Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)([OH:16])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH:29]1([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH:29]1([CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][N:13]3[CH2:12][CH2:11][CH:10]([C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:8][CH:7]=4)([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[OH:16])[CH2:15][CH2:14]3)=[CH:38][CH:39]=2)[CH2:30][CH2:31]1
Reactant: ClCc1ccc(OCC2CC2)cc1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(OCC3CC3)cc2)CC1
Yield: 76.5 %

Procedure:
A solution of 20.5 grams (0.051 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine, 10.0 grams (0.051 mole) of 4-(cyclopropylmeth-oxy)phenylmethyl chloride (prepared as in Step A of Example 1), and 35.4 mL (0.203 mole) of N,N'-diisopropylethylamine in 200 mL of dimethyl sulfoxide was stirred at ambient temperature for about 18 hours. The reaction mixture was then poured into an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with two portions of ethyl acetate, and the extracts combined. The combination was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel with 50% heptane in methylene chloride to 50% acetone in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 22.0 grams of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[OH:2][N:3]=[CH:4][CH:5]([CH2:9][CH2:10]C)[C:6]([O-:8])=O.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].C[O-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[CH2:21]([O:2][N:3]1[CH2:4][CH:5]([CH2:9][CH3:10])[CH:6]([OH:8])[C:12]1=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCCC(C=NO)C(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1CN(OCc2ccccc2)C(=O)C1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10% Aqueous hydrochloric acid (30 ml) was added dropwise over 5 min to a stirred solution of 2-hydroxyliminomethylpentanoate (1.74 g, 8.57 mmol) and pyridine - borane complex (3 ml, 2.7 g, 29 mmol) in ethanol (15 ml) at 0° C. After the addition was complete the mixture was stirred at room temperature for 30 min. basified to pH9 with solid sodium carbonate and extracted with dichloromethane (3×25 ml). The combined organic layers were washed with brine, dried (MgSO4). evaporated in vacuo, the residue dissolved in methanol (20 ml), and sodium methoxide (0.56 g. 10.4 mmol) added. The solution was then refluxed for 2 h, cooled to room temperature. and benzyl bromide (1.5 ml, 2.16 g, 12.6 mmol) added. After stirring for 16 h sodium methoxide (0.5 g) was added, and the mixture stirred for a further 30 min before being poured into water, and extracted with ether (3×30 ml). The combined organic layers were washed with water and brine, dried (MgSO4), evaporated in vacuo, and purified by flash chromatography. eluting with dichloromethane : methanol (96:4 v/v) to give 1-benzyloxy-4-ethyl-3-hydroxypyrrolidin-2-one as a mixture of isomers (2:1 by NMR) (1.10 g, 55%) as an oil. 1H NMR (360 MHz, CDCl3) Major isomer: δ7.4-7.5 (5 H, m, Ph), 5.03 (1 H, d, J=11.0 Hz, OCHAHB), 4.98 (1 H, d, J=11.0 Hz, OCHAHA), 3.91 (1 H, d, J=8.2 Hz, CHOH), 3.31 (1 H, t, J=8.5 Hz, NCHAHB), 2.87 (1 H, t, J=8.5 Hz, NCHAHB), 2.0-2.1 (1 H, m, CHCH2), 1.7-1.8 and 1.3-1.4 (2 H, m, CH2CH3), 0.91 (3 H, t, J= 7.44 Hz, CH3). Minor isomer δ7.4-7.5 (5 H, m, Ph), 5.00 (2 H, s, OCH2), 4.24 (1 H, d, J=7.3 Hz, CHOH), 3.28 (1 H, dd, J=6.8 and 8.8 Hz, NCHAHB), 3.06 (1H, dd, J=4.7 and 8.8 Hz, NCHAHB), 2.1-2.2 (1 H, m, CHCH2), 1.7-1.8 and 1.2-1.3 (2 H, m, CH2CH3), 0.84 (3 H, t, J=7.4 Hz, CH3), m/z (CI, NH3) 236 (M+ +H).
