.[Na+].[Na+]>CO.CCOC(C)=O>[CH3:18][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH:8]([CH3:9])[CH3:10])[N:4]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ncc(Br)c(C(=O)O)n1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
To a stirred, cooled (0° C.) solution of 5-bromo-2-isopropyl-pyrimidine-4-carboxylic acid (3 g, 12.2 mmol) in methanol (50 ml) under an argon atmosphere was added dropwise thionyl chloride (4.37 g, 2.68 ml, 36.7 mmol). When the addition was complete, the mixture was allowed to warm to r.t. and stirring at r.t. was continued for 17 h. The orange mixture was concentrated to leave a paste which was taken up in EtOAc (50 ml)/saturated aqueous Na2CO3 solution (50 ml). The aqueous phase was extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated to leave the product (2.98 g, 94%) as a light brown oil which was used in the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:20](=[O:21])[NH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: CSc1ccc2c(c1Cl)CCN2
Reactant: O=C=Nc1cccnc1
Product: CSc1ccc2c(c1Cl)CCN2C(=O)Nc1cccnc1
Yield: 84 %

Procedure:
4-Chloro-5-methylthioindoline (D49) (0.9 g, 4.51 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was filtered-off and recrystallised from ethanol to give the title compound (1.22 g, 84%) as a white crystalline solid m.p. 237°-241° C.