Reaction SMILES: C1COCC1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:7]([C:12]([OH:14])=O)[CH2:8][CH:9]([CH3:11])[CH3:10].O.[NH:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CN(C=O)C>[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:7]([C:12]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:14])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF (300 ml) was added to BOC-Leu-OH.H2O (149.59 g, 0.6 M). THF (150 ml) and DMF (100 ml) were added thereto to prepare a solution. Then H-Pro-OBzl (152.28 g, 0.63 M) was added thereto, and WSCI (120.8 ml, 0.66 M) was added dropwise at -10° C., and further DMF (100 ml) was added; then the mixture was stirred at room temperature overnight. After distilling off the solvent in vacuo, ethyl acetate (600 ml) was added to the residue, which was then washed three times with 5% aqueous sodium bicarbonate, twice with 1 N HCl and twice with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The resultant oily material was dissolved in benzene (1 l.) and concentrated in vacuo to obtain an oily substance [1].
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[N:20]=[CH:21][CH:22]=[N:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[N:23]2)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 70.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinoxalin-5-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-12) (586 mg, 0.80 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (288 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](CCC3C=C(C=CC=3)N)[CH2:14][CH2:13]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=1)=[O:36]>CN(C=O)C.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:34][C:35]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=3)=[O:36])[CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(=O)Nc1cccc(C(=O)CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(C(=O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Reaction time: 1.5 h
Yield: 42 %

Procedure:
To a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D6, 0.14 g, 1 eq) in dry DMF (5 mL) were added potassium carbonate (0.11 g, 1.2 eq) and a solution of N-[3-(2-chloroacetyl)phenyl]acetamide (J. Chem. Soc., 1949, 552, 553, 0.17 g, 1.2 eq) in DMF (3 mL) under an inert atmosphere. The reaction was stirred for 1.5 hrs. The mixture was diluted with water (8 mL) and extracted with DCM (3×15 mL). The organic phase was washed with brine (25 mL), dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (Silica) using as eluant DCM-methanol (95:5), affording the title compound in 42% yield (0.104 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid benzyl ester (4.68 g, 20 mmol) in 20 mL of DMF at) 0° C. is added sodium hydride (60%, 880 mg, 22 mmol). The suspension is stirred at ambient temperature for one t-butyl bromoacetate (4.68 g, 24 mmol) is added. The resulting mixture is stirred at ambient temperature overnight. After dilution with ethyl acetate (200 mL), the mixture is washed with brine (3×50 mL). The crude residue obtained from concentration of the organic phase is chromatographied on silica gel (30% ethyl acetate/Hexane) to give 5.57 g (80%) of 4-tert-butoxycarbonylmethyl-3-oxopiperazine-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1
Reactant: OC1C=CCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (Example 6; 489 mg, 1.69 mmol) in dichloromethane (10 ML) at 25° C. was treated with 2-cyclohexen-1-ol (0.42 mL, 4.23 mmol) followed by rhodium (II) acetate dimer (15 mg, 0.034 mmol) and the resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) provided rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 58% yield) as a colorless oil: EI-HRMS m/e calcd for C16H19ClSO5 (M+) 358.0642, found 358.0640.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32].O>O1CCCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:32]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1cccc(OC)c1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice bath stirred suspension of methyl 3-amino-3-(3',4'-dimethoxyphenyl)propionate hydrochloride (0.689 grams, 2.50 mmol) and 0.7 milliliters of triethylamine in 20 milliliters of anhydrous tetrahydrofuran was added 3-methoxybenzoyl chloride (2.5 mmol) via syringe. After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then treated with 20 milliliters of water. The tetrahydrofuran was removed in vacuo and the resulting mixture extracted with methylene chloride (2 times with 25 milliliters). The combined extracts were dried over sodium sulfate and contracted to afford a thick oil. The crude product was purified by flash chromatography (silica gel, 1.4/8.6 ethyl acetate/hexanes) to afford 0.5 grams (56%) as a pale green solid (wax): mp 123.5°-125° C.; 1H NMR (CDCl3 /TMS) δ 8.96 (d, J=7.9, 1 H), 8.19 (m, 1 H), 7.45 (m, 1 H), 7.12-6.68 (m, 5 H), 5.59 (m, 1 H), 4.00 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3), 2.96 (m, 2 H, CH2); 13C NMR (CDCl3 /TMS) δ 171.6, 164.4, 157.6, 148.9, 148.2, 133.8, 132.8, 132.3, 121.3, 121.2, 118.1, 111.3, 111.2, 109.9. 55.8, 55.8, 51.6, 49.7, 40.4; TLC (2/8 ehtyl acetate/hexanes, UV) Rf =0.26. Anal. Calcd for C20 H23NO6. Theory C, 64.33; H, 6.21; N, 3.75. Found C, 64.31; H, 6.25; N, 3.63.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:4][N:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26].N.O>C(O)C.Cl.O1CCOCC1>[Cl:30][C:29]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:4][N:3]=2)=[CH:24][C:23]=1[C:22]([F:21])([F:31])[F:32]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1nnc(CCCc2cccnc2)c2ccccc12
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(Nc2nnc(CCCc3cccnc3)c3ccccc23)ccc1Cl

Procedure:
A solution of 321 mg (1.13 mmol) 1-chloro-4-[3-(pyridin-3-yl)propyl]phthalazine, 243 mg (1.24 mmol) 3-trifluoromethyl-4-chloroaniline in 6 ml ethanol and 0.28 ml 4 N HCl in dioxane is stirred for 100 min at 60° C. The cooled reaction solution is poured onto a mixture of 2 ml sat NH3 solution and 20 ml water and extracted immediately 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; EtOAc/acetone 9:1) and stirring in EtOAc/DIPE yield the title compound: m.p. 165-166° C.; TLC (EtOAc/acetone 9:1) Rf=0.21; 1H-NMR (DMSO-d6) 9.50 (s, HN), 8.58 (m, 2H), 8.47 (s, 1H), 8.39 (dd, 1H), 8.33 (dd, 1H), 8.16 (d, 1H), 8.01 (m, 2H), 7.67 (m, 2H), 7.30 (dd, 1H), 3.22 (t, 2H), 2.76 (t, 2H), 2.11 (quint., 2H); FAB-MS (M+H)+=443; an. calc. (C23H18N4ClF3): C, 62.38%; H, 4.10%; N, 12.65%; Cl, 8.01%; F, 12.87%; meas. C, 62.41%; H, 4.07%; N, 12.58%; Cl, 7.99%; F, 12.84%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9](Cl)=[O:10].[CH2:13]([C:20]1[S:21][C:22]([CH2:25][OH:26])=[CH:23][N:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Br:8])[Br:7])[C@H:3]1[C:9]([O:26][CH2:25][C:22]1[S:21][C:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:24][CH:23]=1)=[O:10]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Reactant: OCc1cnc(Cc2ccccc2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Cc3ccccc3)s2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
A solution of 1.26 g of (1R,3R) 2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-carboxylic acid chloride in 8 ml of benzene was added with stirring at 5° C. to a solution of 0.8 g of (2-benzyl-5-thiazolyl)-methanol in 8 ml of benzene and 0.8 ml of pyridine and the mixture was stirred at 20° C. for 17 hours and was poured into aqueous 2N hydrochloric acid solution with stirring. The decanted organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 7-3 hexane-ethyl acetate mixture to obtain 1.41 g of (2-benzyl-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylate melting at 66° C. and having a specific rotation of [α]D20 =+9°±1° (c=1% in benzene).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(F)cc1F
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
10.00 g (0.077 mol) of 2,4-difluorophenol, 100 mL of toluene and 8.17 g (0.081 mol) of triethylamine were mixed at 25° C., and with controlling the temperature of the reaction liquid to be at 20° C. or lower in an ice bath, 9.24 g (0.081 mol) of methanesulfonyl chloride was dropwise added thereto, taking 15 minutes, and these were reacted with stirring at 25° C. for 1 hour. Water was added to the reaction liquid to separate the organic layer, and the organic layer was washed twice with saturated sodium bicarbonate water and once with water, then dried with anhydrous MgSO4 and subjected to distillation under reduced pressure (98° C./3 Torr) to give 15.1 g of 2,4-difluorophenyl methanesulfonate (yield 94%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[C:16]([C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:20][C:19]([C:17]1[C:16]([C:22]([F:23])([F:25])[F:24])=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[N:18]=1)=[N:1]2
Reactant: COc1ccc(C(F)(F)F)c(C(C)=O)n1
Reactant: Nc1nccc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)c(-c2ccc3c(Cl)ccnc3n2)n1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (156 mg, 1.0 mmol) and 1-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-ethanone (219 mg, 1.0 mmol) in anhydrous THF (5 mL) and cool to −40° C. under a N2 atmosphere. Add in portions t-BuOK (168 mg, 1.5 mmol) to the reaction mixture and stir the mixture at −10° C. for 2 hours. Concentrate the reaction mixture by rotary evaporation, collect the solid by filtration and air-dry to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:16])[C:6]([C:17]#[N:18])=[C:5]([Cl:19])[CH:4]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+].O>CC(C)=O>[C:20]([O:23][CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:16])[C:6]([C:17]#[N:18])=[C:5]([Cl:19])[CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)[O-]
Reactant: N#Cc1c(Cl)cc(CBr)n(-c2ccccc2Cl)c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 6-(bromomethyl)-4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (1.53 g) in acetone (42.7 mL) was added sodium acetate (1.75 g) at room temperature. The reaction mixture was stirred at 70° C. for 8 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (670 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10](=[O:12])(=[O:11])[NH:9][C:8](=O)[C:7]=2[CH:14]=1.[CH4:15].O=S(Cl)Cl.[CH3:20][Mg]Cl>CN(C=O)C.C1COCC1>[CH3:15][C:8]1([CH3:20])[C:7]2[CH:14]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[NH:9]1
Reactant: COc1ccc2c(c1)C(=O)NS2(=O)=O
Reactant: C[Mg]Cl
Reactant: C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)NS(=O)(=O)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
Saccharine 5a (290 mg, 4.08 mmol) was dissolved in xylenes (10 mL) containing a small amount of activated charcoal (50 mg). DMF (2 drops) and freshly distilled SOCl2 (0.30 mL, 4.08 mmol) were added and the resulting mixture was heated to reflux for 15 hours. The solution was then cooled to room temperature and concentrated in vacuo to give a paste. The paste was dissolved in THF and the resulting solution was then added dropwise to a solution of MeMgCl (1.36 mL of a 3.0 M solution in THF, 4.08 mmol) in THF (7 mL). The resulting solution was stirred at 40° C. for 24 hours. After removal of solvent, the desired compound (124 mg, 40%) was obtained by flash chromatography (40 to 60% EtOAc in hexanes). To a solution of this material (100 mg, 0.44 mmol) in CH2Cl2 (50 mL) at −78° C. was added a 1.0 M solution of BBr3 (2.64 mL, 2.64 mmol) in CH2Cl2. The resulting mixture was stirred for 16 hours at ambient temperature. Careful quenching by the addition of H2O was followed by extraction with EtOAc. The combined organic extracts were washed with water and brine then dried over MgSO4. Compound 6a (54 mg, 58%) was delivered by flash chromatography (40 to 60% EtOAc in hexanes).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1>O>[N+:6]([C:14]1[CH:13]=[C:12]([C:11]([F:19])([F:20])[F:10])[CH:17]=[CH:16][C:15]=1[I:18])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1I
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 87.6 ml of concentrated sulphuric acid and 46.8 ml of concentrated nitric acid (d=1.52) is prepared at 0° C. This mixture is added dropwise to 272 g of p-trifluoromethyliodobenzene maintained at 50° C., which takes about 1 hour, after which time the application of heat is ceased and stirring is continued for a further 30 minutes. The mixture is then hydrolysed by pouring onto 750 ml of water. The product is subsequently extracted three times with 600 ml of dichloromethane each time, and the organic phase is washed in succession with water and a 20% solution of sodium bicarbonate. The solvent is then evaporated and distillation yields 273 g of 2-nitro-4-trifluoromethyliodobenzene, b.p./8 mm =120°-125° C. (yield 86%).